Internet Mental Health


Internet Mental Health Quality of Life Scale (Client Version)

Internet Mental Health Quality of Life Scale (Therapist Version)

Big 5 Factors Of Mental Illness And Code For This Disorder
(The "6th Big Factor" of Mental Health, "Physical Health", Is Coded Abnormal or Red)

(Note: Recovery = symptomatic remission + full-time gainful employment + weekly contact with friends)


Major Depressive Disorder often starts slowly with a depressive episode of at least 2 weeks consisting of: (1) severe negative emotion (depressed mood, suicidal thoughts) and (2) moderate: decreased intellect (distractibility), [when severe impaired reasoning, psychosis]), detachment (loss of interest or pleasure), and physical symptoms (fatigue, altered sleep and appetite).

When facing adversity, many people develop depressive symptoms, but lack impairment in their usual activites - hence would not be diagnosed as having Major Depressive Disorder. The diagnosis of Major Depressive Disorder requires that the person not only has depressive symptoms, but also has difficulties in day-to-day functioning due to these symptoms.

What Every Suicidal Person Should Read:

Major Depressive Disorder is a time-limited disease. Worldwide, the average duration of an episode of Major Depressive Disorder is 30 weeks.

Individuals with moderate to severe Major Depressive Disorder usually respond to antidepressant medication within 6 weeks, and one-third become symptom-free within 7 weeks. Even if someone doesn't respond to their first antidepressant medication, by switching to another antidepressant (sometimes up to 3 times), antidepressant medication eventually brings about full recovery for 70% of patients. That is why suicide is so tragic. Suicide is a lethal over-reaction to a temporary problem.


In Major Depressive Disorder (MDD) without treatment: 23% recover within 3 months, 32% within 6 months, and 53% within one year. The chance of spontaneous recovery is much less for individuals having severe depression - especially when it is recurrent or chronic.

The chances for full recovery are significantly better and faster with treatment with medication (antidepressant medication +/- lithium) and/or cognitive behavioral therapy. Cognitive behavioral therapy appears to be as effective as antidepressant medication.

For moderate to severe Major Depressive Disorder, after 16 weeks of therapy, there is a 46% remission rate for medication, and a 40% remission rate for cognitive therapy.

Dynamic psychotherapy (DT) has been shown to be as effective as cognitive behavioral therapy in the treatment of MDD.

In the treatment of MDD in children and adolescents, of all the antidepressants tested, only fluoxetine was significantly more effective than placebo.

Problem Solving Therapy has been shown to be effective for MDD in older adults.

Repetitive transcranial magnetic stimulation (rTMS) was found to be no better than sham (placebo) treatment for treatment-resistant major depression. The overall remission rate was 39%, with no significant difference between the active and sham groups.

An active placebo is an inert substance, given on frequent visits to a doctor, which increases the patient's hope for recovery. In research, "response" to a treatment is defined as "having at least a 50% reduction in symptoms". "Remission" is defined as "becoming symptom-free".

The active placebo effect causes most of the treatment benefit in Major Depressive Disorder. When compared to the 40% response rate for treatment of acute MDD on active placebo, the response rate after 8-weeks on the first antidepressant medication used is 45% for mild depression, 52% for moderate depression, and 56% for severe depression.

The current expert consensus is, for mild depression, antidepressant medication is no more effective than an "active placebo" therapy of frequent contact with a competent, supportive clinician who instills hope of a recovery. The warmer and more competent appearing the clinician, the greater the resulting active placebo effect. Treatment by a cold, uncaring, incompetent appearing clinician dramatically decreases the active placebo effect.

Research has shown that antidepressant medication is effective for the treatment of moderate to severe Major Depressive Disorder.

The STAR*D study of individuals with chronic or recurrent Major Depressive Disorder found:

  • It takes an average of 6 weeks of antidepressant medication treatment for patients to achieve a 50% reduction in symptoms and nearly 7 weeks for them to become symptom-free.

  • At the end of 8 weeks of treatment (on the first antidepressant used), on average, 45% respond (lose half of their symptoms), and 30% enter remission (become symptom-free).

  • Of those initial nonresponders who try up to 3 different switches in their antidepressant treatment and do not withdraw from treatment, almost 70% become symptom-free.

Approximately 80% of those with a history of two depressive episodes will have another depressive episode. Once a first depressive episode has occurred, recurrent episodes will usually begin within five years of the initial episode, and, on average, individuals with a history of depression will have 5 to 9 separate depressive episodes in their lifetime. However, maintenance treatment with antidepressant medication reduces the relapse rate by 52% when compared to placebo.

Since severe Major Depressive Disorder has up to a 15% fatality rate due to suicide; it is vitally important to prevent suicide by quickly starting treatment.

Unlike illicit drugs (e.g., heroin, cocaine), antidepressants and lithium take at least 2 weeks to start working, are not addictive, and do not produce elation.

Note: The efficacy of psychotherapy for depression has been significantly overestimated (by 25%) in the published literature because of "publication bias" (i.e., only publishing favorable research studies). The same publication bias has been found for pharmacotherapy.


Most individuals fully recover from their Major Depressive Disorder. However, some only partially recover, and at least 50% recover only to later relapse a few years later. These relapsing individuals may require long-term treatment with medication or psychotherapy to treat their residual depressive symptoms or to prevent their depressive relapses.


Occupational-Economic Problems:

  • Depressive disorders account for 40.5% of the disabililty caused by mental illness worldwide

  • Causes significant impairment in academic, occupational and/or social functioning

  • Only a minority are so chronically disabled that they require a disability pension

Decreased Intellect (Impaired Intellect):

  • Usually impairs concentration, memory, creativity and judgment

  • Severe episodes can cause psychosis

  • In the extreme, some become so depressed that they just sit mute and motionless

Negative Emotions (Negative Emotion):

  • During an episode of depressed mood or loss of interest or pleasure, nearly every day for at least 2 weeks has the majority of the following:

    • Depressed mood most of the day

    • Markedly diminished interest or pleasure

    • Feelings of worthlessness or excessive guilt

    • Diminished ability to think or concentrate, or indecisiveness

    • Recurrent thoughts of death or suicide (or a suicide attempt)


  • During an episode of depressed mood or loss of interest or pleasure, nearly every day for at least 2 weeks has the majority of the following:

    • Insomnia or hypersomnia

    • Fatigue or loss of energy

    • Significant weight loss when not dieting or weight gain

    • Psychomotor agitation or slowing

  • Chronic or disabling medical conditions increase risk of this disorder

Why Do Blameless People Suffer From Severe Depression?

Job 2,500 Years Ago

Every religious tradition has tried to explain why people suffer from severe depression.

The oldest reference to severe depression was written 2,500 years ago in the Bible's Book of Job. The Bible tells the story of Job, a very just and rich man, who suddenly lost everything - his family, his possessions, and his health.

Psychiatrically, it is amazing how Job's resulting symptoms were identical to those of a modern person having Major Depressive Disorder. This is how Job described his severe depression 2,500 years ago:

Depressed mood most of the day

  • "My days are swifter than a weaver's shuttle and come to their end without hope. Remember that my life is a breath; my eye will never again see good."

  • "My face is red with weeping, and on my eyelids is deep darkness."

  • ".. when I hoped for good, evil came, and when I waited for light, darkness came. My inward parts are in turmoil and never still; days of affliction come to meet me. I go about darkened, but not by the sun."

  • "For the thing that I fear comes upon me, and what I dread befalls me. I am not at ease, nor am I quiet; I have no rest, but trouble comes."

Markedly diminished interest or pleasure

  • "I am allotted months of emptiness, and nights of misery are apportioned to me."

Significant weight loss when not dieting

  • "And He (God) has shriveled me up, which is a witness against me, and my leanness has risen up against me; it testifies to my face."


  • "When I lie down I say, 'When shall I arise?' But the night is long, and I am full of tossing till the dawn."

  • "... when deep sleep falls on men, dread came upon me, and trembling, which made all my bones shake."

Fatigue or loss of energy

  • "I ... have laid my strength in the dust." ... "God has worn me out."

Feelings of worthlessness

  • "My relatives have failed me, my close friends have forgotten me. The guests in my house and my maidservants count me as a stranger; I have become a foreigner in their eyes."

  • "Even young children despise me; when I rise they talk against me. All my intimate friends abhor me, and those whom I loved have turned against me."

Recurrent thoughts of death

  • "My spirit is broken; my days are extinct; the graveyard is ready for me."

  • "Oh that I might have my request, and that God would fulfill my hope, that it would please God to crush me, that he would let loose his hand and cut me off!"

  • "When I say, 'My bed will comfort me, my couch will ease my complaint,' then you (God) scare me with dreams and terrify me with visions, so that I would choose strangling and death rather than my bones."

Lessons To Be Learned From 2,500 Years Ago

  • Job correctly believed that "I am blameless" - thus he could not understand why his suffering occurred.

  • The Bible states that, after a number of months, Job fully recovered and did even better than before his severe depression.

  • There are a number of modern lessons that can be learned from this ancient story:

    • People should not be blamed for their severe depression. Their depression is an illness, and not a punishment for sinful behavior or a lack of religious faith.

    • Even without treatment, severe depression is usually time-limited, and in a few months totally recovers.

    • The symptoms of major depressive disorder haven't changed in the past 2,500 years.

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Click Here For Free Diagnosis

Limitations of Self-Diagnosis

Self-diagnosis of this disorder is often inaccurate. Accurate diagnosis of this disorder requires assessment by a qualified practitioner trained in psychiatric diagnosis and evidence-based treatment.

However, if no such professional is available, our free computerized diagnosis is usually accurate when completed by an informant who knows the patient well. Computerized diagnosis is less accurate when done by patients (because they often lack insight).

Example Of Our Computer Generated Diagnostic Assessment

Major Depressive Disorder, Single Episode, Nonpsychotic 296.2X

This diagnosis is based on the following findings:

  • Never had psychotic symptoms in the absence of prominent mood disturbances (when off drugs)

  • Depressive episode is not better accounted for by Schizoaffective Disorder

  • Depressive episode is not superimposed on Schizophrenia or Schizophreniform Disorder

  • Depressive episode is not superimposed on Delusional Disorder or Psychotic Disorder Not Otherwise Specified

  • Depressive episode was not due to a general medical condition

  • Depressive episode was not due to substance use or other treatment

  • Depressive episode caused clinically significant distress or disability for at least 2 weeks (still present)

  • Depressive episode had abnormal depressed mood for at least 2 weeks (still present)

  • Depressive episode had markedly diminished interest or pleasure for at least 2 weeks (still present)

  • Depressive episode had appetite or weight disturbance for at least 2 weeks (still present)

  • Depressive episode had insomnia or hypersomnia for at least 2 weeks (still present)

  • Depressive episode had psychomotor agitation or slowing for at least 2 weeks (still present)

  • Depressive episode had fatigue or loss of energy for at least 2 weeks (still present)

  • Depressive episode had self-reproach or inappropriate guilt for at least 2 weeks (still present)

  • Depressive episode had poor concentration or indecisiveness for at least 2 weeks (still present)

  • Depressive episode had recurrent thoughts of death or suicide for at least 2 weeks (still present)

  • Depressive episode was not due to normal bereavement

  • Depressive episode lacked psychotic symptoms (when off drugs)

  • Has had only one depressive episode lasting at least 2 weeks

Treatment Goals:

  • Goal: prevent depressed mood.
    If this problem persists: She will feel sad, hopeless, discouraged, "down in the dumps", or "blah". She may emphasize somatic complaints (e.g., bodily aches and pains) rather than reporting feelings of sadness. She may exhibit increased irritability (e.g., persistent anger, a tendency to respond to events with angry outbursts or blaming others, or an exaggerated sense of frustration over minor matters).

  • Goal: prevent loss of interest or pleasure.
    If this problem persists: She will feel less interested in hobbies, "not caring anymore," or not feeling any enjoyment in activities that were previously considered pleasurable. There may be a significant reduction in her sexual interest or desire.

  • Goal: prevent appetite or weight disturbance.
    If this problem persists: She will have either abnormally decreased or increased appetite. This may progress to significant loss or gain in weight.

  • Goal: prevent insomnia or hypersomnia.
    If this problem persists: She will sleep too little or too much. Typically she will have middle insomnia (i.e., waking up during the night and having difficulty returning to sleep) or terminal insomnia (i.e., waking too early and being unable to sleep). Initial insomnia (i.e., difficulty falling asleep) may also occur. Less frequently, she may have oversleeping (hypersomnia).

  • Goal: prevent psychomotor agitation or slowing.
    If this problem persists: She will have agitation (e.g., the inability to sit still, pacing, hand-wringing; or pulling or rubbing of the skin, clothing, or other objects) or psychomotor retardation (e.g., slowed speech, thinking, and body movements; increased pauses before answering; speech that is decreased in volume, inflection, amount, or variety of content, or muteness).

  • Goal: prevent fatigue or loss of energy.
    If this problem persists: She will experience decreased energy, tiredness, and fatigue. Eventually, even the smallest tasks will seem to require substantial effort. She may find that washing and dressing in the morning are exhausting and take twice as long as usual.

  • Goal: prevent inappropriate self-reproach or guilt.
    If this problem persists: She will have unrealistic negative evaluations of her worth or guilty preoccupations or ruminations over minor failings. She may often misinterpret neutral or trivial day-to-day events as evidence of her defects and have an exaggerated sense of responsibility for untoward events. This may progress to delusional proportions.

  • Goal: prevent poor concentration or indecisiveness.
    If this problem persists: She will have an impaired ability to think, concentrate, or make decisions.

  • Goal: prevent recurrent thoughts of death or suicide.
    If this problem persists: She will be at risk of suicide. Many studies have shown that it is not possible to predict accurately whether or when a particular individual with depression will attempt suicide. Motivations for suicide may include a desire to give up in the face of perceived insurmountable obstacles or an intense wish to end an excruciatingly painful emotional state that is perceived by the person to be without end.

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Single Depressive Episode F32 - ICD10 Description, World Health Organization

In typical mild, moderate, or severe depressive episodes, the patient suffers from lowering of mood, reduction of energy, and decrease in activity.

Capacity for enjoyment, interest, and concentration is reduced, and marked tiredness after even minimum effort is common.

Sleep is usually disturbed and appetite diminished.

Self-esteem and self-confidence are almost always reduced and, even in the mild form, some ideas of guilt or worthlessness are often present.

The lowered mood varies little from day to day, is unresponsive to circumstances and may be accompanied by so-called "somatic" symptoms, such as loss of interest and pleasurable feelings, waking in the morning several hours before the usual time, depression worst in the morning, marked psychomotor retardation, agitation, loss of appetite, weight loss, and loss of libido.

Depending upon the number and severity of the symptoms, a depressive episode may be specified as mild, moderate or severe.

    F32.0 Mild depressive episode

    Two or three of the above symptoms are usually present.

    The patient is usually distressed by these but will probably be able to continue with most activities.

    F32.1 Moderate depressive episode

    Four or more of the above symptoms are usually present and the patient is likely to have great difficulty in continuing with ordinary activities.

    F32.2 Severe depressive episode without psychotic symptoms

    An episode of depression in which several of the above symptoms are marked and distressing, typically loss of self-esteem and ideas of worthlessness or guilt.

    Suicidal thoughts and acts are common and a number of "somatic" symptoms are usually present.

    F32.3 Severe depressive episode with psychotic symptoms

    An episode of depression as described in F32.2, but with the presence of hallucinations, delusions, psychomotor retardation, or stupor so severe that ordinary social activities are impossible; there may be danger to life from suicide, dehydration, or starvation.

    The hallucinations and delusions may or may not be mood-congruent.

Recurrent Depressive Disorder F33 - ICD10 Description, World Health Organization

A disorder characterized by repeated episodes of depression as described for depressive episode (F32.-), without any history of independent episodes of mood elevation and increased energy (mania).

There may, however, be brief episodes of mild mood elevation and overactivity (hypomania) immediately after a depressive episode, sometimes precipitated by antidepressant treatment.

The more severe forms of recurrent depressive disorder (F33.2 and F33.3) have much in common with earlier concepts such as manic-depressive depression, melancholia, vital depression and endogenous depression.

The first episode may occur at any age from childhood to old age, the onset may be either acute or insidious, and the duration varies from a few weeks to many months.

The risk that a patient with recurrent depressive disorder will have an episode of mania never disappears completely, however many depressive episodes have been experienced. If such an episode does occur, the diagnosis should be changed to bipolar affective disorder (F31.-).

    F33.0 Recurrent depressive disorder, current episode mild

    A disorder characterized by repeated episodes of depression, the current episode being mild, as in F32.0, and without any history of mania.

    F33.1 Recurrent depressive disorder, current episode moderate

    A disorder characterized by repeated episodes of depression, the current episode being of moderate severity, as in F32.1, and without any history of mania.

    F33.2 Recurrent depressive disorder, current episode severe without psychotic symptoms

    A disorder characterized by repeated episodes of depression, the current episode being severe without psychotic symptoms, as in F32.2, and without any history of mania.

    (Includes: Endogenous depression without psychotic symptomsMajor depression, recurrent without psychotic symptomsManic-depressive psychosis, depressed type without psychotic symptomsVital depression, recurrent without psychotic symptoms.)

    F33.3 Recurrent depressive disorder, current episode severe with psychotic symptoms

    A disorder characterized by repeated episodes of depression, the current episode being severe with psychotic symptoms, as in F32.3, and with no previous episodes of mania.

    F33.4 Recurrent depressive disorder, currently in remission

    The patient has had two or more depressive episodes as described in F33.0-F33.3, in the past, but has been free from depressive symptoms for several months.

Major Depressive Disorder - Diagnostic Criteria, American Psychiatric Association

An individual diagnosed with major depressive disorder needs to meet all of the following criteria:

  • Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.

    Note: Do not include symptoms that are clearly attibutable to another medical condition.

    • Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.)

    • Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation).

    • Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.)

    • Insomnia or hypersomnia nearly every day.

    • Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down).

    • Fatigue or loss of energy nearly every day.

    • Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick).

    • Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others).

    • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.

  • The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

  • The episode is not attributable to the physiological effects of a substance or to another medical condition.

    Note: The above criteria represent a major depressive episode.

    Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in the above criteria, which may resemble a depressive episode.

    Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered.

    This decision inevitably requires the exercise of clinical judgment based on the individual's history and the cultural norms for the expression of distress in the context of loss.

  • The occurrence of the major depressive episode is not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders.

  • There has never been a manic episode or a hypomanic episode.

    Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes are substance-induced or are attributable to the physiological effects of another medical condition.

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Diagnostic Features

Major Depressive Disorder is a condition characterized by one or more Major Depressive Episodes without a history of Manic, Mixed, or Hypomanic Episodes.

These Major Depressive Episodes are not due to a medical condition, medication, abused substance, or Psychosis. If Manic, Mixed, or Hypomanic Episodes develop, the diagnosis is changed to Bipolar Disorder.

The Major Depressive Episode must have either depressed mood or loss of interest. A Major Depressive Episode represents a decline from previous functioning which has at least 5 of the following 9 symptoms: (1) depressed mood, (2) loss of interest or pleasure, (3) significant change in appetite/weight, (4) insomnia/hypersomnia, (5) psychomotor agitation/slowing, (6) fatigue/loss of energy, (7) feelings of worthlessness/inappropriate guilt, (8) inability to concentrate/indecisiveness, (9) recurrent thoughts of death/suicide. (Note: do not include symptoms that are clearly attibutable to another medical condition.)

Problems When Severe

  • Need for Institutional Care

  • Phobia (Excessive Fear of Specific Things) [1]

  • Brief, Unprovoked Attacks of Panic [2, 3, 4]

  • Drug or Medication Abuse [5, 6, 7]

  • Alcohol Abuse [8]

  • Prolonged Anxiety, Attention or Worry [9, 10]

  • Overly Dependent Behavior [11, 12, 13]

  • Poor Physical Health [14]

  • Delusions or Hallucinations [15, 16, 17, 18]

  • Poor Memory or Learning Ability [19, 20]

  • Poor Grooming and Hygiene


Completed suicide occurs in up to 15% of individuals with severe Major Depressive Disorder. There is a fourfold increase in deaths in individuals with this disorder who are over age 55. Individuals with this disorder have more pain and physical illness and decreased physical, social, and role functioning.


Alcoholism and illicit drug abuse dramatically worsen the course of this illness, and are frequently associated with it. Persistent Depressive Disorder often precedes the onset of this disorder for 10%-25% of individuals. This disorder also increases risk of also having Panic Disorder, Obsessive-Compulsive Disorder, Anorexia Nervosa, Bulimia Nervosa, and Borderline (Emotionally Unstable) Personality Disorder.

Associated Laboratory Findings

No laboratory test has been found to be diagnostic of this disorder.


Major Depressive Disorder affects approximately one in six men and one in four women in their lifetimes. The US 12-month community prevalence rate for this disorder is 7%. The prevalence in 18- to 29-year-old individuals is threefold higher than the prevalence in those aged 60 or older. The prevalence rates for this disorder appear to be unrelated to ethnicity, education, income, or marital status. In childhood, boys and girls are equally affected. However, in adolescence and adulthood, the prevalence is 1.5- to 3-fold higher in females compared to males


Major Depressive Disorder "is usually highly recurrent, with at least 50% of those who recover from a first episode of depression having one or more additional episodes in their lifetime, and approximately 80% of those with a history of two episodes having another recurrence. Once a first episode has occurred, recurrent episodes will usually begin within five years of the initial episode, and, on average, individuals with a history of depression will have 5 to 9 separate depressive episodes in their lifetime."

The first episode may occur at any age from childhood to old age, the onset may be either acute or insidious, and the duration varies from a few weeks to many months. The average age at onset is in the mid-20s. Some individuals have isolated episodes that are separated by many years without any depressive symptoms, whereas others have clusters of episodes, and still others have increasingly frequent episodes as they grow older.

After the first episode of this disorder, there is a 60% chance of having a second episode. After the second episode, there is a 80% chance of having a third, and after the third episode, there is a 90% chance of having a fourth. Chronicity of depressive symptoms substantially increases the likelihood of underlying personality, anxiety, and substance use disorders and decreases the likelihood that treatment will be followed by full symptom resolution.


In moderate to severe Major Depressive Disorder, one review study found the remission rates after 16 weeks of therapy were 46% for treatment with a single antidepressant medication (tricyclics or phenelzine), 46% for psychotherapy (primarily cognitive behavior and interpersonal therapies), and 24% for control conditions. Another study for moderate to severe depression found the remission rates after 16 weeks of therapy were 46% for medication and 40% for cognitive therapy.

In the famous STAR*D study of individuals with chronic or recurrent moderate to severe Major Depressive Disorder, after 8 weeks of treatment, the remission rate to the first antidepressant medication used (citalopram, a SSRI antidepressant) was 30%. This closely resembled the results seen in most other 8-week antidepressant medication efficacy trials. Repeatedly switching nonresponders to different antidepressant medication +/- cognitive behavior therapy eventually doubled this remission rate.

In Major Depressive Disorder, lower recovery rates are associated with: longer duration, psychotic features, prominent anxiety, personality disorders, and symptom severity.

There is a greater likelihood of developing additional depressive episodes if:
  • the preceding episode was severe
  • the individual is younger
  • the individual has had multiple episodes
  • there was pre-existing Persistent Depressive Disorder
  • the individual has made only a partial recovery
  • the individual has a chronic general medical condition

Among those with an onset of depression in later life, there is evidence of subcortical white matter hyperintensities associated with cerebrovascular disease. These vascular depressions are associated with greater neuropsychological impairments and poorer responses to standard therapies.

Many individuals with Bipolar Disorder begin with one or more depressive episodes. About 5%-10% of individuals with Major Depressive Disorder eventually convert into Bipolar Disorder. The acute onset of severe depression, especially with psychotic features and psychomotor retardation, in a young person without prepubertal psychopathology is more likely to predict a bipolar course.

A family history of Bipolar Disorder may also be suggestive of subsequent development of Bipolar Disorder. The risk that recurrent Major Depressive Disorder will have a Manic Episode never disappears completely, however many Major Depressive Episodes have been experienced.

Major Depressive Disorder, particularly with psychotic features, may also convert into Schizophrenia, a change that is much more frequent than the reverse.

Outcome of Major Depressive Disorder

Mood Disorder Recovery At 10-Year Follow-up Compared To Schizophrenia


Stressors may play a more significant role in the precipitation of the first or second episode of this disorder and play less of a role in the onset of subsequent episodes. Chronic medical conditions and Substance Use Disorders (particularly Alcohol or Cocaine Dependence) may contribute to the onset or exacerbation of this disorder. The presence or absence of stressful life events does not appear to provide a useful guide to prognosis or treatment selection.

Familial Pattern

First-degree biological relatives of individuals with this disorder are 2-4 times more likely to develop Major Depressive Disorder. They also have an increased risk of having Alcohol Dependence, Anxiety Disorder (e.g., Panic Disorder, Social Anxiety Disorder), and Attention Deficit - Hyperactivity Disorder compared with the general population. Heritability is approximately 40%, and the personality trait neuroticism accounts for a substantial portion of this genetic liability.

Controlled Clinical Trials Of Therapy

Click here for a list of all the controlled clinical trials of therapy for this disorder.

Treatment As Usual

In research many controlled clinical trials use "treatment as usual" (TAU) as their control group. For Major Depressive Disorder, meta-analysis of 38 such studies (having 2099 patients) showed that in TAU 33% of the patients remitted from depression and 12% of the patients deteriorated. TAU varied considerably from study to study; thus TAU is a poor control group in research. A fraudulent research design is one in which the experimental treatment is given by expert therapists, and the TAU is given by inexpert therapists.


The major psychological treatments for depression [cognitive behavior therapy (CBT), mindfulness-based cognitive therapy (MBCT), interpersonal therapy (IPT), short-term psychodynamic psychotherapy (STPP)] when compared to each other are equally effective.

One large NIMH study on major depressive disorder found that the remission rate (after 16 weeks of treatment, at 18-month followup) did not differ statistically among four treatments: 30% for cognitive behavior therapy, 26% for interpersonal therapy, 19% for imipramine plus clinical management, and 20% for placebo plus clinical management. Among patients who had recovered, rates of relapse back into depression (at 18-month followup) were 36% for cognitive behavior therapy, 33% for interpersonal therapy, 50% for imipramine plus clinical management, and 33% for placebo plus clinical management.

A second study on moderate to severe major depressive disorder found (at 12-month followup) a 31% relapse rate back into depression for cognitive behavioral therapy, and a 47% relapse rate for patients who kept taking medication. A third study on moderate to severe major depressive disorder found that (after 16 weeks of therapy) there was a 46% remission rate for medication, and a 40% remission rate for cognitive therapy.

The addition of psychological treatment (CBT, MBCT, IPT, STTP) to antidepressant medication results in an improvement in outcome. St John's wort and regular exercise appear mildly effective in the treatment of depression (but their effect size is small).


Research on antidepressant medication has made startling findings: (1) all second-generation antidepressant medications are equally effective, (2) treatment with a combination of antidepressant medications (especially TCA + SSRI) is more effective than treatment with a single antidepressant medication, (3) only 60% of individuals with major depression respond to antidepressant medication, (4) antidepressant medication (like psychotherapy) has relatively modest effects when compared with an active placebo, and (5) more than 50% of the patients fail to respond to the first antidepressant medication they receive; hence require a switch to another antidepressant medication.

An active placebo is an inert substance, given by a doctor, which increases the patient's hope for recovery. The warmer and more competent appearing the doctor, the greater the resulting active placebo effect. Treatment by a cold, uncaring, incompetent appearing physician dramatically decreases the active placebo effect.

The active placebo effect causes most of the treatment benefit in major depressive disorder. When compared to the 40% remission rate on active placebo, the remission rate on antidepressant medication is 45% for mild depression, 52% for moderate depression, and 56% for severe depression.

Placebo effects make good medicine better (TEDMED talk)

Harnessing the power of placebos (TEDMED talk)

Since antidepressant medication is no more effective than active placebo for the treatment of mild Major Depressive Disorder; antidepressant medication has proven benefit only in the treatment of moderate to severe Major Depressive Disorder. For those whose depression causes marked distress or disability; antidepressant medication significantly reduces the risk of suicide, and returns the individual back to health, months sooner than would have been the case without treatment.

It should be remembered that, even without treatment, the median duration of major depressive disorder is 30 weeks.

In the famous STAR*D study of individuals with chronic or recurrent major depression, the 8-week response rate to the first antidepressant medication used (citalopram) was 47%, and the remission rate was about 30%. This closely resembled the results seen in most other 8-week antidepressant medication efficacy trials. Participants not responding to citalopram were switched to a different antidepressant or had another medication added to their existing antidepressant medication. This change in medication happened up to 3 times if the participant didn't respond. Eventually switching antidepressants brought the response rate up to 60% (counting everyone in the study). This response rate is considerably higher than the placebo response rate for chronic or recurrent MMD. If dropouts weren't counted, the final remission (symptom-free) rate was 70%. However, the rate at which participants withdrew from the STAR*D study was significant - 21% withdrew after citalopram, 30% withdrew after the 1st switch, and 42% withdrew after the 2nd switch.

If antidepressant medication/lithium is used, it should be started at a half of the therapeutic dose for the first week before being increased to the full therapeutic dose. Prematurely starting at the full therapeutic dose significantly increases adverse effects and causes a high drop-out rate.

Optimal effectiveness of an antidepressant medication occurs within 4-8 weeks. If there has been no response after the first 6 weeks, the dose should be increased. If there has been no response after 8 weeks, the antidepressant should be changed or another medication added to it. After successful treatment with an antidepressant medication, the effective dose is usually continued for another 4-9 months. Stopping before that time often triggers a return of the depression. The more severe or frequent the depressive episodes, the longer the antidepressant medication/lithium therapy should be continued.

Stopping antidepressant medication/lithium should be done slowly over 1-2 months. Lithium has no withdrawal symptoms, but two antidepressant medications (paroxetine and venlafaxine) have significant withdrawal symptoms which limits their use.

Treatment refractory depressions may respond to a combination of an antidepressant plus lithium or electroconvulsive therapy (ECT). In terms of symptom reduction, some atypical antipsychotic medications added to antidepressant medications result in a small benefit [aripiprazole (NNT= 7), risperidone (NNT= 8)]; whereas others are ineffective [quetiapine (NNT= 10), and olanzapine/fluoxetine combination (NNT= 19)]. (Note: A treatment with a Number Needed To Treat (NNT) >8 is generally considered clinically insignificant.) The only antidepressants approved for use in depressed children in the U.S. are fluoxetine and escitalopram.

Electroconvulsive Therapy (ECT)

When given ECT, 55% of individuals with major depressive disorder will go into remission. Unfortunately, there is a very high relapse rate 6 months after ECT. Of those going into remission with ECT, at 6 months posttreatment: (1) on placebo 84% relapse, and (2) on antidepressant medication plus lithium 39% relapse. Thus ECT is effective during the acute treatment phase in hospital, but steadily loses its benefit after hospital discharge. The effectiveness of ECT vs sham ECT at one or more months posttreatment is still controversial.

Ineffective Therapies

Vitamins, dietary supplements, and acupuncture are all ineffective for depression.

Is The Active Placebo Effect The Key To Understanding Recovery?

Many cases of major depressive disorder occur after events which trigger hopelessness (e.g., bereavement, divorce, job loss, academic failure). Also many activities that foster hope serve to decrease depression (e.g., socializing with friends, supportive counselling, religious involvement).

To get a significant active placebo effect, the placebo treatment must be given by a warm, competent physician who instills hope for recovery. Thus it isn't the placebo that causes the improvement. It is the active encouragement of hope done by a warm, competent physician that makes the placebo work.

Antidepressant medication is 5% more effective than active placebo in mild depression, 12% more effective than active placebo in moderate depression, and 16% more effective than active placebo in severe depression. Thus, for moderate to severe major depression, it is important to have both antidepressant medication and active treatment with a warm, competent physician who instills hope of recovery.

A Dangerous Cult

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  • Major Depressive Disorder - Google

  • Major Depressive Disorder In Childhood - Child Mind Institute

  • Depression in children - Epocrates Online

  • Depression in adults - Epocrates Online

  • Seasonal affective disorder - Epocrates Online

  • Major depression - PubMed Health

  • Major Depressive Disorder - Wikipedia

  • Clinical depression - NHS choices (UK)

  • Major Depression Genetics Online Mendelian Inheritance in Man

  • Neuroticism and Extraversion in Youth Predict Mental Wellbeing and Life Satisfaction 40 Years Later - Journal of research in personality (2013)

  • Most Antidepressants Ineffective for Kids With Depression - Medscape (2016)
    "'In adults, mainly in the elderly, depression is a lot about mood, while in young people, it's a lot about irritability and difficulty with concentration,' said Dr Cipriani. 'We tend to call it all depression and assume that the same drugs work for young people.'

    The analysis showed that in terms of efficacy, only fluoxetine was better than placebo (standardized mean difference [SMD], - 0.51; 95% credible interval [CrI], -0.99 to -0.03). However, the authors point out that 'the large credible interval and its upper limit close to the point of no difference raise the question of whether this estimate is robust enough to inform clinical practice.'

    Although the current study could not comprehensively assess the risk for suicidality for all drugs, there was robust evidence suggesting a significantly increased risk for suicidality for young people given venlafaxine. According to Dr Cipriani, 50% to 60% of patients respond to an antidepressant, and about 40% respond to placebo, so the "added value" is about 10% to 15%.

    Dr Jureidini suggests taking a 'watchful waiting' approach, even in cases of moderate and severe depression. It might be a matter of helping the child make sense of what they are feeling. For example, he or she might still be grieving from the loss of a beloved grandmother. Dr Jureidini pointed out that (childhood) depression usually lasts weeks, not months."


Rating Scales

Lack Of Social Skills During Major Depressive Disorder

There are social skills that are essential for healthy social functioning. During major depressive disorder, individuals lack the essential social skills of self-confidence, optimism, belonging, and sociability. These are the same social skills that are lacking in individuals with persistent depressive disorder, avoidant personality disorder and social anxiety disorder.

    Social Skills That Are Lacking During Major Depressive Disorder

    Self-Confidence Feeling inferior or shy Having a good opinion of one's self and abilities; socially confident and out-going
    Optimism Pessimism or expecting the worst Having a positive outlook on life; expecting a good outcome; hopeful
    Belonging Fearing rejection by others Feeling liked and accepted by friends, and included in their group; not fearing rejection
    Sociability Social withdrawal Friendly; interested in social contacts and activities

What Improves When You Recover From Depression?

Over 5 years (2005-2011) I studied my outpatient psychiatric patients that had a DSM-IV diagnosis of Major Depressive Disorder. I recorded their progress on every office visit using my Internet Mental Health Quality of Life Scale. At the end of this study, I compared 72 of them when they were moderately or severely depressed, to another 30 of them when they had fully recovered or were only mildly depressed. In this way, I could statistically determine which symptoms were elevated in major depressive disorder.

Explanation Of Terms And Symbols

Fatigue, sleep disturbance, appetite disturbance, occupational impairment and social impairment are all part of the diagnostic criteria for major depressive disorder. These classical symptoms of major depression decreased as my patients recovered. The Quality of Life Scale showed additional symptoms which decreased as my patients recovered from their depression, namely:
  • Overall physical health (i.e., less physical illness)

  • Friendship problems

  • Mistrust

  • Dependent behavior

  • Housing problems

  • Financial problems

  • Agoraphobia (fear of leaving home)

Explanation Of Terms And Symbols

Depressed mood, guilt, self-harm, agitation, distractibility, apathy, and impaired executive functioning are all part of the diagnostic criteria for major depressive disorder. As expected, these classical symptoms of major depression decreased as my patients recovered. However, the Quality of Life Scale also showed that other important symptoms decreased as my patients recovered from their depression, namely:
  • Generalized anxiety

  • Hostility

  • Forgetfulness

  • Personal neglect

It's important to note that, except for 2 patients that committed suicide, none of the other depressed patients remained suicidal. The terrible pain of depression was time-limited. Eighty percent of individuals with major depressive disorder recover within one year. Some even recover after 3 months. Thus suicide is a tragic waste of life; especially when major depressive disorder is so time-limited.

Explanation Of Terms And Symbols

The most striking finding was the extent to which depression had impaired my patients' social functioning. The following behaviors were induced by depression, and disappeared when my patients recovered from their depression:
  • Avoidant-Dependent Behaviors

    • Low self-esteem (previous chart)

    • Pessimism

    • Loneliness

    • Separation insecurity

    • Submissiveness

    • Difficulty handling conflict

  • Schizoid Behaviors

    • Intimacy avoidance

    • Social withdrawal

    • Lack of emotional expression

  • Obsessive-Compulsive Behaviors

    • Perfectionism

    • Inflexibility

  • Histrionic-Borderline Behaviors

    • Emotional instability

    • Unstable self-image

  • Paranoid Behavior

    • Feeling victimized

People Becoming Depressed After 4 Days Of Starvation

Studies on starvation have repeatedly shown that, after a few days of starvation, some individuals can become clinically depressed. Recently there was a 10 day experiment in which 10 individuals agreed to be cavemen and go into the Colorado wildness equipped only with caveman clothing and tools.

Psychiatrically, the results were amazing.

The group was able to catch fish on the first day, then they ran out of food. By the fourth day of starvation, the entire group suffered from severe fatigue, insomnia and apathy. Three members of the group became dysfunctional and just spent the day lying down or sitting. One woman, a vegetarian, was very weak and inactive because she couldn't find nutritious vegetarian food. Another female member became very tearful, pessimistic, and emotionally unstable. This woman gave up on the fifth day of starvation, and exited the experiment.

On the sixth day of starvation, a male member of the group just gave up, and said that they had no chance of getting any more food. He then exited the experiment.

Fortunately, on the seventh day of starvation, the four group members that still had the energy and optimism to hunt, actually killed an elk using their caveman spears. To everyone's surprise, the vegetarian woman refused to eat the meat, and - had the experiment run longer than 10 days - would have starved to death.

When you watch the video of this caveman experiment, you can see practically all of the symptoms of major depressive disorder appear. By the fourth day of starvation, all the group had developed severe fatigue, insomnia, hunger, apathy, and half the group developed crippling pessimism. Those that exited the experiment had developed marked loneliness and social withdrawal. In addition, the woman that exited the group had developed emotional instability. The vegetarian's meat-refusal, even if it meant her starvation, could be interpreted as perfectionism and inflexibility. By the 7th day of starvation, 4 group members were still functional (and saved the group by going hunting), and the other 4 remaining members were dysfunctional and so fatigued and apathetic that all they could do is stay in the camp and lie down.

So What Causes Major Depressive Disorder?

This disorder can be triggered by exposure to any major physical, psychological, or social adversity. So depression can be triggered by a physical illness or stress, an addiction to alcohol or drugs, or a significant psychological or social stress. It appears that depression is nature's way of shutting down the body (similar to hibernation).

Many animals hibernate during adversity (e.g., during foodless winter, frogs and bears hibernate; during the foodless summer dry season of Madagascar, the dwarf lemur hibernates).

In terms of survival, hibernation or "shutting down" makes sense if there is nothing more you can do in the face of adversity. However, if this ancient hibernation or "shutting down" circuit in the brain becomes active at an inappropriate time, the resulting depression could prove disastrous.


General Topics

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World Health Organization Depression Treatment Guidelines

Treatment Guidelines


Summary Of Practice Guideline For The Treatment Of Patients With Major Depressive Disorder. 3rd ed. - American Psychiatric Association (2010)

Rating Scheme for the Strength of the Recommendations

Each recommendation is identified as falling into one of three categories of endorsement, indicated by a bracketed Roman numeral following the statement. The three categories represent varying levels of clinical confidence:

  • [I] Recommended with substantial clinical confidence.

  • [II] Recommended with moderate clinical confidence.

  • [III] May be recommended on the basis of individual circumstances.

Major Recommendations

Provide Education to the Patient and the Family

  • With the patient's permission, family members and others involved in the patient's day-to-day life may also benefit from education about the illness, its effects on functioning (including family and other interpersonal relationships), and its treatment [I].

  • Common misperceptions about antidepressants (e.g., they are addictive) should be clarified [I].

  • In addition, education about major depressive disorder should address the need for a full acute course of treatment, the risk of relapse, the early recognition of recurrent symptoms, and the need to seek treatment as early as possible to reduce the risk of complications or a full-blown episode of major depression [I].

  • Patients should also be told about the need to taper antidepressants, rather than discontinuing them precipitously, to minimize the risk of withdrawal symptoms or symptom recurrence [I].

  • Patient education also includes general promotion of healthy behaviors such as exercise, good sleep hygiene, good nutrition, and decreased use of tobacco, alcohol, and other potentially deleterious substances [I].

  • Educational tools such as books, pamphlets, and trusted web sites can augment the face-to-face education provided by the clinician [I].

Treatment Of Acute Phase Of Major Depressive Disorder


  • An antidepressant medication is recommended as an initial treatment choice for patients with mild to moderate major depressive disorder [I] and definitely should be provided for those with severe major depressive disorder unless ECT is planned [I].

  • Because the effectiveness of antidepressant medications is generally comparable between classes and within classes of medications, the initial selection of an antidepressant medication will largely be based on the anticipated side effects, and additional factors such as medication response in prior episodes, cost, and patient preference [I].

  • For most patients, a selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion is optimal [I].

  • In general, the use of nonselective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, tranylcypromine, isocarboxazid) should be restricted to patients who do not respond to other treatments [I], given the necessity for dietary restrictions with these medications and the potential for deleterious drug-drug interactions.

      • In patients who prefer complementary and alternative therapies, S-adenosyl methionine (SAMe) [III] or St. John's wort [III] might be considered, although evidence for their efficacy is modest at best.

  • Careful attention to drug-drug interactions is needed with St. John's wort [I].

  • Patients receiving pharmacotherapy should be systematically monitored on a regular basis to assess their response to treatment and assess patient safety [I].

  • If antidepressant side effects do occur, an initial strategy is to lower the dose of the antidepressant or to change to an antidepressant that is not associated with that side effect [I].

Other Somatic Therapies

  • ECT is recommended as a treatment of choice for patients with severe major depressive disorder that is not responsive to psychotherapeutic and/or pharmacological interventions, particularly in those who have significant functional impairment or have not responded to numerous medication trials [I].

  • ECT is also recommended for individuals with major depressive disorder who have associated psychotic or catatonic features [I], for those with an urgent need for response (e.g., patients who are suicidal or nutritionally compromised due to refusal of food or fluids) [I], and for those who prefer ECT or have had a previous positive response to ECT [II].

      • Bright light therapy might be used to treat seasonal affective disorder as well as nonseasonal depression [III].


  • Use of a depression-focused psychotherapy alone is recommended as an initial treatment choice for patients with mild to moderate major depressive disorder [I], with clinical evidence supporting the use of cognitive-behavioral therapy (CBT) [I], interpersonal psychotherapy [I], psychodynamic therapy [II], and problem-solving therapy [III] in individual [I] and in group [III] formats.

  • In women who are pregnant, wish to become pregnant, or are breastfeeding, a depression-focused psychotherapy alone is recommended [II] and depending on the severity of symptoms, should be considered as an initial option [I].

  • As with patients who are receiving pharmacotherapy, patients receiving psychotherapy should be carefully and systematically monitored on a regular basis to assess their response to treatment and assess patient safety [I].

    • Marital and family problems are common in the course of major depressive disorder, and such problems should be identified and addressed, using marital or family therapy when indicated [II].

  • The combination of psychotherapy and antidepressant medication may be used as an initial treatment for patients with moderate to severe major depressive disorder [I].

    • Combining psychotherapy and medication may be a useful initial treatment even in milder cases for patients with psychosocial or interpersonal problems, intrapsychic conflict, or co-occurring personality disorder [II].

Assessing the Adequacy of Treatment Response

  • Onset of benefit from psychotherapy tends to be a bit more gradual than that from medication, but no treatment should continue unmodified if there has been no symptomatic improvement after 1 month [I].

    • Generally, 4-8 weeks of treatment are needed before concluding that a patient is partially responsive or unresponsive to a specific intervention [II].

Strategies to Address Nonresponse

  • For individuals who have not responded fully to treatment, the acute phase of treatment should not be concluded prematurely [I], as an incomplete response to treatment is often associated with poor functional outcomes.

  • If at least a moderate improvement in symptoms is not observed within 4-8 weeks of treatment initiation, the diagnosis should be reappraised, side effects assessed, complicating co-occurring conditions and psychosocial factors reviewed, and the treatment plan adjusted [I]. It is also important to assess the quality of the therapeutic alliance and treatment adherence [I].

  • For patients in psychotherapy, additional factors to be assessed include the frequency of sessions and whether the specific approach to psychotherapy is adequately addressing the patient's needs [I].

  • With some TCAs, a drug blood level can help determine if additional dose adjustments are required [I].

    • For patients treated with an antidepressant, optimizing the medication dose is a reasonable first step if the side effect burden is tolerable and the upper limit of a medication dose has not been reached [II].

  • Particularly for those who have shown minimal improvement or experienced significant medication side effects, other options include augmenting the antidepressant with a depression-focused psychotherapy [I] or with other agents [II] or changing to another non-MAOI antidepressant [I].

    • Patients may be changed to an antidepressant from the same pharmacological class (e.g., from one SSRI to another SSRI) or to one from a different class (e.g., from an SSRI to a tricyclic antidepressant [TCA]) [II].

    • For patients who have not responded to trials of SSRIs, a trial of an SNRI may be helpful [II].

    • Augmentation of antidepressant medications can utilize another non-MAOI antidepressant [II], generally from a different pharmacological class, or a non-antidepressant medication such as lithium [II], thyroid hormone [II], or a second-generation antipsychotic [II].

      • Additional strategies with less evidence for efficacy include augmentation using an anticonvulsant [III], omega-3 fatty acids [III], folate [III], or a psychostimulant medication [III], including modafinil [III].

      • If anxiety or insomnia are prominent features, consideration can be given to anxiolytic and sedative-hypnotic medications [III], including buspirone, benzodiazepines, and selective gamma-aminobutyric acid (GABA) agonist hypnotics (e.g., zolpidem, eszopiclone).

  • For patients whose symptoms have not responded adequately to medication, ECT remains the most effective form of therapy and should be considered [I].

  • In patients capable of adhering to dietary and medication restrictions, an additional option is changing to a nonselective MAOI [II] after allowing sufficient time between medications to avoid deleterious interactions [I].

    • Transdermal selegiline, a relatively selective MAO B inhibitor with fewer dietary and medication restrictions, or transcranial magnetic stimulation could also be considered [II].

      • Vagus nerve stimulation (VNS) may be an additional option for individuals who have not responded to at least four adequate trials of antidepressant treatment, including ECT [III].

  • For patients treated with psychotherapy, consideration should be given to increasing the intensity of treatment or changing the type of therapy [II]. If psychotherapy is used alone, the possible need for medications in addition to or in lieu of psychotherapy should be assessed [I].

    • Patients who have a history of poor treatment adherence or incomplete response to adequate trials of single treatment modalities may benefit from combined treatment with medication and a depression-focused psychotherapy [II].

Treatment Of Continuation Phase Of Major Depressive Disorder

  • During the continuation phase of treatment, the patient should be carefully monitored for signs of possible relapse [I].

    • Systematic assessment of symptoms, side effects, adherence, and functional status is essential [I] and may be facilitated through the use of clinician- and/or patient-administered rating scales [II].

  • To reduce the risk of relapse, patients who have been treated successfully with antidepressant medications in the acute phase should continue treatment with these agents for 4-9 months [I].

    • In general, the dose used in the acute phase should be used in the continuation phase [II].

  • To prevent a relapse of depression in the continuation phase, depression-focused psychotherapy is recommended [I], with the best evidence available for cognitive-behavioral therapy.

  • Patients who respond to an acute course of ECT should receive continuation pharmacotherapy [I], with the best evidence available for the combination of lithium and nortriptyline. Alternatively, patients who have responded to an acute course of ECT may be given continuation ECT, particularly if medication or psychotherapy has been ineffective in maintaining remission [II].

Treatment Of Maintenance Phase Of Major Depressive Disorder

  • In order to reduce the risk of a recurrent depressive episode, patients who have had three or more prior major depressive episodes or who have chronic major depressive disorder should proceed to the maintenance phase of treatment after completing the continuation phase [I].

    • Maintenance therapy should also be considered for patients with additional risk factors for recurrence, such as the presence of residual symptoms, ongoing psychosocial stressors, early age at onset, and family history of mood disorders [II].

  • For many patients, particularly for those with chronic and recurrent major depressive disorder or co-occurring medical and/or psychiatric disorders, some form of maintenance treatment will be required indefinitely [I].

    • During the maintenance phase, an antidepressant medication that produced symptom remission during the acute phase and maintained remission during the continuation phase should be continued at a full therapeutic dose [II].

    • If a depression-focused psychotherapy has been used during the acute and continuation phases of treatment, maintenance treatment should be considered, with a reduced frequency of sessions [II].

      • For patients whose depressive episodes have not previously responded to acute or continuation treatment with medications or a depression-focused psychotherapy but who have shown a response to ECT, maintenance ECT may be considered [III].

      • Maintenance treatment with vagus nerve stimulation is also appropriate for individuals whose symptoms have responded to this treatment modality [III].

    • Due to the risk of recurrence, patients should be monitored systematically and at regular intervals during the maintenance phase [I]. Use of standardized measurement aids is recommended for the early detection of recurrent symptoms [II].

Discontinuation of Treatment

  • When pharmacotherapy is being discontinued, it is best to taper the medication over the course of at least several weeks [I].

  • To minimize the likelihood of discontinuation symptoms, patients should be advised not to stop medications abruptly and to take medications with them when they travel or are away from home [I].

    • A slow taper or temporary change to a longer half-life antidepressant (e.g., fluoxetine) may reduce the risk of discontinuation syndrome [II] when discontinuing antidepressants or reducing antidepressant doses.

  • Before the discontinuation of active treatment, patients should be informed of the potential for a depressive relapse and a plan should be established for seeking treatment in the event of recurrent symptoms [I].

  • After discontinuation of medications, patients should continue to be monitored over the next several months and should receive another course of adequate acute phase treatment if symptoms recur [I].

  • For patients receiving psychotherapy, it is important to raise the issue of treatment discontinuation well in advance of the final session [I], although the exact process by which this occurs will vary with the type of therapy.

Clinical Factors Influencing Treatment

Psychiatric Factors

  • Factors to consider in determining the nature and intensity of treatment include (but are not limited to) the nature of the doctor-patient alliance, the availability and adequacy of social supports, access to and lethality of suicide means, the presence of a co-occurring substance use disorder, and past and family history of suicidal behavior [I].

  • For suicidal patients, psychiatrists should consider an increased intensity of treatment, including hospitalization when warranted [I] and/or combined treatment with pharmacotherapy and psychotherapy [II].

  • For patients who exhibit psychotic symptoms during an episode of major depressive disorder, treatment should include a combination of antipsychotic and antidepressant medications or ECT [I].

  • When patients exhibit cognitive dysfunction during a major depressive episode, they may have an increased likelihood of future dementia, making it important to assess cognition in a systematic fashion over the course of treatment [I].

  • Catatonic features that occur as part of a major depressive episode should be treated with a benzodiazepine [I] or barbiturate [II], typically in conjunction with an antidepressant [II]. If catatonic symptoms persist, ECT is recommended [I]. To reduce the likelihood of general medical complications, patients with catatonia may also require supportive medical interventions, such as hydration, nutritional support, prophylaxis against deep vein thrombosis, turning to reduce risks of decubitus ulcers, and passive range of motion to reduce risk of contractures [I]. If antipsychotic medication is needed, it is important to monitor for signs of neuroleptic malignant syndrome, to which patients with catatonia may have a heightened sensitivity [II].

    • Benzodiazepines may be used adjunctively in individuals with major depressive disorder and co-occurring anxiety [II], although these agents do not treat depressive symptoms, and careful selection and monitoring is needed in individuals with co-occurring substance use disorders [I].

  • In patients who smoke, bupropion [I] or nortriptyline [II] may be options to simultaneously treat depression and assist with smoking cessation.

    • When possible, a period of substance abstinence can help determine whether the depressive episode is related to substance intoxication or withdrawal [II]. Factors that suggest a need for antidepressant treatment soon after cessation of substance use include a family history of major depressive disorder and a history of major depressive disorder preceding the onset of the substance use disorder or during periods of sobriety [II].

    • For patients who have a personality disorder as well as major depressive disorder, psychiatrists should institute treatment for the major depressive disorder [I] and consider treatment for personality disorder symptoms [II].

Demographic and Psychosocial Factors

  • When prescribing medications to women who are taking oral contraceptives, the potential effects of drug-drug interactions must be considered [I].

    • For women in the perimenopausal period, SSRI and SNRI antidepressants are useful in ameliorating depression as well as in reducing somatic symptoms such as hot flashes [II].

  • Both men and women who are taking antidepressants should be asked whether sexual side effects are occurring with these medications [I]. Men for whom trazodone is prescribed should be warned of the risk of priapism [I].

  • For women who are currently receiving treatment for depression, a pregnancy should be planned, whenever possible, in consultation with the treating psychiatrist, who may wish to consult with a specialist in perinatal psychiatry [I].

    • In women who are pregnant, planning to become pregnant, or breast-feeding, depression-focused psychotherapy alone is recommended [II] and should always be considered as an initial option, particularly for mild to moderate depression, for patients who prefer psychotherapy, or for those with a prior positive response to psychotherapy [I].

    • Antidepressant medication should be considered for pregnant women who have moderate to severe major depressive disorder as well as for those who are in remission from major depressive disorder, are receiving maintenance medication, and are deemed to be at high risk for a recurrence if the medication is discontinued [II].

  • When antidepressants are prescribed to a pregnant woman, changes in pharmacokinetics during pregnancy may require adjustments in medication doses [I].

    • Electroconvulsive therapy may be considered for the treatment of depression during pregnancy in patients who have psychotic or catatonic features, whose symptoms are severe or have not responded to medications, or who prefer treatment with ECT [II].

  • When a woman decides to nurse, the potential benefits of antidepressant medications for the mother should be balanced against the potential risks to the newborn from receiving antidepressant in the mother's milk [I].

  • For women who are depressed during the postpartum period, it is important to evaluate for the presence of suicidal ideas, homicidal ideas, and psychotic symptoms [I]. The evaluation should also assess parenting skills for the newborn and for other children in the patient's care [I].

  • In individuals with late-life depression, identification of co-occurring general medical conditions is essential, as these disorders may mimic depression or affect choice or dosing of medications [I]. Older individuals may also be particularly sensitive to medication side effects (e.g., hypotension, anticholinergic effects) and require adjustment of medication doses for hepatic or renal dysfunction [I]. In other respects, treatment for depression should parallel that used in younger age groups [I].

    • When antidepressants are prescribed, the psychiatrist should recognize that ethnic groups may differ in their metabolism and response to medications [II].

  • A family history of bipolar disorder or acute psychosis suggests a need for increased attention to possible signs of bipolar illness in the patient (e.g., with antidepressant treatment) [I].

    • A family history of recurrent major depressive disorder increases the likelihood of recurrent episodes in the patient and supports a need for maintenance treatment [II].

      • Family history of a response to a particular antidepressant may sometimes help in choosing a specific antidepressant for the patient [III].

    • Because problems within the family may become an ongoing stressor that hampers the patient's response to treatment, and because depression in a family is a major stress in itself, such factors should be identified and strong consideration given to educating the family about the nature of the illness, enlisting the family's support, and providing family therapy, when indicated [II].

  • For patients who have experienced a recent bereavement, psychotherapy or antidepressant treatment should be used when the reaction to a loss is particularly prolonged or accompanied by significant psychopathology and functional impairment [I].

      • Support groups may be helpful for some bereaved individuals [III].

Co-occurring General Medical Conditions

  • Communication with other clinicians who are providing treatment for general medical conditions is recommended [I].

  • The clinical assessment should include identifying any potential interactions between medications used to treat depression and those used to treat general medical conditions [I].

  • Assessment of pain is also important as it can contribute to and co-occur with depression [I]. In addition, the psychiatrist should consider the effects of prescribed psychotropic medications on the patient's general medical conditions, as well as the effects of interventions for such disorders on the patient's psychiatric condition [I].

  • In patients with preexisting hypertension or cardiac conditions, treatment with specific antidepressant agents may suggest a need for monitoring of vital signs or cardiac rhythm (e.g., electrocardiogram [ECG] with TCA treatment; heart rate and blood pressure assessment with SNRIs and TCAs) [I].

  • When using antidepressant medications with anticholinergic side effects, it is important to consider the potential for increases in heart rate in individuals with cardiac disease, worsening cognition in individuals with dementia, development of bladder outlet obstruction in men with prostatic hypertrophy, and precipitation or worsening of narrow angle glaucoma [I].

    • Some antidepressant drugs (e.g., bupropion, clomipramine, maprotiline) reduce the seizure threshold and should be used with caution in individuals with preexisting seizure disorders [II].

    • In individuals with Parkinson's disease, the choice of an antidepressant should consider that serotonergic agents may worsen symptoms of the disease [II], that bupropion has potential dopamine agonist effects (benefitting symptoms of Parkinson's disease but potentially worsening psychosis) [II], and that selegiline has antiparkinsonian and antidepressant effects but may interact with L-dopa and with other antidepressant agents [I].

  • In treating the depressive syndrome that commonly occurs following a stroke, consideration should be given to the potential for interactions between antidepressants and anticoagulating (including antiplatelet) medications [I].

  • Given the health risks associated with obesity and the tendency of some antidepressant medications to contribute to weight gain, longitudinal monitoring of weight (either by direct measurement or patient report) is recommended [I], as well as calculation of body mass index (BMI) [II]. If significant increases are noted in the patient's weight or BMI, the clinician and patient should discuss potential approaches to weight control such as diet, exercise, change in medication, nutrition consultation, or collaboration with the patient's primary care physician [I].

  • In patients who have undergone bariatric surgery to treat obesity, adjustment of medication formulations or doses may be required because of altered medication absorption [I].

    • For diabetic patients, it is useful to collaborate with the patient's primary care physician in monitoring diabetic control when initiating antidepressant therapy or making significant dosing adjustments [II].

  • Clinicians should be alert to the possibility of sleep apnea in patients with depression, particularly those who present with daytime sleepiness, fatigue, or treatment-resistant symptoms [II]. In patients with known sleep apnea, treatment choice should consider the sedative side effects of medication, with minimally sedating options chosen whenever possible [I].

  • Given the significant numbers of individuals with unrecognized human immunodeficiency virus (HIV) infection and the availability of effective treatment, consideration should be given to HIV risk assessment and screening [I]. For patients with HIV infection who are receiving antiretroviral therapy, the potential for drug-drug interactions needs to be assessed before initiating any psychotropic medications [I]. Patients who are being treated with antiretroviral medications should be cautioned about drug-drug interactions with St. John's wort that can reduce the effectiveness of HIV treatments [I].

  • In patients with hepatitis C infection, interferon can exacerbate depressive symptoms, making it important to monitor patients carefully for worsening depressive symptoms during the course of interferon treatment [I].

  • Because tamoxifen requires active 2D6 enzyme function to be clinically efficacious, patients who receive tamoxifen for breast cancer or other indications should generally be treated with an antidepressant (e.g., citalopram, escitalopram, venlafaxine, desvenlafaxine) that has minimal effect on metabolism through the cytochrome P450 2D6 isoenzyme [I].

    • When depression occurs in the context of chronic pain, SNRIs and TCAs may be preferable to other antidepressive agents [II].

  • When ECT is used to treat major depressive disorder in an individual with a co-occurring general medical condition, the evaluation should identify conditions that could require modifications in ECT technique (e.g., cardiac conditions, hypertension, central nervous system lesions) [I]; these should be addressed insofar as possible and discussed with the patient as part of the informed consent process [I].

Cognitive Behavioral Therapy


  • Major Depressive Disorder Treatment - Google

  • Clinical depression - Treatment - NHS choices (UK)

  • Paxil Withdrawal Syndrome - ABC Primetime Live

    • [Editor: A few antidepressant medications have potentially severe withdrawal syndromes, especially Paxil (paroxetine) and Effexor (venlafaxine). This video correctly reports that physicians were not warned of these severe withdrawal syndromes. Most patients never experience this problem if they slowly withdraw from Paxil or Effexor over 3 months. Often simultaneously starting Prozac (fluoxetine) while withdrawing from Paxil or Effexor can minimize this withdrawal syndrome. It should be remembered that 60% of severely depressed individuals recover on antidepressant medication, and most antidepressant medications do not have severe withdrawal syndromes.]

    Warning: Do Not Mix Paxil (paroxetine) with Pravachol (pravastatin)

  • First 'gold-standard' trial of ketamine's anti-depressant effects launched
    • WARNING: Ketamine is an illegal hallucinogenic dance drug for clubbers. At a low dose, it causes elation, and at higher doses it causes dissociation (i.e., an unreal, trace-like state) and hallucinations. Long-term use and abuse of ketamine is associated with liver inflammation, destruction of the bladder lining, cognitive problems and other serious medical complications. Some researchers are now experimenting with this illegal drug as a treatment for major depresssive disorder. Depression research so far has involved only giving a single dose of ketamine to seriously depressed individuals. In these studies, depressed patients do feel better - but this only lasts for a few days. Thus a long-term study of the treatment of major depressive disorder with ketamine is needed before this treatment can be recommended. Ethically, an effective treatment for clinical depression must do more than make a patient "feel good". All of the illegal drugs (e.g., heroin, crack cocaine) make people "feel good" - at least initially. To be acceptable, a treatment for clinical depression must also significantly improve the depressed patient's ability to work, love and play - in addition to being nonaddictive and medically safe. This is where the addictive, illegal "recreational drugs" differ from scientifically proven, government approved treatments for depression.

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    Self-Help Resources

    Self-Blaming vs. Self-Compassion

    Some individuals are constantly at war with themselves.

    They believe: "I am stupid", "I am a failure", "Nothing goes right for me". They constantly analyze themselves and their behavior for flaws. They are cynical and pessimistic. Because of their gloomy, depressed or angry mood, they withdraw and socially isolate themselves. This lack of cooperation with others makes them feel even more hopeless, depressed or angry.

    These individuals are at a high risk for developing Persistent Depressive Disorder or Major Depressive Disorder. Healthy people are self-confident, optimistic, sociable, and feel accepted and supported by friends. Individuals suffering from excessive self-blaming are pessimistic, socially withdrawn, and feel rejected by others.

    If you suffer from excessive self-blaming; here are ways you can remedy this by learning increased self-compassion and social cooperation:

    • Self-Confidence vs. Self-Blaming:
      You must be kind towards yourself, instead of always blaming yourself for everything. Accept and love yourself for who you are - with all your human imperfections. You must strive to have a good opinion of yourself and your abilities, and to be socially confident. Quit constantly comparing yourself to others.

    • Optimism vs. Pessimism:
      Strive to replace your unrealistic, pessimistic, negative thinking with more realistic, optimistic, positive thinking.

    • Sociability vs. Social Withdrawal:
      In order to feel good, you have to do good. Thus to feel better, you have to get out and help others (and remember to frequently smile).

    • Feeling Accepted vs. Feeling Rejected:
      You can not control how other people behave towards you. All you can do is control how you behave towards other people. Much of your life is not under your control; hence you can not change it. You are only responsible for the small part of your life which is under your control - the part you can change. Thus remain friendly and out-going - especially towards people that haven't accepted you.

    Afternoon Meditation (Learn How To Have Healthy Relationships)

    Life Satisfaction Scale (Video)

    Healthy Social Behavior Scale (Video)

    Mental Health Scale (Video)

    Click Here For More Self-Help

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      "In physical science a first essential step in the direction of learning any subject is to find principles of numerical reckoning and practicable methods for measuring some quality connected with it. I often say that when you can measure what you are speaking about and express it in numbers you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind: it may be the beginning of knowledge, but you have scarcely, in your thoughts, advanced to the stage of science, whatever the matter may be."

      Lord Kelvin (1824 – 1907)

    • The best summary on bad research is given by Laura Arnold in this TEDx lecture. If you read nothing else about research, you owe it to yourself to watch this short video - it is excellent!

    • Canadian researchers who commit scientific fraud are protected by privacy laws: There are criminals in every community - even in the scientific research community (especially if a lot of money is at stake). Criminal researchers can hide their fraud behind outdated privacy laws.

    • The power of asking "what if?"

    • The active placebo effect: 2300 years ago, the Greek Stoic philosophers taught that it is not the objective event, but our subjective judgment about the event, that determines our behavior. The active placebo effect bears witness to this ancient wisdom.

    • Criteria For High Quality Research Studies

    • It is troubling that a recent study found that two-thirds of important psychological research studies couldn't be replicated. High quality research must meet the following criteria:

      • Randomized Controlled Trial:
        Ask: Was the trial randomized? Was the randomization procedure described and was it appropriate? The best research design is to have research subjects randomly assigned to an experimental or control group. It is essential that confounding factors be controlled for by having a control group or comparator condition (no intervention, placebo, care as usual etc.).

      • Representative Sample:
        Ask: Do the research subjects represent a normal cross-section of the population being studied? Many psychological research studies using university students are flawed because their subjects are not representative of the normal population since they are all W.E.I.R.D. (White, Educated, Intelligent, Rich, and living in a Democracy).

      • Single Blind Trial:
        Ask: Was the treatment allocation concealed? It is essential that the research subjects are kept "blind" as to whether they are in the experimental or control group (in order to control for any placebo effects).

      • Double Blind Trial (Better Than Single Blind Trial):
        Ask: Were blind outcome assessments conducted? In a double blind study, neither the research subjects nor the outcome assessors know if the research subject is in the experimental or control group. This controls for both the placebo effect and assessor bias.

      • Baseline Comparability:
        Ask: Were groups similar at baseline on prognostic indicators? The experimental and control groups must be shown to be comparable at the beginning of the study.

      • Confounding Factors:
        Ask: Were there factors, that weren't controlled for, that could have seriously distorted the study's results? For example, research studies on the effectiveness of mindfulness cognitive therapy in preventing depressive relapse forgot to control for whether the research subjects were also simultaneously receiving antidepressant medication or other psychological treatments for depression.

      • Intervention Integrity:
        Ask: Was the research study protocal strictly followed? The research subjects must be shown to be compliant (e.g., taking their pills, attending therapy) and the therapists must be shown to be reliably delivering the intervention (e.g., staying on the research protocol).

      • Statistical analysis:
        Ask: Was a statistical power calculation described? The study should discuss its statistical power analysis; that is whether the study size is large enough to statistically detect a difference between the experimental and control group (should it occur) and usually this requires at least 50 research subjects in the study.

        Ask: Are the results both statistically significant and clinically significant? Many medical research findings are statistically significant (with a p-value <0.05), but they are not clinically significant because the difference between the experimental and control groups is too small to be clinically relevant.

        For example, the effect of a new drug may be found to be 2% better than placebo. Statistically (if the sample size was large enough) this 2% difference could be statistically significant (with a p-value <0.05). However, clinicians would say that this 2% difference is not clinically significant (i.e., that it was too small to really make any difference).

        Statistically, the best way to test for clinical significance is to test for effect size (i.e., the size of the difference between two groups rather than confounding this with statistical probability).

        When the outcome of interest is a dichotomous variable, the commonly used measures of effect size include the odds ratio (OR), the relative risk (RR), and the risk difference (RD).

        When the outcome is a continuous variable, then the effect size is commonly represented as either the mean difference (MD) or the standardised mean difference (SMD) .

        The MD is the difference in the means of the treatment group and the control group, while the SMD is the MD divided by the standard deviation (SD), derived from either or both of the groups. Depending on how this SD is calculated, the SMD has several versions such, as Cohen's d, Glass's Δ, and Hedges' g.

          Clinical Significance: With Standard Mean Difference, the general rule of thumb is that a score of 0 to 0.25 indicates small to no effect, 0.25-0.50 a mild benefit, 0.5-1 a moderate to large benefit, and above 1.0 a huge benefit. It is a convention that a SMD of 0.5 or larger is a standard threshold for clinically meaningful benefit.

        The statistical summary should report what percentage of the total variance of the dependent variable (e.g., outcome) can be explained by the independent variable (e.g., intervention).

        In clinical studies, the study should report the number needed to treat for an additional beneficial outcome (NNTB), and the number needed to treat for an additional harmful outcome (NNTH).

          Number Needed To Benefit (NNTB): This is defined as the number of patients that need to be treated for one of them to benefit compared with a control in a clinical trial. (It is defined as the inverse of the absolute risk reduction.) Note: Statistically, the NNTB depends on which control group is used for comparison - e.g., active treatment vs. placebo treatment, or active treatment vs. no treatment.

          Number Needed To Harm (NNTH): This is defined as the number of patients that need to be treated for one of them to be harmed compared with a control in a clinical trial. (It is defined as the inverse of the absolute increase in risk.)

          Tomlinson found “an NNTB of 5 or less was probably associated with a meaningful health benefit,” while “an NNTB of 15 or more was quite certain to be associated with at most a small net health benefit.”

        Ask: Does the researcher accept full responsibility for the study's statistical analysis? The researcher should not just hand over the study's raw data to a corporation (that may have $1,000 million invested in the study) to do the statistical analysis.

      • Completeness of follow-up data:
        Ask: Was the number of withdrawals or dropouts in each group mentioned, and were reasons given for these withdrawals or dropouts? Less than 20% of the research subjects should drop out of the study. The intervention effect should persist over an adequate length of time.

      • Handling of missing data:
        Ask: Was the statistical analysis conducted on the intention-to-treat sample? There must be use of intention-to-treat analysis (as opposed to a completers-only analysis). In this way, all of the research subjects that started the study are included in the final statistical analysis. A completers-only analysis would disregard those research subjects that dropped out.

      • Replication of Findings:
        Ask: Can other researchers replicate this study's results? The research study's methodology should be clearly described so that the study can be easily replicated. The researcher's raw data should be available to other researchers to review (in order to detect errors or fraud).

      • Fraud:
        Ask: Is there a suspicion of fraud? In a research study, examine the independent and dependent variables that are always measured as a positive whole number (e.g., a variable measured on a 5-point Likert-type scale ranging from "1 = definitely false to 5 = definitely true" etc.). For each of these variables, look at their sample size (n), mean (M) and standard deviation (SD) before they undergo statistical analysis. There is a high suspicion of fraud in a study's statistics:

        • If the M is mathematically impossible (online calculator): This is one of the easiest ways to mathematically detect fraud. The mean (M) is defined as "the sum (Sum) of the values of each observation divided by the total number (n) of observations". So: M = Sum/n. Thus: (Sum) = (M) multiplied by (n). We know that, if a variable is always measured as a positive whole number, the sum of these observations always has to be a whole number. For these variables to test for fraud: calculate (M) multiplied by (n). This calculates the Sum which MUST be a positive whole number. If the calculated Sum isn't a positive whole number; the reported mean (M) is mathematically impossible - thus the researcher either cooked the data or made a mistake. A recent study of 260 research papers published in highly reputable psychological journals found that 1 in 2 of these research papers reported at least one impossible value, and 1 in 5 of these research papers reported multiple impossible values. When the authors of the 21 worst offending research papers were asked for their raw data (so that its reliability could be checked) - 57% angrily refused. Yet such release of raw data to other researchers is required by most scientific journals. (Here is an example of a research paper filled with mathematically impossible means.)

        • If the SD is mathematically impossible (online calculator): When researchers fraudulently "cook" their data, they may accidently give their data a mean and standard deviation that is mathematically impossible.

        • If the SD/M is very small (i.e., the variable's standard deviation is very small compared to the mean suggesting data smoothing).

        • If the SD's are almost identical (i.e., the variables have different means but almost identical standard deviations).

        • If the 4th digit of the values of the variables aren't uniformly distributed - since each should occur 10% of the time (Benford's Law).

        • If the researcher is legally prevented from publishing negative findings about a drug or therapy because that would violate the "nondisclosure of trade secrets" clause in the research contract (i.e., it is a "trade secret" that the drug or therapy is ineffective - hence this can not be "disclosed"). Approximately half of all registered clinical trials fail to publish their results.

        • If the researcher refuses to release his raw data to fellow researchers (so that they can check its validity). In order to be published in most scientific journals, a researcher must promise to share his raw data with fellow researchers. Thus a researcher's refusal to do so is almost a sure indicator of fraud.

        • If the research study's data contradicts the study's own conclusions - surprisingly, this often occurs.

    • Calling Bullshit In The Age of Big Data - "Bullshit is language, statistical figures, data graphics, and other forms of presentation intended to persuade by impressing and overwhelming a reader or listener, with a blatant disregard for truth and logical coherence." Reading the syllabus of this university course should be required reading for every student of mental health. This syllabus is absolutely fantastic!

    • Statistical Methods in Psychology Journals: Guidelines and Explanations - American Psychologist 1999

    • Not All Scientific Studies Are Created Equal - video

    • The efficacy of psychological, educational, and behavioral treatment

    • Estimating the reproducibility of psychological science

    • Psychologists grapple with validity of research

    • Industry sponsorship and research outcome (Review) - Cochrane Library

    • 'We've been deceived': Many clinical trial results are never published - (text and video)

    • Junk science misleading doctors and researchers

    • Junk science under spotlight after controversial firm buys Canadian journals

    • Medicine with a side of mysticism: Top hospitals promote unproven therapies - Are some doctors becoming modern witchdoctors?

    • When Evidence Says No, But Doctors Say Yes

    • Major pharmaceutical company fined $3 billion US for making false claims - (text and video) [Editor: This is an example of how a major pharmaceutical company purposely produced fraudulant research in order to increase its sales.] In 2001, GlaxoSmithKline, the manufacturer of the antidepressant Paxil, published research that falsely claimed that Paxil was effective in the treatment of adolescent depression. This claim and others were found to be fraudulant, and in 2012 GlaxoSmithKline was fined $3 billion US in court settlements. Subsequent independent reanalysis of the original Paxil research data clearly proved that the original study was fraudulant. This fraudulant research paper was published in a top psychiatric journal, and has never been retracted or corrected.

    • Cochrane Collaboration - the best evidence-based, standardized reviews available

    Research Topics:

    Major Depressive Disorder - Core Clinical Journals

    Major Depressive Disorder - All Journals

    Major Depressive Disorder - Review Articles - Core Clinical Journals

    Major Depressive Disorder - Review Articles - All Journals

    Cochrane Review (The best evidence-based, standardized reviews available)

    Strong evidence of effectiveness:
    • Paroxetine versus other anti-depressive agents for depression (2014) (There was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.)

    • Pharmacological treatment for psychotic depression (2013) (We found only 12 randomised controlled trials (RCTs) that met our inclusion criteria. These trials involved a total of 929 people. From these trials, we found evidence that the combination of an antidepressant plus an antipsychotic provides more effective treatment for psychotic depression than either treatment alone. However, our confidence in this conclusion is limited because the information came from only a small number of RCTs, which included small numbers of people.)

    • Fluoxetine compared with other antidepressants for depression in adults (2013) (The present study detected differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain. Moreover, the assessment of quality with the risk of bias tool showed that the great majority of included studies failed to report details on methodological procedures. Of consequence, no definitive implications can be drawn from the studies' results. The better efficacy profile of sertraline and venlafaxine (and possibly other ADs) over fluoxetine may be clinically meaningful, as already suggested by other systematic reviews. In addition to efficacy data, treatment decisions should also be based on considerations of drug toxicity, patient acceptability and cost.)

    • Fluvoxamine versus other anti-depressive agents for depression (2013) (We found no strong evidence that fluvoxamine was either superior or inferior to any other antidepressants in terms of efficacy and tolerability in the acute phase treatment of depression. However, differing side effect profiles were evident.)

    • Citalopram versus other antidepressants for depression (2012) (Thirty-seven randomised controlled trials (more than 6000 participants) were included in the present review. In terms of efficacy, citalopram was more efficacious than other reference compounds like paroxetine or reboxetine, but worse than escitalopram. In terms of side effects, citalopram was more acceptable than older antidepressants, like tricyclics. As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings. Economic analyses were not reported in the included studies, however, cost effectiveness information is needed in the field of antidepressant trials.)

    • Amitriptyline for the treatment of depression (2012) (Amitriptyline is a tricyclic antidepressant drug that has been used for decades in the treatment of depression. The current review includes 39 trials with a total of 3509 participants and confirms its efficacy compared to placebo or no treatment. This finding is important, because the efficacy of antidepressants has recently been questioned. However, the review also demonstrated that amitriptyline produces a number of side effects such as vision problems, constipation and sedation.)

    • Duloxetine versus other antidepressive agents for depression (2012) (In the present review we assessed the evidence for the efficacy, acceptability and tolerability of duloxetine in comparison with all other antidepressants in the acute-phase treatment of major depression. Sixteen randomised controlled trials (5735 participants) were included. Duloxetine was not more effective than some other new antidepressant agents in the acute-phase treatment of major depression, and it was less well tolerated than escitalopram and venlafaxine as more patients allocated to duloxetine withdrew treatment before study end. However, due to the limited number of studies per comparison these results should be interpreted with caution.)

    • Psychological and pharmacological interventions for depression in patients with diabetes mellitus (2012) (This review examined clinical trials on psychological treatments and antidepressant drugs in depressed patients with diabetes. The objective was to determine the effects of these treatments on depression, blood sugar, adherence to diabetic treatment regimens, diabetes complications, death from any cause, healthcare costs and health-related quality of life. Nineteen trials with 1592 participants were identified as relevant for the review. Eight trials with 1122 participants investigated psychological treatments versus usual care (duration of therapy three weeks to 12 months, follow-up after treatment zero to six months). Eight trials with 377 participants examined antidepressant drugs versus placebo (duration of intervention three weeks to six months, no follow-up after treatment). Three trials with 93 participants compared the effects of two different antidepressant medications (duration of intervention 12 weeks, no follow-up after treatment). In summary, psychological treatments and antidepressant drugs have a moderate, yet positive, effect on depression outcomes in diabetes patients. Antidepressant drugs have a positive effect on blood glucose, whereas effects on blood glucose are inconclusive for psychological treatments. Patient-rated quality of life did not benefit from psychological or antidepressant drug treatments. Healthcare costs, death from any cause and diabetes complications have not been examined sufficiently. Serious or severe adverse effects were either rare (pharmacological treatments) or not reported (psychological treatments). )

    • Mirtazapine versus other antidepressive agents for depression (2011) (The evidence from this review, which included findings from 29 randomised controlled trials (4974 participants in total), suggests that mirtazapine is likely to have a faster onset of action than the most frequently used type of antidepressants, which are the selective serotonin reuptake inhibitors (SSRIs). It would appear that mirtazapine is superior to SSRIs at the end of treatment over 6 to 12 weeks. Mirtazapine causes adverse events that lead to a similar frequency of dropouts as SSRIs and tricyclic antidepressants, although adverse event profile of mirtazapine is unique. Mirtazapine is likely to cause weight gain or increased appetite and somnolence but is less likely to cause nausea or vomiting and sexual dysfunction than SSRIs.)

    • Sertraline versus other antidepressive agents for depression (2010) ( In the present review we assessed the evidence for the efficacy, acceptability and tolerability of sertraline in comparison with all other antidepressants in the acute-phase treatment of major depression. Fifty-nine randomised controlled trials (about 10,000 participants) were included in the review. The review showed evidence of differences in efficacy, acceptability and tolerability between sertraline and other antidepressants, with meta-analyses highlighting a trend in favour of sertraline over other antidepressants, both in terms of efficacy and acceptability, in a homogeneous sample of clinical trials, using conservative statistical methods. The included studies did not report on all the outcomes that were pre-specified in the protocol of this review. Outcomes of clear relevance to patients and clinicians, in particular, patients and their carers' attitudes to treatment, their ability to return to work and resume normal social functioning, were not reported in the included studies.)

    • Antidepressants for depression in physically ill people (2010) (We extracted information on fifty-one studies in the review. Our results found that antidepressants are better than a placebo (inactive) drug in treating depression in physically ill people. Both the two main classes of antidepressant, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), were shown to be more effective than a placebo. Antidepressants improved depressive symptoms within 4-5 weeks of treatment, and this benefit persisted after 18 weeks. However, patients taking an antidepressant were more likely to experience sexual dysfunction and dry mouth, and were more likely to stop taking their medication after 6-8 weeks of treatment. There are no grounds to recommend one antidepressant over another on the basis of this review. We conclude that antidepressants appear to be useful in treating depression and should be considered for physically ill patients. )

    • Amitriptyline for depression (2009) (This present systematic review indicates that amitriptyline is at least as efficacious as other tricyclics or newer compounds. However, the burden of side-effects in patients receiving it was greater. In comparison with selective serotonin reuptake inhibitors amitriptyline was less well tolerated, and although counterbalanced by a higher proportion of responders, the difference was not statistically significant. )

    • Antidepressants plus benzodiazepines for major depression (2009) (The reviewers report that a combination of benzodiazepines with antidepressants works in favour for the treatment of depression, because it decreases drop outs from treatment and it increases short-term response up to four weeks. However, there are downsides to this combination therapy because benzodiazepines can induce dependence, which is estimated to occur in one third of patients, as well as a decline in the drug's effect over time. Benzodiazepines have been associated with an increase in accident proneness.)

    • Antidepressants for depressed older people (2009) (This review compared the efficacy, withdrawal rates and side effects of different antidepressant classes in the treatment of depression in older people. Thirty-two studies provided data for the review. Our main findings indicate that tricyclic antidepressants (classical and tricyclic related) and selective serotonin reuptake inhibitors (SSRIs) are equally efficacious. However, when comparing the two tricyclic groups with SSRIs we found that tricyclic related antidepressants were similar to SSRIs in terms of overall withdrawal rate, and classical tricyclic antidepressants were associated with a higher withdrawal rate due to side effects. These findings are reflected in the differing side effect profiles when comparing both tricyclic groups with SSRIs. The findings of the review must be interpreted with some caution in view of the relatively low patient numbers and lack of side effect data.)

    • Escitalopram versus other antidepressive agents for depression (2009) (Twenty-two randomised controlled trials (about 4000 participants) were included in the present review. Escitalopram appears to be suitable as first-line antidepressant treatment for people with moderate to severe major depression. It has been compared with only a few other antidepressants and so we are unable to say whether it is better, worse or the same as many of the other drugs used in practice. However, it did perform better than citalopram when we brought together the results of six studies in nearly two thousand patients)

    • Low dose tricyclic antidepressants (TCAs) for depression (2009) (This systematic review of 39 studies (2564 participants) found that tricyclic antidepressants between 75-100 mg/day and possibly below this range result in more reduction in depression than placebo. On the other hand, there was no strong evidence to show that standard dosage tricyclic brings about more response than low dosage tricyclic. The findings suggest that administration of low dosage tricyclic antidepressant is a defensible practice.)

    • Antidepressants compared with placebos for depressed older people (2009) (TCAs, SSRIs and MAOIs are effective in the treatment of older community patients and inpatients likely to have severe physical illness. At least six weeks of antidepressant treatment is recommended to achieve optimal therapeutic effect. There is little evidence concerning the efficacy of low dose TCA treatment. Further trials are required before low dose TCA treatment is routinely recommended.)

    • Antidepressants versus placebo for depression in primary care (2009) (We found 14 studies conducted in adults (not the elderly) in primary care setting, in which tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs) were compared against a placebo control group in the treatment of depression. The results showed that both TCAs and SSRIs were effective for depression. Most of the studies were supported by funds from pharmaceutical companies and were of short duration. There appeared to be more adverse effects with TCAs than with SSRIs, however rates of withdrawal from study medication due to adverse effects were very similar between the two antidepressant classes. Adverse effects not leading to medication cessation seemed to be more common with TCAs than SSRIs.)

    Some evidence of effectiveness:
    • Antidepressants for postnatal depression (2014) (We were able to combine data from three studies comparing a type of commonly used antidepressant called selective serotonin reuptake inhibitors (SSRIs) with placebo. The results showed that women with postnatal depression who were given SSRIs were more likely to improve or recover than those given placebo. We were unable to combine the data from studies comparing antidepressants with other treatments or treatment as usual due to the very small number of studies identified for these comparisons. There was insufficient evidence to conclude whether, and for whom, antidepressant or psychosocial/psychological treatments are more effective, or whether some antidepressants are more effective or better tolerated (or both) than others. Conclusions were also limited by the lack of data on long-term follow-up, the safety of breastfeeding or child outcomes.)

    • Interventions to help depressed people resume work (2014) (We evaluated the effectiveness of interventions that can help depressed workers to resume work activities. In three studies with 251 participants, researchers looked at changes at work such as work modification or coaching in addition to regular care and found that these reduced sickness absence to a moderate extent. In three studies with 326 participants, researchers found that cognitive behavioural therapy that was provided online or by telephone reduced sickness absence to a moderate extent compared to regular care. Three studies compared antidepressant pills with each other but there were no consistent effects on sickness absence. One study found that participants had a reduction in sick leave after doing stretching exercises. Two other studies did not find an effect on sick leave after physical exercises such as running or using the gymnasium. A structured telephone outreach and care management program that included medication reduced sickness absence compared to usual care.)

    • Pharmacological treatment for psychotic depression (2013) (We found only 12 randomised controlled trials (RCTs) that met our inclusion criteria. These trials involved a total of 929 people. From these trials, we found evidence that the combination of an antidepressant plus an antipsychotic provides more effective treatment for psychotic depression than either treatment alone. However, our confidence in this conclusion is limited because the information came from only a small number of RCTs, which included small numbers of people.)

    • Treatments for preventing the recurrence of depression in children and adolescents (2013) (Currently, there is little evidence to conclude which type of treatment approach is most effective in preventing relapse or recurrence of depressive episodes in children and adolescents. Limited trials found that antidepressant medication reduces the chance of relapse-recurrence in the future, however, there is considerable diversity in the design of trials, making it difficult to compare outcomes across studies. Some of the research involving psychological therapies is encouraging, however at present more trials with larger sample sizes need to be conducted in order to explore this treatment approach further.)

    • Exercise for depression (2013) (Exercise is moderately more effective than a control intervention for reducing symptoms of depression, but analysis of methodologically robust trials only shows a smaller effect in favour of exercise. When compared to psychological or pharmacological therapies, exercise appears to be no more effective, though this conclusion is based on a few small trials.)

    • Behavioural therapies versus other psychological therapies for depression (2013) (We found low- to moderate-quality evidence that behavioural therapies and other psychological therapies are equally effective. The current evidence base that evaluates the relative benefits and harms of behavioural therapies is very weak. This limits our confidence in both the size of the effect and its precision for our key outcomes related to response and withdrawal. Studies recruiting larger samples with improved reporting of design and fidelity to treatment would improve the quality of evidence in this review.)

    • Alprazolam for depression (2012) (Alprazolam appears to reduce depressive symptoms more effectively than placebo and as effectively as tricyclic antidepressants. However, the studies included in the review were heterogeneous, of poor quality and only addressed short-term effects, thus limiting our confidence in the findings. Whilst the rate of all-cause withdrawals did not appear to differ between alprazolam and placebo, and withdrawals were less frequent in the alprazolam group than in any of the conventional antidepressants combined group, these findings should be interpreted with caution, given the dependency properties of benzodiazepines.)

    • Newer antidepressants for depression in children and adolescents (2012) (Depression is common in young people and can contribute to a variety of negative outcomes, such as poor academic functioning, difficulties in peer and family relationships, increases in substance use, and both attempted and completed suicide. This review contained 19 trials (with a total of 3353 participants) testing the effectiveness of newer generation antidepressants (these are antidepressants developed and used since tricyclic antidepressants were developed). Based on 14 of the trials (2490 participants in total), there was evidence that those treated with an antidepressant had lower depression severity scores than those on placebo, however, the size of this difference was small. Based on 17 trials (3229 participants in total), there was evidence of an increased risk (64%) of suicide-related outcomes for those on antidepressants compared with those given placebo. Where rates of adverse events were reported, this was higher for those prescribed an antidepressant. There was no evidence that one particular type of newer generation antidepressant had a larger effect than the others when compared to placebo. It is unclear how meaningful the results regarding the effectiveness of these medications are in terms of a young person's day-to-day functioning. Children and adolescents with other conditions (such as anxiety, substance use disorder or a conduct disorder) as well as depression, and those at risk of suicide, were often excluded from trials. However, these young people are more representative of the population who present to clinical services, therefore it is not possible to predict how they would respond to antidepressants. There was often insufficient information to judge the quality of the trials accurately. With these limitations, it is difficult to answer questions about the effectiveness and safety of antidepressants for treating depression in children and adolescents. Clinicians need to provide accurate information to children and adolescents, and their families, about the uncertainties regarding the benefits and risks of newer generation antidepressant medication as a treatment option for depression. If a decision to use medication is agreed then fluoxetine might be the medication of first choice given guideline recommendations and, if used, the risk of suicide should be assessed and monitored particularly closely.)

    • Collaborative care for people with depression and anxiety (2012) ("Collaborative care" is an innovative way of treating depression and anxiety. It involves a number of health professionals working with a patient to help them overcome their problems. Collaborative care often involves a medical doctor, a case manager (with training in depression and anxiety), and a mental health specialist such as a psychiatrist. The case manager has regular contact with the person and organises care, together with the medical doctor and specialist. The case manager may offer help with medication, or access to a "talking therapy" to help the patient get better. In this review we found 79 randomised controlled trials (RCTs) (90 comparisons) including 24,308 patients worldwide, comparing collaborative care with routine care or alternative treatments (such as consultation-liaison) for depression and anxiety. There were problems with the methods in some of the studies. For example, the methods used to allocate patients to collaborative care or routine care were not always free from bias, and many patients did not complete follow-up or provide information about their outcomes. Most of the studies focused on depression and the evidence suggests that collaborative care is better than routine care in improving depression for up to two years. A smaller number of studies examined the effect of collaborative care on anxiety and the evidence suggests that collaborative care is also better than usual care in improving anxiety for up to two years. Collaborative care increases the number of patients using medication in line with current guidance, and can improve mental health related quality of life. Patients with depression and anxiety treated with collaborative care are also more satisfied with their treatment.)

    • Tricyclic antidepressants compared with active placebos for depression (2012) (This review examined trials which compared antidepressants with 'active' placebos, that is placebos containing active substances which mimic side effects of antidepressants. Small differences were found in favour of antidepressants in terms of improvements in mood. This suggests that the effects of antidepressants may generally be overestimated and their placebo effects may be underestimated.)

    • St. John's wort for treating depression (2009) (We have reviewed 29 studies in 5489 patients with depression that compared treatment with extracts of St. John's wort for 4 to 12 weeks with placebo treatment or standard antidepressants. The studies came from a variety of countries, tested several different St. John's wort extracts, and mostly included patients suffering from mild to moderately severe symptoms. Overall, the St. John's wort extracts tested in the trials were superior to placebo, similarly effective as standard antidepressants, and had fewer side effects than standard antidepressants. However, findings were more favourable to St. John's wort extracts in studies form German-speaking countries where these products have a long tradition and are often prescribed by physicians, while in studies from other countries St. John's wort extracts seemed less effective. This differences could be due to the inclusion of patients with slightly different types of depression, but it cannot be ruled out that some smaller studies from German-speaking countries were flawed and reported overoptimistic results.)

    • Psychostimulants for depression (2009) (This review evaluated the evidence from randomised controlled trials (RCTs) evaluating the effectiveness of psychostimulants (PS) in the treatment of depression. Twenty-four RCTs were identified, of which 14 had data for meta-analysis. Five drugs were evaluated, including dexamphetamine, methylphenidate, methylamphetamine, pemoline and modafinil. Modafinil was evaluated separately as its pharmacology differs from other PS. Three small trials of PS involving a total of 62 participants indicated that oral treatment with PS in the short term (up to four weeks) significantly reduced depressive symptoms when compared with placebo, however, the overall quality of the trials was poor, limiting confidence in the findings. Two trials involving 411 participants compared modafinil against placebo when combined with antidepressant treatment at 6-8 weeks, and showed a non-significant difference in reducing depression symptoms. One small trial of 50 participants compared oral modafinil against placebo after 12 weeks of treatment, and also showed a non-significant difference in reducing depression symptoms. No trials examined the longer-term effect of PS. Further well conducted trials with long term follow-up are required to find out which PS may be more effective in the treatment of depression, and whether PS are more effective in certain subgroups of depressed patients.)

    • Relaxation for depression (2009) (Many people with depression do not get treatment or delay getting treatment. One reason for this is that they do not like antidepressants. Another is the limited availability of specialized psychological treatments, such as cognitive-behavior therapy. Relaxation techniques are a simple psychological treatment that can be administered after brief training. The review of 15 trials found that it was better than no treatment or minimal treatment, but not as effective as psychological therapies like cognitive-behavior therapy. Relaxation techniques have potential as a simple first-line psychological treatment for depression. Those who do not respond within a set time could be offered more complex psychological treatment such as cognitive-behavior therapy.)

    • Tryptophan and 5-Hydroxytryptophan for depression (2009) (Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluate the efficacy and safety of 5-HTP and tryptophan before their widespread use can be recommended. The possible association between these substances and the potentially fatal Eosinophilia-Myalgia Syndrome has not been elucidated. Because alternative antidepressants exist which have been proven to be effective and safe the clinical usefulness of 5-HTP and tryptophan is limited at present.)

    • Psychotherapeutic treatments for older depressed people (2009) ( In this review we included seven small trials, involving a total of 153 participants, that examined psychotherapeutic treatments for depression in older people. Five trials compared a form of cognitive behavioural therapy (CBT) against control conditions, and the findings showed that CBT was more effective than control. Two individual trials compared CBT against psychodynamic therapy, with no significant difference in effectiveness indicated between the two approaches. If taken on their own merit, the findings do not provide strong support for psychotherapeutic treatments in the management of depression in older people.)

    • Light treatment for non-seasonal depression (2009) (For patients suffering from non-seasonal depression, light therapy offers modest though promising antidepressive efficacy, especially when administered during the first week of treatment, in the morning, and as an adjunctive treatment to sleep deprivation responders. Hypomania as a potential adverse effect needs to be considered. Due to limited data and heterogeneity of studies these results need to be interpreted with caution. )

    • Psychosocial and psychological interventions for postpartum depression (2009) (Postpartum depression affects approximately 13% of all new mothers. Many women desire to try treatment options other than medication. This review examined nine trials involving 956 women which studied either psychosocial (e.g., peer support, non-directive counselling) or psychological (e.g., cognitive behavioural therapy and interpersonal psychotherapy) treatments for postpartum depression. Although the methodological quality of the majority of trials was, in general, not strong, the meta-analysis results suggest that psychosocial and psychological interventions are an effective treatment option for women suffering from postpartum depression. The long-term effectiveness remains unclear.)

    • Lithium for maintenance treatment of mood disorders (2009) (This systematic review investigated the efficacy of lithium compared to that of placebo in the maintenance treament of mood disorders (unipolar and bipolar disorder). Nine randomised studies (reporting on 825 participants) were included in the review. Lithium was more effective than placebo in preventing relapse in mood disorder overall. Lithium was more effective than placebo in bipolar disorder, though estimates of the size of the effect varied between studies. In unipolar disorder, lithium appeared to be more effective than placebo but the evidence for this was less clear cut. Lithium should be considered for maintenance treatment in bipolar disorder and, although the evidence is less reliable, it may be considered as one of a range of treatments with possible benefit in preventing relapse in unipolar disorder. Caution should be exercised in abruptly stopping lithium therapy in patients who have been taking it successfully for some time, due to the high risk of relapse.)

    No evidence of effectiveness:
    • Antidepressants for people with epilepsy and depression (2014) (We found eight studies that included 471 patients with epilepsy treated with an antidepressant. Three were randomised controlled trials and five were non-randomised prospective cohort studies. Taking all the evidence into account, the review found that there is very limited evidence demonstrating a significant effect of antidepressants on depressive symptoms in epilepsy. There was limited information on the effect of antidepressants on seizure control, however in the studies reporting this outcome there did not appear to be any significant worsening of seizures.)

    • Psychotherapy for depression among cancer patients who are incurable (2013) (Evidence from RCTs of moderate quality suggest that psychotherapy is useful for treating depressive states in advanced cancer patients. However, no evidence supports the effectiveness of psychotherapy for patients with clinically diagnosed depression.)

    • Tricyclic drugs for depressed children and adolescents (2013) (Data suggest tricyclic drugs are not useful in treating depression in children. There is marginal evidence to support the use of tricyclic drugs in the treatment of depression in adolescents.)

    • Dietary supplements for preventing postnatal depression (2013) (There is insufficient evidence to conclude that selenium, DHA or EPA prevent postnatal depression. There is currently no evidence to recommend any other dietary supplement for prevention of postnatal depression.)

    • Second-generation antipsychotic drugs for major depressive disorder (2012) (This review found 28 studies on five second-generation antipsychotic drugs (amisulpride, aripiprazole, olanzapine, quetiapine and risperidone) comparing the effects of the drugs alone or adding them or placebo to antidepressants for major depressive disorder and dysthymia. There is evidence that amisulpride might lead to symptom reduction in dysthymia, while no important differences were seen for major depression. There is limited evidence that aripiprazole leads to symptom reduction when added to antidepressants. Olanzapine had no beneficial effects for treatment of depression when compared to antidepressants or compared to placebo but there was limited evidence for the benefits of olanzapine as additional treatment. Data on quetiapine indicated beneficial effects for quetiapine alone or as additional treatment when compared to placebo; data on quetiapine versus duloxetine did not show beneficial effects in terms of symptom reduction for either group, but quetiapine treatment was less well tolerated. The data, however, are very limited. Slight benefits of risperidone as additional treatment, in terms of symptom reduction, are also based on a rather small number of randomised participants. Generally, treatment with second-generation antipsychotic drugs was associated with worse tolerability, mainly due to sedation, weight gain or laboratory values such as prolactin increase.)

    • Drug treatment for depression in multiple sclerosis (2011) (Many patients with multiple sclerosis (MS) suffer from depression. In this review we summarized studies of antidepressant drug treatments in patients with MS. We found two studies that met the inclusion criteria of methodological quality, comprising of a total of 70 participants: one (28 participants) reported the effects of desipramine, the other (42 participants) the effects of paroxetine. The two studies showed no improvement of depression with both treatments in the short term (five/twelve weeks). Adverse effects, such as nausea or headache occurred frequently. Further studies on drug treatment of depression in MS with a longer duration are clearly needed, as the results may be affected by the small size of participants and by the fact that many participants did not complete the studies.)

    • Acupuncture for depression (2010) (We found insufficient evidence to recommend the use of acupuncture for people with depression. The results are limited by the high risk of bias in the majority of trials meeting inclusion criteria.)

    • Screening and case finding instruments for depression (2009) (The use of depression screening or case finding instruments has little or no impact on the recognition, management or outcome of depression in primary care or the general hospital.)

    • Transcranial magnetic stimulation (TMS) for depression (2009) (There is no strong evidence for benefit from using transcranial magnetic stimulation to treat depression, although the small sample sizes do not exclude the possibility of benefit. )

    Not yet possible to draw any definite conclusions due to insufficient evidence:
    • Is dance movement therapy an effective treatment for depression? A review of the evidence (2015) (The low-quality evidence from three small trials with 147 participants does not allow any firm conclusions to be drawn regarding the effectiveness of DMT for depression. Larger trials of high methodological quality are needed to assess DMT for depression, with economic analyses and acceptability measures and for all age groups.)

    • Alternating current cranial electrotherapy stimulation in the treatment of depression (2014) (Cranial electrotherapy stimulation (CES) has been proposed as an alternative treatment for symptoms of depression. CES is a treatment in which a low intensity electrical current is administered to the head through the use of a small, portable electrical device. A sample treatment regimen might consist of daily application of the device for 30 minutes for a month, but treatment instructions vary with the device and condition being treated. In the United States CES devices require a prescription. In most other countries, marketing of CES devices is approved for stress reduction but not specific medical conditions such as depression. We found no high quality clinical trials comparing CES with sham CES in people with acute depression. Currently, there is insufficient evidence to support the use of CES in treatment of acute depression. )

    • Agomelatine versus other antidepressant medication for depression (2013) (The overall methodological quality of the studies was low, and, therefore, no firm conclusions can be drawn concerning the efficacy and tolerability of agomelatine.)

    • Long term treatment for depression in older people (2012) (This systematic review evaluated the efficacy and acceptability of antidepressant drugs, psychological therapies (talking treatments) and combinations of these treatments in preventing the recurrence of depression in people aged 60 and over who had recovered from depression while taking antidepressant medication. Remaining on antidepressant drugs for one year appears to reduce the risk of depression returning from 61% to 42% but the benefits at other time intervals could not be determined. Antidepressant treatment appeared to be as well tolerated as placebo treatment. The benefits of psychological therapies were not clear, due to the small number of research studies. This review cannot be used to make firm recommendations on the optimal long-term treatment of depression in older people due to the limited number and small size of research studies involved.)

    • Second-generation antidepressants for winter depression (2011) (Evidence for the effectiveness of second generation antidepressants (SGAs) is limited to one small trial of fluoxetine compared with placebo, which shows a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy, which suggest equivalence between the two interventions. The lack of available evidence precludes the ability to draw any overall conclusions on the use of SGAs for winter depression.)

    • Psychosocial and psychological interventions for treating antenatal depression (2010) (Although for many women pregnancy was once thought of as a time of emotional wellbeing, approximately 12% of women will suffer from antenatal depression. Research suggests that women who are on low-income, lack social support, experience significant stress or negative life events, and have poor relationships may be at higher risk of developing antenatal depression. Unfortunately, depression during the pregnancy is related to poor maternal self-care behaviours, which may influence the baby's health, and it places a woman at significant risk of developing postpartum depression. Many women are unwilling to take medication during their pregnancy and are often interested in psychosocial and psychological interventions as a form of treatment. The review found only one trial involving 50 US women evaluating interpersonal psychotherapy for the treatment of antenatal depression. This trial provided insufficient evidence to determine if psychological therapies are effective treatment for antenatal depression. Further research is needed.)

    • Inositol for depression (2009) (Inositol is a nutritional supplement that has been suggested as a treatment for depressive disorders. The reviewers found the current evidence is unclear whether or not inositol is of benefit in the treatment of depression.)

    • Folate for depression (2009) (This systematic review was undertaken to see if giving folate to people with depressive disorders reduced their depressive symptoms. Three randomized trials were identified, involving a total of 247 people. In all three trials, folate was well tolerated. In two of these trials, folate was added to other antidepressant drug treatment and there was limited evidence that folate helped. In the third trial, folate was compared to trazodone, an antidepressant drug. No difference was found. There is therefore limited evidence that adding folate to other antidepressant may be helpful, but larger trials are needed before patients and clinicians can be confident that it will be helpful. )

    • The involvement of paraprofessionals for anxiety and depressive disorders (2009) (The few studies included in the review did not allow conclusions about the effect of paraprofessionals compared to professionals, but three studies (women only) indicated a significant effect for paraprofessionals (all volunteers) compared to no treatment. The evidence to date may justify the development and evaluation of programs incorporating paraprofessionals in treatment programs for anxiety and depressive disorders.)

    • Music therapy for depression (2009) (Findings from individual randomised trials suggest that music therapy is accepted by people with depression and is associated with improvements in mood. However, the small number and low methodological quality of studies mean that it is not possible to be confident about its effectiveness. High quality trials evaluating the effects of music therapy on depression are required.)

    • Family therapy for depression (2009) (The current evidence base is too heterogeneous and sparse to draw conclusions on the overall effectiveness of family therapy in the treatment of depression. At this point, use of psychological interventions for the treatment of depression for which there is already an evidence-base would seem to be preferable to family therapy. Further high quality trials examining the effectiveness and comparative effectiveness of explicitly defined forms of family therapy are required. )

    • Marital therapy for depression (2009) (There is no evidence to suggest that marital therapy is more or less effective than individual psychotherapy or drug therapy in the treatment of depression. Improvement of relations in distressed couples might be expected from marital therapy. Future trials should test whether marital therapy is superior to other interventions for distressed couples with a depressed partner, especially considering the role of potential effect moderators in the improvement of depression. )

    • Antidepressant prevention of postnatal depression (2009) (Only two small trials met the criteria for inclusion. Both trials used medication immediately postpartum. The drugs were nortriptyline, a tricylic antidepressant (TCA) and sertraline, a selective serotonin reuptake inhibitor (SSRI). Both drugs were compared only to placebo. Nortripyline was not shown to have any benefit over placebo; there was some evidence that sertraline was effective both in reducing the incidence of recurrent postpartum depression and in increasing the time to recurrence. However, both trials involved only very small numbers of women and did not use intention to treat analyses. There is, therefore, no clear evidence for the use of these antidepressants in the prevention of postnatal depression.)

    • Milnacipran versus other antidepressive agents for depression (2009) (A total of 16 randomised controlled trials (2277 participants) were included in this review. Currently, there is inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events (acceptability) and the rates of experiencing adverse events (tolerability). Information about other clinically meaningful outcomes such as cost-effectiveness and social functioning, including the ability to return to work, is lacking. Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression.)

    • Electroconvulsive therapy (ECT) for depression in elderly people (2009) (This review involved searching the literature for well-conducted (randomised) studies that compared ECT to both simulated ECT and to antidepressants. The review found only four studies, all of which had serious problems in their methods. At present, therefore, it is not possible to draw firm conclusions on whether ECT is more effective than antidepressants,.or on the safety or side effects of ECT in elderly people with depression.)

    • Anti-depressant therapies may be able to help relieve depression in people with Parkinson's disease but more research is needed on safety and effectiveness. (2009) (Insufficient data on the effectiveness and safety of any antidepressants therapies in Parkinson's disease are available on which to make recommendations for their use. Further large scale randomised controlled trials are urgently required in this area.)

    Note: The Cochrane Reviews are the best in psychiatry, but they do not cover all psychiatric topics. Thus it is essential that you also read the following Research Review Articles.

    Review Articles On The Effectiveness Of Therapy

    2012 Review Articles

    Physical Treatments:

    Pharmaceutical Treatments:

    Psychological Treatments:

    Social Treatments:

    Delivery Of Care Issues:

    Diagnostic/Prognostic Issues :

    2011 Review Articles

    Physical Treatments:

    Pharmaceutical Treatments:

    • Solving the antidepressant efficacy question: effect sizes in major depressive disorder. - Relative antidepressant versus placebo benefit increased linearly from 5% in mild depression to 12% in moderate depression to 16% in severe depression. Thus antidepressants are effective in acute depressive episodes that are moderate to severe, but are not effective in mild depression. These considerations only apply to acute depression, however. For maintenance, the long-term efficacy of antidepressants is unproven, but research shows they are not harmful.
        [ Editor: The finding that antidepressant medications are only 12% more effective than placebo for moderate depression is very important (and humbling). The remission rate for antidepressant treatment of moderate depression is 52%; whereas on active placebo the remission rate is 40%. Obviously we should study what makes this (active) placebo effect of seeing a physician so effective, in that this placebo effect causes three-quarters of the remission.]

    • Second-generation antidepressants for seasonal affective disorder. - No conclusive evidence.

    • Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. - All second-generation antidepressants are equally effective.

    • Four potential criteria for deciding when to use antidepressants or psychotherapy for unipolar depression: a literature review. - Antidepressants, rather than psychotherapy, should be used when the patient has a family history of depression, and when the depression has melancholic features. The presence of personality disorder or other demographic information doesn't predict whether to use psychotherapy rather than pharmacotherapy.

    • What do the terms "drug-specific response/remission rate" and "placebo" really mean? - Placebo is frequently misrepresented by the media as representing nothing. In fact, placebo represents everything except the investigational treatment. That is an important distinction. The second is the concept of the drug-specific response/remission rate. While manufacturers frequently cite the overall response/remission rate observed in the group treated with their drug in their clinical trials, that is not the true rate specifically attributable to the drug. Instead, it represents the combined rate due to both the drug and the non-drug (or "placebo") therapeutic aspects of the trial. To determine the drug-specific response/remission rate, the placebo response/remission rate must be subtracted from the overall response/remission rate observed in the drug treated group. That is because the drug treated group receives both the therapeutic benefit of the drug and all of the nondrug therapeutic benefit of the trial (i.e., the "placebo" condition). Viewed from this perspective, only about one out of four patients with major depression responds specifically to either selective serotonin or serotonin-norepinephrine reuptake inhibitors. These principles are important if one is to put the recent controversy about the effectiveness of modern antidepressant treatment into perspective. The critical issue is not how good the drugs are but rather how serious our diseases are. When evaluating the current antidepressants, the principal issue is not how many patients with major depression they treat but instead how well they treat the patients they do treat. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study has clearly documented that approximately 40% of patients with major depression do not respond to existing antidepressants. That finding is consistent with the concept that there are likely many forms of depressive illness, only a fraction of which are responsive to drugs that work via effects on biogenic amines.

    • The impact of psychotherapy, pharmacotherapy, and their combination on quality of life in depression. - Significant improvements in depressive symptomatology and Quality of life (QOL) measurements were found with pharmacotherapy, psychotherapy, and their combination, with some studies showing greater improvement following combined treatment than with either intervention alone.

    • The small specific effects of antidepressants in clinical trials: what do they mean to psychiatrists? - Antidepressants have relatively modest effects (as compared with placebo). The contribution of placebo-expectancy factors to individual outcomes is often underestimated.

    • Agomelatine for the treatment of major depressive disorder. - Agomelatine (Valdoxan/Thymanax), is a melatonin (MT1/MT2) agonist and serotonin (5-HT2c) receptor antagonist. Agomelatine produces strong effects on circadian sleep phase disturbances, improving time to sleep onset and quality of sleep. It has been shown to be superior to placebo and similar to existing antidepressants. However, 3 - 4.5% of patients treated with 50 mg/day showed elevated transaminases. Although none of these reactions so far seem to have been serious, the adverse effects in the liver may present a regulatory and marketing challenge.

    • Pharmacotherapy in depressed children and adolescents. - In the treatment of mild and moderate depressive symptoms, non-pharmacological approaches such as psychotherapy play a major role, a severe symptomatology may demand a combination with antidepressants. As first-choice medication for the treatment of juvenile depression, the selective serotonin reuptake inhibitor (SSRI) fluoxetine is recommended, due to its efficacy and approval. As second-choice antidepressants the SSRIs sertraline, escitalopram and citalopram might be used. Other antidepressants - such as tricyclic antidepressants, ?(2)-adrenoceptor antagonists, selective noradrenalin reuptake inhibitors (SNRI) - may be alternatively used, but not as first- or second-choice medications.

    • Escitalopram for the treatment of major depressive disorder in youth. - The efficacy of escitalopram in adolescent major depressive disorder was demonstrated in a double-blind, randomized, controlled trial. The optimal dose is 10 mg/day and the magnitude of the antidepressant effect is modest. Escitalopram treatment is generally well tolerated by adolescents, but treatment-emergent agitation, suicidal behavior and manic symptoms should be closely monitored.

    • A guide to the treatment of depression in women by estrogens. - Transdermal estrogens in the appropriate dose will suppress ovulation and suppress the cyclical hormonal changes that produce premenstrual depression. Estrogens also have a mood-enhancing effect in postnatal depression and the depression in the transitional phase of the menopause. It is possible to add transdermal testosterone which will improve mood, energy and libido. The problem is the progestogen as these women are often progestogen-intolerant. Progestogen should be used in the lowest dose and for the shortest duration necessary to prevent endometrial hyperplasia or the return of premenstrual syndrome-type symptoms if the women are progestogen-intolerant. The use of estrogens for depression in these women does not exclude the use of antidepressants. Hormone-responsive depression cannot be diagnosed by measuring hormone levels but can only be diagnosed by a careful history relating depression to the menstrual cycle, pregnancies and the perimenopausal years.

    • Quetiapine extended release: adjunctive treatment in major depressive disorder. - Quetiapine extended release (XR) is a once-daily oral formulation of the atypical antipsychotic quetiapine that is available for use as adjunctive therapy in major depressive disorder (MDD). The numbers needed to treat to achieve an additional response over antidepressant plus placebo were 11-18 and 8-9 in the quetiapine XR 150 and 300?mg/day dosage groups, respectively. Treatment-emergent adverse events were mostly of mild to moderate severity; 1% of adjunctive quetiapine XR and 1.3% of antidepressant plus placebo recipients reported serious adverse events.
        [ Editor: In mental health, a number needed to treat (NNT) above 8 is considered clinically insignificant. Thus this medication's NNT of 8-9 for 300 mg/day to produce a response would mean that it's antidepressant effect was on the border of clinical insignificance.]

    • Agomelatine: a narrative review. - Agomelatine, a melatonergic receptor agonist (MT(1)/MT(2)) and 5HT(2C) receptor antagonist. It is efficacious in both the acute phase and the continuation phase of treatment of depression and anxiety symptoms associated with major depression. It has comparable efficacy with other antidepressants. It has a low incidence of treatment emergent sexual dysfunction and weight gain. Transient aminotransferase elevations without clinical signs of liver damage have been observed more frequently than with placebo (1.1% versus 0.7%), and a hepatic monitoring schedule is therefore recommended.

    • A benefit-risk assessment of agomelatine in the treatment of major depression. - Six European trials demonstrated a small, statistically significant, marginally clinically relevant difference in efficacy favouring agomelatine over placebo. The only placebo-controlled study in elderly patients did not demonstrate a significant benefit for agomelatine. Because elevated liver enzymes are common, and there is a rare risk of more serious liver reactions, routine laboratory monitoring of liver function is recommended. Agomelatine does not have clinically significant advantages compared with other antidepressant drugs. It should only be considered as an alternative drug for patients who do not respond to or cannot tolerate other antidepressant drugs.

    • Novel melatonin-based therapies: potential advances in the treatment of major depression. - In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23-9%) than do those receiving placebo (50-0.
        [ Editor: This article conveniently failed to mention that agomelatine increases liver enzymes, and there is a rare risk of more serious liver reactions.]

    • Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. - Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimer's disease should be reconsidered.

    • Vilazodone for the treatment of depression. - Vilazodone is a new agent recently approved by the FDA for treating major depressive disorder. Response rates seen with vilazodone are similar to those of currently available antidepressants.

    • Herbal medicine for depression, anxiety and insomnia: a review of psychopharmacology and clinical evidence. - Controlled studies have shown efficacy for Hypericum perforatum for major depression, and Piper methysticum for anxiety disorders. However, these studies' effect sizes were not reported. Many of these studies have not been replicated.

    • Therapeutic options in treatment-resistant depression. - Treatment-resistant depression responds to antidepressant medication combined with lithium, atypical antipsychotics or electroconvulsive therapy (ECT). The use of cognitive behavior therapy is recommended for unipolar treatment-resistant depression (TRD), but there is no evidence supporting its use in bipolar TRD.

    • A critical review of pharmacotherapy for major depressive disorder. - No single antidepressant drug from any class has distinguished itself as the obvious first-line treatment of major depression.

    • Therapy for prevention of post-stroke depression. - Depression is the most common psychiatric disorder after stroke that adversely affects stroke outcomes. Antidepressants and psychological therapies may be effective and safe in preventing post-stroke depression.

    • Genome-wide association studies of antidepressant outcome: a brief review. - None of the studies reported results that achieved genome-wide significance, suggesting that larger samples and better outcome measures will be needed.

    • Safety considerations in drug treatment of depression in HIV-positive patients: an updated review. - HIV patients respond to antidepressant treatment like the general population, and medication adverse effects and patient adherence are the best predictors of treatment outcome.

    • A systematic review of treatments for refractory depression in older people. - Half of the participants responded to pharmacological treatments, indicating the importance of managing treatment-refractory depression actively in older people. The only treatment for which there was replicated evidence was lithium augmentation. The authors found no double-blind randomized placebo-controlled trials of treatments for refractory depression in older people.

    • Specificity profile of paroxetine in major depressive disorder: meta-regression of double-blind, randomized clinical trials. - Paroxetine was significantly characterized by better response in females and in Caucasians, whilst for patients who have been ill for a longer time before treatment, the smaller was the antidepressant effect.
        [ Editor: I find it incredible that these authors failed to mention that paroxetine has severe withdrawal symptoms on sudden termination.]

    • Complementary and alternative medicine for the treatment of major depressive disorder. - St John's wort and regular exercise appear effective in the treatment of depression (Editor: but their effect size is small). Acupuncture appears ineffective for depression.

    • Antidepressant combinations: widely used, but far from empirically validated. - The efficacy of even the most widely prescribed combinations of antidepressants has not been established by properly controlled, adequately powered, clinical trials.

    • Late-life depression: evidence-based treatment and promising new directions for research and clinical practice. - Although response and remission rates to pharmacotherapy and electroconvulsive therapy are comparable with those in midlife depression, relapse rates are higher.

    • Switch antidepressants: when? How? Why? - It is recommended to wait 4 to 8 weeks before changing treatment if the response is insufficient. However, an early switch is possible in case of non-response at 2-4 weeks. Direct switch is possible and well tolerated in most instances, except for situations implicating a monoamine oxidase inhibitor (MAOI) or a tricyclic antidepressant.

    • Maternal omega-3 fatty acid supplementation and risk for perinatal maternal depression. - No conclusive evidence.

    • Treatment-resistant depression: no panacea, many uncertainties. Adverse effects are a major factor in treatment choice. - At least 50% of patients with depression do not enter remission after several weeks of antidepressant therapy. Depression should only be considered drug-resistant after at least 6 weeks of therapy. Increasing the dose of the first-line antidepressant is only based on weak evidence. Trials comparing continuing the first-line antidepressant versus switching to another pharmacological class have yielded conflicting results. Combining two antidepressants mainly increases the risk of adverse effects, without a tangible clinical benefit. Two meta-analyses suggest that adding a so-called atypical neuroleptic to ongoing antidepressant therapy leads to 1 extra remission per 7 to 10 treated patients, but also to treatment cessation due to adverse effects in 8% to 9% of cases. Older neuroleptics have not been properly evaluated in this setting. There is no firm evidence that adding lithium increases the chances of remission. Adding an antiepileptic or a psychostimulant is more harmful than beneficial. Adding a thyroid hormone, a benzodiazepine, buspirone or pindolol has no proven antidepressive effect. There is no firm evidence that adding psychotherapy increases the chances of remission. Electroconvulsive therapy is probably effective for some patients with refractory depression but it necessitates general anaesthesia and carries a risk of memory disorders. Vagal nerve electrostimulation has no proven efficacy. Transcranial magnetic stimulation seems to have some efficacy and few adverse effects.

    • Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects. - The hypothesized teratogenicity of SSRIs remains undemonstrated.

    • The role of the glutamatergic system in pathophysiology and pharmacotherapy for depression: preclinical and clinical data - Glutamate is the most important excitatory neurotransmitter in the central nervous system. Glia cells are crucial regulators of the glutamatergic metabolism. Several studies have reported a dysfunction or reduced number of glia cells in patients suffering from depression. This could result in hyperfunctioning of the glutamatergic system leading to a toxic accumulation of glutamate. Commonly used antidepressants influence the glutamate metabolism and antiglutamatergic substances [e. g., riluzol] and NMDA-receptor antagonists [e. g., ketamine] have shown antidepressant properties in mostly preclinical and some clinical trials.

    • Efficacy of antidepressants: a re-analysis and re-interpretation of the Kirsch data. - Recently there has been much debate on the true usefulness of antidepressant therapy especially after the publication of a meta-analysis by Kirsch et al. (PLoS Medicine 2008, 5, e45). It seems that the Kirsch et al.'s meta-analysis suffered from important flaws in the calculations; reporting of the results was selective and conclusions unjustified and overemphasized.

    • Herbal medicines, other than St. John's Wort, in the treatment of depression: a systematic review. - Saffron stigma was found to be significantly more effective than placebo and equally as efficacious as fluoxetine and imipramine. Saffron petal was significantly more effective than placebo and was found to be equally efficacious compared to fluoxetine and saffron stigma. Lavender was found to be less effective than imipramine, but the combination of lavender and imipramine was significantly more effective than imipramine alone. When compared to placebo, Echium was found to significantly decrease depression scores at week 4, but not week 6. Rhodiola was also found to significantly improve depressive symptoms when compared to placebo.
        [Editor: These studies fail to report the treatment effect sizes; thus these findings may be statistically significant, but not clinically significant.]

    • St. John's wort and S-adenosyl methionine as "natural" alternatives to conventional antidepressants in the era of the suicidality boxed warning: what is the evidence for clinically relevant benefit? - Evidence of effectiveness was conclusive for St. John's wort (SJW) as it appears to be useful for the short-term treatment of mild-to-moderate depressive illness in adults (with a median effect size of 0.48). In the few studies that included patients with severe symptoms, however, or which evaluated long-term maintenance of effect, SJW did not differentiate from placebo. Evidence of effectiveness is not conclusive for S-adenosyl methionine (SAM-e).

    • The development of evidence-based European guidelines on the management of depression in palliative cancer care. - This is the first comprehensive, evidence-based guideline on managing depression in palliative care.

    • Antidepressants for major depressive disorder in patients with a co-morbid axis-III disorder: a meta-analysis of patient characteristics and placebo response rates in randomized controlled trials. - Antidepressants are effective for major depressive disorder (MDD) in patients who present with co-morbid axis-III disorders and as effective (vs. placebo) in this population as they are in the general MDD population.

    • Efficacy of escitalopram compared to citalopram: a meta-analysis. - In this meta-analysis, the statistically significant superior efficacy of escitalopram compared to citalopram was shown to be clinically relevant, with a number-needed-to-treat (NNT) value of 5.7 (p<0.0001) for the difference in remission rates.

    • Aripiprazole as adjunctive therapy for patients with major depressive disorder: overview and implications of clinical trial data. - In November 2007, aripiprazole was approved by the US FDA as an adjunctive therapy to antidepressants for treating MDD. Aripiprazole was demonstrated to be safe and well tolerated, and showed a minimal trend for weight gain over the course of a 6-week treatment. The incidence of akathisia was higher than that reported in studies of patients with schizophrenia; however, most cases were mild to moderate and infrequently lead to discontinuation (5 patients out of 1090).

    • Placebo-controlled, antidepressant clinical trials cannot be shortened to less than 4 weeks' duration: a pooled analysis of randomized clinical trials employing a diagnostic odds ratio-based approach. - Four weeks is the minimum adequate length of a trial in order to reliably detect drug versus placebo differences.

    • Use of risperidone as augmentation treatment for major depressive disorder. - Use of risperidone as adjunctive therapy for treatment-resistant depression may improve rates of response and remission, but long-term effectiveness and safety cannot be determined at this time. Risperidone augmentation may be effective and safe when used at low doses (0.25 to 2 mg/day). The most common adverse effects associated with risperidone therapy were headache, dry mouth, and increased appetite.

    • If at first you don't succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. - In treatment-resistant depression, the strength of evidence supporting a trial of augmentation or a switch to a new agent is very similar, with remission rates between 25% and 50% in both cases. although it is true that adjunctive lithium and thyroid hormone have established efficacy, we can only be confident that this is true for use in combination with tricyclic antidepressants (TCAs), and the trials were done in less treatment-resistant patients than those who typically receive TCAs today. Of these two options, triiodothyronine augmentation seems to offer the best benefit/risk ratio for augmentation of modern antidepressants. After failure of a first-line selective serotonin reuptake inhibitor (SSRI), neither a switch within class nor a switch to a different class of antidepressant is unequivocally supported by the data, although switching from an SSRI to venlafaxine or mirtazapine may potentially offer greater benefits. Interestingly, switching from a newer antidepressant to a TCA after a poor response to the former is not supported by strong evidence. Of all strategies to augment response to new-generation antidepressants, quetiapine and aripiprazole are best supported by the evidence, although neither the cost effectiveness nor the longer-term benefit of these strategies has been established.

    • Time-lag bias in trials of pediatric antidepressants: a systematic review and meta-analysis. - There is an obvious publication bias; successful drug trials are reported one to two years more promptly than failed drug trials.

    • Second-generation antipsychotics in major depressive disorder: update and clinical perspective. - In major depressive disorder, second-generation antipsychotics (SGA) monotherapy or adjunctive therapy to conventional antidepressants showed rapid onset of antidepressant efficacy. Although maintenance data are limited, quetiapine monotherapy, risperidone adjunctive therapy, and amisulpride adjunctive therapy significantly delayed the time to relapse as compared with placebo. In general, extrapyramidal symptoms appeared to be low with SGAs, but a higher incidence of akathisia was observed with aripiprazole. An elevated risk of weight gain was observed with olanzapine-fluoxetine combination, risperidone, aripiprazole, and quetiapine compared with placebo.

    • Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: a meta-analytic review. - There is little difference in antidepressant responses in patients with bipolar vs. unipolar depression, but there is a substantial risk of mania and hypomania with bipolar depression.

    Psychological Treatments:

    Social Treatments:

    • Group treatment for postpartum depression: a systematic review. - Postpartum depression (PPD) is a serious public health problem affecting 10% to 15% of women during the first year after delivery with negative consequences for both mother and infant. Research shows that group treatment is effective in reducing PPD symptoms.

    • Is group psychotherapy effective in older adults with depression? A systematic review. - Group psychotherapy is an effective intervention in older adults with depression in comparison to waiting list controls, the overall effect size is very modest. The reported benefits of group intervention in comparison to other active interventions did not reach statistical significance. The benefits of group psychotherapy were maintained at follow-up.

    Delivery Of Care Issues:

    Diagnostic/Prognostic Issues:

    • Quality of life: the ultimate outcome measure of interventions in major depressive disorder. - Patients with major depressive disorder (MDD) have a significantly diminished quality-of-life (QOL) . Treatment for MDD has been shown to improve QOL in the acute treatment phase, but QOL remains low compared to healthy controls even when symptoms are in remission following treatment. Future treatment studies of MDD should track QOL as the ultimate outcome measure of treatment success.

    • Psychomotor retardation in depression: biological underpinnings, measurement, and treatment. - Manifestations of psychomotor retardation include slowed speech, decreased movement, and impaired cognitive function. It is common in patients with melancholic depression and those with psychotic features. Biological correlates may include abnormalities in the basal ganglia and dopaminergic pathways. Available evidence suggests that depressed patients with psychomotor retardation may respond well to electroconvulsive therapy (ECT). Current literature regarding antidepressants is inconclusive, though tricyclic antidepressants may be considered for treatment of patients with psychomotor retardation.

    • Postpartum depression: an essential overview for the practitioner. - Postpartum depression (PPD) may have a variety of etiologies, which include changing plasma levels of estrogen and progesterone, postpartum hypothyroidism, sleep deprivation, or difficult life circumstances. Standard treatments for PPD include psychotherapy and antidepressants. However, treatment of a thyroid condition or insomnia, or even regular exercise or massage may also be beneficial. PPD is underdiagnosed, therefore more screening is needed.

    • Pharmacogenetics of antidepressant response. - The small effect sizes of genetic variants and heterogeneity between studies have significantly hindered attempts to find robust genetic predictors of response to antidepressants.

    • Vascular depression: where do we go from here? - Vascular depression encompasses not only depression with small vessel disease of the brain, but also poststroke depression, and depression related to myocardial infarction. The treatment outcome and natural course of vascular depression have been much worse than that of the nonvascular depression. Poststroke antidepressant and psychoeducation therapy and vascular preventive interventions can probably improve outcome.

  • 2009 Review Articles

  • 2008 Review Articles

  • Cognitive-Behavioral Therapy (Placebo Controlled Trials)

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    Which Behavioral Dimensions Are Involved?

    Research has shown that there are 5 major dimensions (the "Big 5 Factors") of personality disorders and other mental disorders. There are two free online personality tests that assess your personality in terms of the "Big 5 dimensions of personality". Although not computerized online, the Big Five Inventory (BFI) is a 44-item test often used in personality research.

    This website uses these 5 major dimensions of human behavior to describe all mental disorders. (This website adds one more dimension, "Physical Health", but our discussion will focus on the first 5 major dimensions.)

    These major dimensions of human behavior seem to represent the major dimensions whereby our early evolutionary ancestors chose their hunting companions or spouse. To maximize their chance for survival, our ancestors wanted companions who were agreeable, conscientious, intelligent, sociable, emotionally stable, and physically healthy.

      Which Dimensions of Human Behavior are Impaired in Major Depressive Disorder?

      Agreeableness Antagonism       Agreeableness
      Conscientiousness Disinhibition       Disinhibition
      Intellect Decreased Intellect       Decreased Intellect
      Sociability (Extraversion) Detachment       Detachment
      Emotional Stability Negative Emotion       Negative Emotion

    The 5 Major Dimensions of Mental Illness

    The Big 5 Factors or dimensions of mental illness each has a healthy side and an unhealthy side. Thus the Big 5 Factors are: (1) Agreeableness vs. Antagonism, (2) Conscientiousness vs. Disinhibition, (3) Intellect vs. Decreased Intellect, (4) Sociability (Extraversion) vs. Detachment (Introversion), and (5) Emotional Stability vs. Negative Emotion.

    The problems that are diagnostic of this disorder are highlighted in   Pink  . Other problems that are often seen in this disorder are highlighted in   Yellow  .

    Treatment Goals for Individuals With Disinhibition

    Description: Conscientiousness is synonymous with being self-disciplined, industrious and orderly. The Conscientiousness dimension measures the behaviors that are central to the concept of SELF-CONTROL - organizing and controlling one's behavior in order to achieve one's goals. This involves traits like paying attention, controlling impulses, and delaying gratification. High conscientiousness is associated with better: longevity, health, school and job performance. (This dimension appears to measure the behaviors that differentiate behavioral order and inhibition from chaos and disinhibition.)
    Descriptors: Industrious, self-disciplined, rule-abiding, organized
    Language Characteristics: Many positive emotion words (e.g. happy, good), few negative emotion words (e.g. hate, bad), more perspective, careful to check that information is conveyed correctly, straight to the point, formal, few negations, few swear words, few references to friends, few disfluencies or filler words, many insight words, not impulsive.
    Research: Higher scores on Conscientiousness predict greater success in school and at work. *MRI research found that Conscientiousness was associated with increased volume in the lateral prefrontal cortex, a region involved in planning and the voluntary control of behavior.
    "I do a thorough job. I want everything to be 'just right'. I want every detail taken care of."
    "I am careful."
    "I am a reliable hard-worker."
    "I am organized. I follow a schedule and always know what I am doing."
    "I like order. I keep things tidy."
    "I see that rules are observed."
    "I do things efficiently. I get things done quickly."
    "I carry out my plans and finish what I start."
    "I am not easily distracted."
    Rigid Perfectionism
    "Even though it drives other people crazy, I insist on absolute perfection in everything I do."
    "I simply won't put up with things being out of their proper places."
    "People complain about my need to have everything all arranged."
    "People tell me that I focus too much on minor details."
    "I have a strict way of doing things."
    "I postpone decisions."
    Description: Disinhibition is synonymous with being distractible, impulsive and disorganized.
    Descriptors: Distractible, impulsive, irresponsible, disorganised, unreliable, careless, forgetful
    Language Characteristics: Few positive emotion words, many negative emotion words, less perspective, less careful, more vague, informal, many negations, many swear words, many references to friends (e.g. pal, buddy), many disfluencies or filler words, few insight words, impulsive.
    * Irresponsibility:
    "I've skipped town to avoid responsibilities."
    "I just skip appointments or meetings if I'm not in the mood."
    "I'm often pretty careless with my own and others' things."
    "Others see me as irresponsible."
    "I make promises that I don't really intend to keep."
    "I often forget to pay my bills."
    * Impulsivity:
    "I usually do things on impulse without thinking about what might happen as a result."
    "Even though I know better, I can't stop making rash decisions."
    "I feel like I act totally on impulse."
    "I'm not good at planning ahead."
    * Reckless Risk Taking:
    "I like to take risks."
    "I have no limits when it comes to doing dangerous things."
    "People would describe me as reckless."
    "I don't think about getting hurt when I'm doing things that might be dangerous."
    * Hyperactivity [In Agitated Depression]:
    "I move excessively (e.g., can't sit still; restless; always on the go)."
    "I'm starting lots more projects than usual or doing more risky things than usual."
    * Over-Talkativeness:
    "I talk excessively (e.g., I butt into conversations; I complete people's sentences)."
    "Often I talk constantly and cannot be interrupted."
    * Elation:
    "I feel very happy or exhilarated."
    "I'm feeling a rush of good feelings."
    ("Conscientiousness vs. Disinhibition" modified from "PID-5" by Kreuger RF, Derringer J, Markon KE, Watson D, Skodol AE and Between facets and domains: 10 aspects of the Big Five)
    *MRI Research: Testing predictions from personality neuroscience. Brain structure and the big five.

    Treatment Goals for Individuals With Decreased Intellect

    Description: Intellect (or "Openness To Experience") is one's capacity for thinking and acquiring knowledge. It is synonymous with being open-minded and creative. Open-minded individuals constantly ask "why" the world is as it is. Whereas closed-minded individuals just accept the world as it is without asking "why". The Intellect dimension measures the behaviors that are central to the concept of WISDOM - having curiosity, experience, knowledge, and good judgment. (This dimension appears to measure the behaviors that differentiate open-minded from close-minded individuals.) Open-minded people are usually creative, sophisticated, intellectual, curious and interested in art. Their curiosity propels them to try new things, and ask novel questions. High intellect is associated with better: longevity, school and creative performance.
    Descriptors: Receptive to new ideas, curious, imaginative, creative, unconventional
    Language Characteristics: Many positive emotion words (e.g. happy, good), high meaning elaboration, more perspective, politeness, few self-references, complex sentence constructions, few causation words, many inclusive words (e.g. with, and), few third person pronouns, many tentative words (e.g. maybe, guess), many insight words (e.g. think, see), few filler words and within-utterance pauses, stronger uncommon verbs.
    Research: Higher scores on Intellect are associated with greater creativity and general intelligence. *MRI research found that Intellect did not have any significant correlation with the volume of any localized brain structure.
    Relationship To General Intelligence: Research has shown that Intellect can be separated into 2 factors: Openness and Intellect. Intellect was independently associated with general intelligence (g) and with verbal and nonverbal intelligence about equally. Openness was independently associated only with verbal intelligence.
    Example: This video shows how we see what we want to see. What we pay attention to (or what we believe about the world) blinds us to reality. (Exit YouTube after first video.)
    "I am original, and come up with new ideas."
    "I am curious about many different things."
    "I am quick to understand things."
    "I can handle a lot of information."
    "I like to solve complex problems."
    "I have a rich vocabulary."
    "I think quickly and formulate ideas clearly."
    "I enjoy the beauty of nature."
    "I believe in the importance of art."
    "I love to reflect on things."
    "I get deeply immersed in music."
    "I see beauty in things that others might not notice."
    "I need a creative outlet."
    Description: Decreased Intellect (or "Closed To Experience") is synonymous with being closed-minded and uncreative. Closed-minded individuals just accept the world as it is without asking "why"; whereas open-minded individuals constantly ask "why" the world is as it is. Decreased Intellect is associated with narrow-mindedness, unimaginativeness and ignorance.
    Descriptors: Narrow-minded, conservative, ignorant, simple
    Language Characteristics: Few positive emotion words, low meaning elaboration, less perspective, less politeness, few positive emotion words, many self-references, simple sentence construction, many causation words (e.g. because, hence), many third person pronouns, few tentative words, few insight words, many filler words and within-utterance pauses, milder verbs.
    "I prefer work that is routine."
    "I have difficulty understanding abstract ideas."
    "I think slowly."
    "People find it hard to follow my logic or understand my thoughts."
    "I avoid philosophical discussions."
    "I avoid difficult reading material."
    "People find it hard to follow my logic or understand my thoughts."
    "I have few artistic interests."
    "I seldom notice the emotional aspects of paintings and pictures."
    "I do not like poetry."
    "I seldom get lost in thought."
    "I seldom daydream."
    * Distractibility:
    "I can't focus on things for very long."
    "I am easily distracted."
    "I have trouble pursuing specific goals even for short periods of time."
    "I can't achieve goals because other things capture my attention."
    "I often make mistakes because I don't pay close attention."
    "I waste my time ."
    "I find it difficult to get down to work."
    "I mess things up."
    "I don't put my mind on the task at hand."
    * Memory Impairment:
    "I have difficulty learning new things, or remembering things that happened a few days ago."
    "I often forget a conversation I had the day before."
    "I often forget to take my medications, or to keep my appointments."
    * Impaired Reasoning:
    "My judgment or ability to solve problems isn't good."
    "I have difficulty understanding abstract ideas."
    "I think slowly."
    "People find it hard to follow my logic or understand my thoughts."
    Description: Psychoticism is the state of being psychotic or of being predisposed to develop psychosis.
    Descriptors: Unusual beliefs and experiences, eccentricity, perceptual dysregulation.
    * Eccentricity (Disorganized Speech or Behavior):
    "I often have thoughts that make sense to me but that other people say are strange."
    "Others seem to think I'm quite odd or unusual."
    "My thoughts are strange and unpredictable."
    "My thoughts often don’t make sense to others."
    "Other people seem to think my behavior is weird."
    "I have several habits that others find eccentric or strange."
    "My thoughts often go off in odd or unusual directions."
    * Unusual Beliefs and Experiences [When Severely Depressed]:
    "I often have unusual experiences, such as sensing the presence of someone who isn't actually there."
    "I've had some really weird experiences that are very difficult to explain."
    "I have seen things that weren’t really there."
    "I have some unusual abilities, like sometimes knowing exactly what someone is thinking."
    "I sometimes have heard things that others couldn’t hear."
    "Sometimes I can influence other people just by sending my thoughts to them."
    "I often see unusual connections between things that most people miss."
    * Perceptual Dysregulation:
    "Things around me often feel unreal, or more real than usual."
    "Sometimes I get this weird feeling that parts of my body feel like they're dead or not really me."
    "It's weird, but sometimes ordinary objects seem to be a different shape than usual."
    "Sometimes I feel 'controlled' by thoughts that belong to someone else."
    "Sometimes I think someone else is removing thoughts from my head."
    "I have periods in which I feel disconnected from the world or from myself."
    "I can have trouble telling the difference between dreams and waking life."
    "I often 'zone out' and then suddenly come to and realize that a lot of time has passed."
    "Sometimes when I look at a familiar object, it's somehow like I'm seeing it for the first time."
    "People often talk about me doing things I don't remember at all."
    "I often can't control what I think about."
    "I often see vivid dream-like images when I’m falling asleep or waking up."
    ("OPENNESS TO EXPERIENCE vs. BEING CLOSED TO EXPERIENCE" modified from "PID-5" by Kreuger RF, Derringer J, Markon KE, Watson D, Skodol AE and Between facets and domains: 10 aspects of the Big Five)
    *MRI Research: Testing predictions from personality neuroscience. Brain structure and the big five.

    Treatment Goals for Individuals With Detachment

    Description: Sociability (Extraversion) is synonymous with being enthusiastic and assertive. Assertiveness encompasses traits relating to leadership, dominance, and drive. Enthusiasm encompasses both sociability and the tendency to experience and express positive emotion. Extraverts tend to engage in social interaction; they are enthusiastic, risk-taking, talkative and assertive. The Extraversion dimension measures the behaviors that are central to the concept of SOCIABILITY - seeking and enjoying companionship. High sociability is associated with better: longevity, leadership, job [sales] performance. (This dimension appears to measure the behaviors that differentiate approach from avoidance.)
    Descriptors: Sociable, gregarious, reward-seeking, talkative.
    Language Characteristics: Many topics, higher verbal output, think out loud, pleasure talk, agreement, compliment, positive emotion words, sympathetic, concerned about hearer (but not empathetic), simple constructions, few unfilled pauses, few negations, few tentative words, informal language, many swear words, exaggeration (e.g. "I'm really smart" ), many words related to humans (e.g. "man", "pal"). poor vocabulary.
    Research: Higher scores on Sociability (extraversion) are associated with greater happiness and broader social connections. *MRI research found that Sociability (extraversion) was associated with increased volume of medial orbitofrontal cortex, a region involved in processing reward information.
    "I'm talkative"
    "I'm not reserved."
    "I'm full of energy."
    "I generate a lot of enthusiasm."
    "I'm not quiet."
    "I have an assertive personality."
    "I'm not shy or inhibited."
    "I am outgoing and sociable."
    "I make friends easily."
    "I warm up quickly to others."
    "I show my feelings when I'm happy."
    "I have a lot of fun."
    "I laugh a lot."
    "I take charge."
    "I have a strong personality."
    "I know how to captivate people."
    "I see myself as a good leader."
    "I can talk others into doing things."
    "I am the first to act."
    Attention Seeking
    "I like to draw attention to myself."
    "I crave attention."
    "I do things to make sure people notice me."
    "I do things so that people just have to admire me."
    "My behavior is often bold and grabs peoples' attention."
    Description: Detachment is synonymous with being reserved and quiet.
    Descriptors: Withdrawn, anhedonic (pleasureless), intimacy avoiding, detached, shy, passive, solitary, moody
    Language Characteristics: Single topic, doesn't think out loud, problem talk, dissatisfaction, negative emotion words, not sympathetic, elaborated sentence constructions, many unfilled pauses, formal language, many negations, many tentative words (e.g. maybe, guess), few swear words, little exaggeration, few words related to humans, rich vocabulary.
    * Social Withdrawal:
    "I don’t like to get too close to people."
    "I don't deal with people unless I have to."
    "I'm not interested in making friends."
    "I don’t like spending time with others."
    "I say as little as possible when dealing with people."
    "I keep to myself."
    "I am hard to get to know."
    "I reveal little about myself."
    "I do not have an assertive personality."
    "I lack the talent for influencing people."
    "I wait for others to lead the way."
    "I hold back my opinions."
    * Intimacy Avoidance:
    "I steer clear of romantic relationships."
    "I prefer to keep romance out of my life."
    "I prefer being alone to having a close romantic partner."
    "I'm just not very interested in having sexual relationships."
    "II break off relationships if they start to get close."
    * Loss of Interest or Pleasure:
    "I often feel like nothing I do really matters."
    "I almost never enjoy life."
    "Nothing seems to make me feel good."
    "Nothing seems to interest me very much."
    "I almost never feel happy about my day-to-day activities."
    "I rarely get enthusiastic about anything."
    "I don't get as much pleasure out of things as others seem to."
    * Restricted Emotions:
    "I don't show emotions strongly."
    "I don't get emotional."
    "I never show emotions to others."
    "I don't have very long-lasting emotional reactions to things."
    "People tell me it's difficult to know what I'm feeling."
    "I am not a very enthusiastic person."
    ("Sociability vs. Detachment" modified from "PID-5" by Kreuger RF, Derringer J, Markon KE, Watson D, Skodol AE and Between facets and domains: 10 aspects of the Big Five)
    *MRI Research: Testing predictions from personality neuroscience. Brain structure and the big five.

    Treatment Goals for Individuals With Negative Emotion

    Description: Emotional Stability is synonymous with being calm and emotionally stable. The Emotional Stability dimension measures the behaviors that are central to the concept of COURAGE - having calm composure and endurance when confronting adversity. High emotional stability is associated with better: longevity, leadership, job [team] performance, and marital success. (This dimension appears to measure the behaviors that differentiate safety from danger.)
    Descriptors: Calm, even-tempered, peaceful, confident
    Language Characteristics: Pleasure talk, agreement, compliment, low verbal productivity, few repetitions, neutral content, calm, few self-references, many short silent pauses, few long silent pauses, many tentative words, few aquiescence, little exaggeration, less frustration, low concreteness.
    "I am relaxed, and I handle stress well."
    "I am emotionally stable, and not easily upset."
    "I remain calm in tense situations."
    "I rarely get irritated."
    "I keep my emotions under control."
    "I rarely lose my composure."
    "I am not easily annoyed."
    "I seldom feel blue."
    "I feel comfortable with myself."
    "I rarely feel depressed."
    "I am not embarrassed easily."
    Description: Degree to which people experience persistent anxiety or depression and are easily upset. (This could be thought of as high threat sensitivity or low stress tolerance.)
    Descriptors: Emotionally unstable, anxious, separation-insecure, depressed, self-conscious, oversensitive, vulnerable.
    Language Characteristics: Problem talk, dissatisfaction, high verbal productivity, many repetitions, polarised content, stressed, many self-references, few short silent pauses, many long silent pauses, few tentative words, more aquiescence, many self references, exaggeration, frustration, high concreteness.
    Research: Lower scores on Emotional Stability are associated with unhappiness, dysfunctional relationships, and mental health problems. *MRI research found that Low Emotional Stability (= Negative Emotion or Neuroticism) was associated with increased volume of brain regions associated with threat, punishment, and negative emotions.
    * Emotional Instability:
    "I get emotional easily, often for very little reason."
    "I get emotional over every little thing."
    "My emotions are unpredictable."
    "I never know where my emotions will go from moment to moment."
    "I am a highly emotional person."
    "I have much stronger emotional reactions than almost everyone else."
    "My emotions sometimes change for no good reason."
    "I get angry easily."
    "I get upset easily."
    "I change my mood a lot."
    "I am a person whose moods go up and down easily."
    "I get easily agitated."
    "I can be stirred up easily."
    * Anxiety:
    "I worry about almost everything."
    "I'm always fearful or on edge about bad things that might happen."
    "I always expect the worst to happen."
    "I am a very anxious person."
    "I get very nervous when I think about the future."
    "I often worry that something bad will happen due to mistakes I made in the past."
    "I am filled with doubts about things."
    "I feel threatened easily."
    "I am afraid of many things."
    * Separation Insecurity:
    "I fear being alone in life more than anything else."
    "I can't stand being left alone, even for a few hours."
    "I’d rather be in a bad relationship than be alone."
    "I'll do just about anything to keep someone from abandoning me."
    "I dread being without someone to love me."
    * Submissiveness:
    "I usually do what others think I should do."
    "I do what other people tell me to do."
    "I change what I do depending on what others want."
    * Perseveration:
    "I get stuck on one way of doing things, even when it's clear it won't work."
    "I get stuck on things a lot."
    "It is hard for me to shift from one activity to another."
    "I get fixated on certain things and can’t stop."
    "I feel compelled to go on with things even when it makes little sense to do so."
    "I keep approaching things the same way, even when it isn’t working."
    * Depressed Mood:
    "I have no worth as a person."
    "Everything seems pointless to me."
    "I often feel like a failure."
    "The world would be better off if I were dead."
    "The future looks really hopeless to me."
    "I often feel just miserable."
    "I'm very dissatisfied with myself."
    "I often feel like nothing I do really matters."
    "I know I'll commit suicide sooner or later."
    "I talk about suicide a lot."
    "I feel guilty much of the time."
    "I'm so ashamed by how I've let people down in lots of little ways."
    "I am easily discouraged."
    "I become overwhelmed by events."
    ("Emotional Stability vs. Negative Emotion" modified from "PID-5" by Kreuger RF, Derringer J, Markon KE, Watson D, Skodol AE and Between facets and domains: 10 aspects of the Big Five)
    *MRI Research: Testing predictions from personality neuroscience. Brain structure and the big five.

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