Internet Mental Health

Prediction: 50% Recover Within 6 Mos; 80% Recover Within 1 Year

  • Depressive disorder accounts for 40.5% of the disability caused by mental illness; a minority are chronically disabled and require a disability pension
  • Disability can range from moderate to so severe that the person is mute and motionless
      Wisdom vs Irrationality:
  • Depression can impair judgment; severe episodes can cause psychosis
      Courage vs Negative Emotion:
  • Depressed mood, generalized anxiety, guilt, anger, suicidal behavior
  • Low self-confidence, pessimism, hypersensitivity to rejection
      Helping Others vs Detachment:
  • Social withdrawal
      Self-Control vs Disinhibition: N/A
      Justice vs Antagonism: N/A
  • Chronic or disabling medical conditions increase risk of this disorder


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. 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.

This diagnosis requires that an individual has had at least one major depressive episode, but no manic, hypomanic, or mixed episodes. This major depressive episode must cause significant distress or life impairment, and not be due to a drug, medication, other medical condition, or psychotic disorder. These depressive symptoms are not due to a normal response to a significant loss (e.g., normal bereavement).

Effective Therapies


Recent 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 much more effective than treatment with a single antidepressant medication, (3) only 60% of individuals with major depression respond to antidepressant medication, and (4) antidepressant medications have relatively modest effects when compared with an active placebo - such as patients seeing their GP for brief counselling. The active placebo effect causes three-quarters of the remission from major depression. 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. 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. However, for those whose depression causes marked distress or disability; antidepressant medication dramatically 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 6 months.

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.


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 significantly 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 a small improvement in outcome. St John's wort and regular exercise appear mildly effective in the treatment of depression (but their effect size is small).


Although almost two-thirds of individuals with major depressive disorder respond to current therapies; at least one-third of those entering remission relapse back into depression 18 months posttreatment.

Ineffective Therapies

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

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

Which Behavioral Dimensions Are Involved?

The ancient Greek civilization lasted for 1,300 years (8th century BC to 6th century AD). The ancient Greek philosophers taught that the 5 pillars of their civilization were: wisdom, courage, helping others, self-control, and justice. Psychiatry named the opposite of each of these 5 ancient themes as being a major dimension of psychopathology (i.e., irrationality, negative emotion, detachment, disinhibition, and antagonism). (Psychology named these same factors the "Big 5 dimensions of personality": "intellect", "neuroticism", "extraversion", "conscientiousness", and "agreeableness")

    Major Depressive Disorder: Negative Emotion
            Wisdom vs Irrationality:
      • Depression can impair judgment; severe episodes can cause psychosis
            Courage vs Negative Emotion:
      • Depressed mood, generalized anxiety, guilt, anger, suicidal behavior
      • Low self-confidence, pessimism, hypersensitivity to rejection
            Helping Others vs Detachment:
      • Social withdrawal
            Self-Control vs Disinhibition: N/A
            Justice vs Antagonism: N/A

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. Dysthymic 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 Emotionally Unstable (Borderline) Personality Disorder.

Associated Laboratory Findings

No laboratory test has been found to be diagnostic of this disorder. Sleep EEG abnormalities are evident in 40%-60% of outpatients and in up to 90% of inpatients with this disorder. The most frequent EEG sleep abnormalities are reduced rapid eye movement [REM] latency, increased REM density, reduced slow-wave sleep, and impaired sleep continuity. In some depressed individuals, hormonal disturbances have been observed, including elevated glucocorticoid secretion (e.g., elevated urinary free cortisol levels or dexamethasone nonsuppression of plasma cortisol) and blunted growth hormone, thyroid-stimulating hormone, and prolactin responses to various challenge tests. In some individuals, functional brain imaging shows increased blood flow in limbic and paralimbic regions and decreased blood flow in the lateral prefrontal cortex. Depression beginning in late life is associated with alterations in brain structure, including periventricular vascular changes (suggesting vascular depression).


Lifetime prevalence for this disorder in the general population is 10% to 25% for women and from 5% to 12% for men. In any year, 5% to 9% of women will have this disorder and from 2% to 3% of men will have it. 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, this disorder is twice as common in females as in males.


This disorder may begin at any age, with an average age at onset 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 70% chance of having a third, and after the third episode, there is a 90% chance of having a fourth. About 5%-10% of individuals with this disorder subsequently develop Bipolar I 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.


In two-thirds of cases, the Major Depressive Episode ends with complete recovery. For individuals that have only a partial recovery, there is a greater likelihood of developing additional episodes of this disorder and of continuing the pattern of partial interepisode recovery. Individuals that have pre-existing Dysthymic Disorder prior to the onset of this disorder are more likely to have additional Major Depressive Episodes, have poorer interepisode recovery, and have more difficult to treat Major Depressive Episodes. One year after the diagnosis of this disorder, 40% have no mood disorder; 20% are partially recovered; and 40% still have symptoms that are sufficiently severe to meet the criteria for a full Major Depressive Episode. The severity of the initial Major Depressive Episode appears to predict persistence. Chronic general medical conditions are also a risk factor for more persistent episodes. 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.


Episodes of this disorder often follow a severe psychosocial stressor, such as the death of a loved one or divorce. 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 Dependence (particularly Alcohol or Cocaine Dependence) may contribute to the onset or exacerbation of this disorder.

Familial Pattern

First-degree biological relatives of individuals with this disorder are 1.5-3 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 Phobia), and Attention-Deficit/Hyperactivity Disorder compared with the general population.

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

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 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 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 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

You Can Watch A Video Of 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.



Free Diagnosis Of This Disorder

Rating Scales

Web Community


Cognitive Therapy For Major Depressive Disorder

Cognitive-Behavioral Therapy (Online Resources)

Cognitive-Behavioral Therapy (Placebo Controlled Trials)

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 behaviour 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.


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