Major depressive disorder

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Major depressive disorder a psychiatric disorder characterized by a pervasive low mood, loss of interest in usual activities, and a diminished ability to experience pleasure (anhedonia).

Depressive symptoms may affect quality of life more that the cardiac ejection fraction or cardiac ischemia^[1] or other illnesses^[2].

Clinical depression was originally considered to be a chemical imbalance in transmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms.

Based on the duration of symptoms, timing, and the presumed etiologies, depressive disorders are classified into 7 subtypes: major depressive disorder, persistent depressive disorder (or dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder.

The exact pathogenesis of major depressive disorder is not fully understood. However, it is thought that major depressive disorder is the result of decreased levels of serotonin, norepinephrine, and dopamine.

Current theories regarding the causes of major depressive disorder can be broadly classified into two categories, Physiological and Sociopsychological.

Major depressive disorder must be differentiated from other causes of depressive symptoms.

The one-year prevalence of major depressive disorder is approximately 7,000 per 100,000 (7%) of the overall population with marked differences by age groups.

Risk factors for clinical depression include genetic, temperamental, environmental, and psychological factors.

According to theU.S. Preventive Services Task Force (USPSTF), screening for major depressive disorder is recommended in children and adolescents 12 to 18 years of age, in older adults, and in pregnant women (at least once during pregnancy and again 4-8 weeks after delivery).

Common complications of [[major depressive disorder include alcohol or substance abuse, physical health problems, and suicide.

Major depressive disorder is diagnosed based on the DSM-V Diagnostic Criteria.

Clinical depression can present with a variety of symptoms, but almost all patients display a marked change in mood, a deep feeling of sadness, and a noticeable loss of interest or pleasure in favorite activities.

Physical examination of patients with major depressive disorder is usually normal.

There are no diagnostic laboratory findings associated with major depressive disorder.

There are no gross CT scan findings associated with major depressive disorder.

There are no MRI findings associated with major depressive disorder.

There are no other imaging findings associated with major depressive disorder.

A number of psychological tests can be used to help in the diagnosis and assessment of treatment efficacy in patients with major depressive disorder.

The mainstay of treatment for major depressive disorder is pharmacologic therapy with serotonergic agents.

There are a number of psychotherapies for depression, which may be provided individually or in a group format. Psychotherapy can be delivered by a variety of mental health professionals, including psychotherapists, psychiatrists, psychologists, clinical social workers, or psychiatric nurses.

Electroconvulsive therapy (ECT), also known as electroshock or electroshock treatment, uses short bursts of a controlled current of electricity (typically fixed at 0.9 amperes) into the brain to induce a brief, artificial seizure while the patient is under general anesthesia.

Surgery is not the first-line treatment option for patients with [[major depressive disorder]. Surgery may be used for selected patients.

There are no established measures for the primary prevention of major depressive disorder.

Effective measures for the secondary prevention of major depressive disorder include antidepressant maintenance therapy and psychotherapy.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Clinical depression was originally considered to be a chemical imbalance in transmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms.

The modern idea of depression appears similar to the much older concept of melancholia. The name melancholia derives from “black bile”, one of the “four humours” postulated by Galen.

Clinical depression was originally considered to be a chemical imbalance in transmitters in the brain, a theory based on observations made in the 1950s of the effects of reserpine and isoniazid in altering monoamine neurotransmitter levels and affecting depressive symptoms. ^[1] Since these suggestions, many other causes for clinical depression have been proposed.^[2]

Some medical professionals and anthropologists have formed several theories as to how depression may have evolutionary advantages, i.e., how it might have increased genetic fitness in ancestral populations. For example, psychic pain may have evolved in an analogous way to physical pain so that organisms avoid behaviour that hinders reproduction. This insight may be helpful in counseling therapy. ^[3][4] Proponents of the psychic pain theory tend to view clinical depression as a dysfunctional extreme of low mood or mild depression.

• Insulin shock therapy is an old and largely abandoned treatment for severe depression, psychosis, catatonia, and other mental disorders. It consists of induction of hypoglycemic coma by intravenous infusion of insulin.

• Atropinic shock therapy, also known as atropinic coma therapy, is an old and rarely used method. It consists of induction of atropinic coma by rapid intravenous infusion of atropine. Atropinic shock treatment is considered safe, but it entails prolonged coma (between four and five hours), with careful monitoring and preparation, and it has many unpleasant side effects, such as blurred vision. ^[5]

• Treatment with psychotherapy including psychodynamic therapy and psychoanalysis was developed around the 19th century. ^[6]
• One of the first drugs used for the treatment of depression was imipramine. This was followed by other medications belonging to the class of tricyclic antidepressants (TCAs).
• Other antidepressants belonging to the class selective serotonin reuptake inhibitors (SSRIs) emerged
  • Fluoxetine in 1987
  • Sertraline in 1991
  • Paroxetine in 1992

Numerous celebrities both dead and alive have been diagnosed with depression and spoken publicly about it. Some Hollywood celebrities include-

• Kristen Bell
• Jim Carrey
• Ellen Degeneres
• Cara Delevingne
• Johnny Depp
• Eminem
• Chris Evans
• Harrison Ford
• Joseph Gordon-Levitt
• Angelina Jolie
• Anne Hathaway
• Lady Gaga
• Hugh Laurie
• Dolly Parton

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Based on the duration of symptoms, timing, and the presumed etiologies, depressive disorders are classified into 7 subtypes: major depressive disorder, persistent depressive disorder (or dysthymia), premenstrual dysphoric disorder, substance/medication-induced depressive disorder, depressive disorder due to another medical condition, other specified depressive disorder, and unspecified depressive disorder.

• The common feature of all depressive disorders is the presence of dysphoric mood (i.e., sad, empty, or irritable mood), with accompanying somatic and cognitive symptoms that significantly affect the functional capacity of the individuals. Depressive disorders may be classified according to the duration, timing, and presumed etiologies into the following subtypes: ^[1]
  • Major depressive disorder: is characterized by single or discrete episodes of depressed mood (most of the day) and/or anhedonia and at least four other depressive symptoms that last at least for 2 weeks. All symptoms must be present nearly every day, except for thoughts of death or suicidal ideation/suicidal attempts.
  • Persistent depressive disorder (or dysthymia): Dysthymia is mild, chronic depression that lasts at least 2 years in adults and 1 year in children, and on most days, patients experience depressed mood for most of the day and at least two other symptoms of depression.
  • Premenstrual dysphoric disorder:This distinctive depressive condition is responsive to treatment. The depressive symptoms begin in the final week of the menstrual cycle and remit early in the menstrual phase. The characteristic symptoms include mood lability, irritability, anxiety, depressed mood, hopelessness, poor concentration, fatigue, changes in appetite and sleep, and physical symptoms (breast tenderness, swelling, and bloating).
  • Substance/medication-induced depressive disorder: This condition is characterized by a depressed mood that is due to a substance, for example, alcohol or medications (e.g. barbiturates).
  • Depressive disorder due to another medical condition:This condition is characterized by a depressed mood secondary to a medical disorder such as hypothyroidism, or Cushing’s syndrome.
  • Other specified depressive disorder: This diagnostic category includes two subtypes:
    • 1) Recurrent depressive episode: depression that lasts 2-13 days and occurs at least once a month
    • 2) Short-duration depressive episode: a depressed mood lasting 4-14 days, and is nonrecurrent
  • Unspecified depressive disorder: This diagnostic category includes 4 major subtypes:
    • 1) Melancholia: a severe form of depression characterized by anhedonia, hopelessness, and psychomotor retardation
    • 2) Atypical depression: is characterized by weight gain and hypersomnia
    • 3) Peripartum depression (previously called postpartum depression): The onset of symptoms is around parturition or within 4 weeks postpartum. These patients commonly have psychotic symptoms.
    • 4) Seasonal pattern (previously called seasonal affective disorder SAD): Patients with a seasonal pattern to their depressive symptoms tend to experience a depressed mood during a particular season, most commonly winter. These patients may preferentially respond to light therapy.
  • Disruptive mood dysregulation disorder: This disorder is characterized by frequent episodes of temper tantrums, persistent irritability, and angry mood in children 6-12 years of age.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

The exact pathogenesis of major depressive disorder is not fully understood. However, it is thought that major depressive disorder is the result of decreased levels of serotonin, norepinephrine, and dopamine.

• The exact pathogenesis of major depressive disorder is not completely understood; however, following etiologies have been suggested to play a role in the development of major depressive disorder.
  • 1. Neurotransmitters
    • Serotonin: Serotonin depletion has been most commonly shown to be associated with depression. ^[1] For this reason, serotonergic agents are first-line treatment of major clinical depression.
    • Norepinephrine: Abnormal norepinephrine metabolites have been shown in blood, urine, and CSF in patients with major depressive disorder. ^[2] Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine) increase both serotonin and norepinephrine levels and are used as the firs-line treatment of major depressive disorder.
    • Dopamine: Major depressive disorder may be associated with decreased dopaminergic activity. ^[3] It has been suggested that patients with major depressive disorder may have dysfunctional masolimbic dopamine pathway and/or hypoactive dopamine D1 receptors. Reduced dopamine concentrations with drugs (e.g. reserpine) or certain pathologic conditions (e.g. Parkinson’s disease) have been linked to symptoms of depression. In addition, drus increasing dopamine concentrations, such as amphetamine, bupropion, and tyrosine can reduce depressive symptoms.
  • 2. Psychosocial
  • 3. Cognitive: Cognitive theory of Aaron Beck describes a triad of 1) negative self-view 2) negative interpretation of experience and 3) negative view of future. Closing </ref> missing for <ref> tag
  • 4. Learned helplessness: Based on this theory, depression is linked to an individual’s inability to control events.
  • 5. Stressful life events: Stressful life events may result in permanent neuronal alterations, subsequently predisposing an individual to mood disorders. The most often associated life event linked to the development of depression is losing a parent before age 11.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Aditya Govindavarjhulla, M.B.B.S. [3] Mitra Chitsazan, M.D.[4]

Current theories regarding the causes of major depressive disorder can be broadly classified into two categories, Physiological and Sociopsychological.

Current theories regarding the causes of major depressive disorder can be broadly classified into two categories, Physiological and Sociopsychological.

The tendency to develop depression may be inherited: according to the National Institute of Mental Health^[1] there is some evidence that depression may run in families. Most experts believe that both biological and psychological factors play a role.

Many modern antidepressant drugs change levels of certain neurotransmitters, namely serotonin and norepinephrine (noradrenaline). However, the relationship between serotonin, SSRIs, and depression is typically greatly oversimplified when presented to the public, though this may be due to the lack of scientific knowledge regarding the mechanisms of action.^[2] Evidence has shown the involvement of neurogenesis in depression, though the role is not exactly known. Recent research has suggested that there may be a link between depression and neurogenesis of the hippocampus.^[3] This horseshoe-shaped structure is a center for both mood and memory. Loss of neurons in the hippocampus is found in depression and correlates with impaired memory and dysthymic mood. The most widely accepted explanation for this is that the drugs increase serotonin levels in the brain which in turn stimulate neurogenesis and therefore increase the total mass of the hippocampus and would in theory restore mood and memory, therefore assisting in the fight against the mood disorder.

In about one-third of individuals diagnosed with attention-deficit hyperactivity disorder (ADHD), a disorder widely believed to be neurological and developmental, depression is recognized as comorbid.^[4] Dysthymia, a form of chronic, low-level depression, is particularly common in adults with undiagnosed ADHD who have encountered years of frustrating ADHD-related problems with education, employment, and interpersonal relationships.^[5]

New evidence shows that individuals with clinical depression exhibit markedly higher levels of monoamine oxidase A (MAO-A) in the brain compared to people without depression.^[6] MAO-A is an enzyme which reacts with and decreases the concentration of monoamines such as serotonin, norephinephrine and dopamine.

Certain illnesses, including cardiovascular disease,^[7] hepatitis, mononucleosis, hypothyroidism, fructose malabsorption,^[8] sleep apnea, and organic brain damage caused by degenerative conditions such as Parkinson disease, Multiple Sclerosis or by traumatic blunt force injury may contribute to depression, as may certain prescription drugs such as hormonal contraception methods and steroids. Depression also occurs in patients with chronic pain, such as chronic back pain, much more frequently than in the general population. Fibromyalgia Syndrome sufferers also experience depression and anxiety. Dampness or mold in the home is associated with depression,^[9] as is the frequent use of aerosols and air fresheners in the home.^[10]

Poor diet has been linked with depression. An imbalanced diet or a diet that does not provide enough calories can worsen or induce depression.

Excessive consumption of sugar has been proven to alter mood (causing a ‘rush’ or ‘high’, hyperactivity and subsequent deterioration of mood for exapmple, iritability), such consumption can be detrimental regarding the mood changes experienced in depressive conditions. Alcoholic beverages contain the psychoactive drug ethanol, a depressant; If included to a diet in large quantities, it can induce depression. If it is introduced into the diet of a person who is already a depressive, comparatively little can greatly worsen depression both in the short and longer term.^[11]

Poor sleep quality co-occurs with major depression. Major depression leads to alterations in the function of the hypothalamus and pituitary causing excessive release of cortisol which can lead to poor sleep quality. Individuals suffering from major depression have been found to have an abnormal sleep architecture, often entering REM sleep sooner than usual, along with highly emotionally-charged dreaming. Antidepressant drugs, which often function as REM sleep suppressants, may serve to dampen abnormal REM activity and thus allow for a more restorative sleep to occur.

Seasonal affective disorder (SAD) is a type of depressive disorder that occurs in the winter when daylight hours are short. It is believed that the body’s production of melatonin, which is produced at higher levels in the dark, plays a major part in the onset of SAD and that many sufferers respond well to bright light therapy, also known as phototherapy.^[12]

Postpartum depression refers to the intense, sustained and sometimes disabling depression experienced by women after giving birth. Postpartum depression, which has incidence rate of 10-15%, typically sets in within three months of labor, and can last for as long as three months.^[13] About two new mothers out of 1000 experience Postnatal Psychosis, which includes hallucinations and/or delusions.

Low self-esteem and self-defeating or distorted thinking are connected with depression. However, it has been proposed that it is the result of depression and not necessarily the cause of it. This is still debated in the scientific community. Although it is not clear which is the cause and which is the effect, it is known that depressed persons who are able to make corrections in their thinking patterns can show improved mood and self-esteem (Cognitive Behavioral Therapy).^[14] Psychological factors related to depression include the complex development of one’s personality and how one has learned to cope with external environmental factors, such as stress.^[15]

Events such as the death of a parent, issues with biological development, school related problems, abandonment or rejection, neglect, chronic illness, and physical, psychological, or sexual abuse can also increase the likelihood of depression later in life. Post-traumatic stress disorder (PTSD) includes depression as one of its major symptoms.^[16]

The following experiences or circumstances may trigger depression:

• Divorce or the end of a serious relationship
• Eating disorders
• Financial difficulties or poverty
• Gambling addiction
• Grief over the death of a child, spouse, other family member or friends.
• Job loss or unemployment
• Loss of religious faith^[17]
• Ongoing major health problems
• Rape
• Sexual difficulties
• Trauma
• Work-related stress

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Major depressive disorder must be differentiated from other causes of depressive symptoms.

• Major depressive disorder is characterized by one or more episodes of depressed mood or diminished interest or pleasure (anhedonia) that last at least 2 weeks and are accompanied by 4 or more of the characteristic associated symptoms (including changes in sleep, appetite, or activity level); energy loss and fatigue; difficulty concentrating; excessive guilt or feelings of worthlessness; suicidal ideation or suicidal behavior). ^[1]
• Major depressive disorder must be differentiated from other causes of depressive symptoms: ^{[2] [3]}

Differential diagnosis for Major Depressive Disorder
Depressive disorder	Distinguishing feature from Major depressive Disorder
Bipolar I or Bipolar II disorder	One or more manic or hypomanic episodes are required for diagnosis. If manic or hypomanic episodes have ever been present, the patient cannot be diagnosed with major depressive disorder. If patients with major depressive symptoms have some manic or hypomanic symptoms that are not enough for diagnosis of mania and hypomania episode (i.e. fewer symptoms or shorter duration), they are specified as “major depressive disorder with mixed features“.
Depressive disorder due to another medical condition	Diagnosis of Depressive disorder due to another medical condition requires the presence of a medical condition as the etiology of depressive symptoms. In Fact, major depressive disorder is not diagnosed if depressive symptoms are due to the direct physiologic effects of a medical condition.
Substance/medication-induced depressive disorder	Substance/medication-induced depressive disorder is diagnosed when depressive symptoms are due to direct physiologic effects of a substance or medication. In Fact, a diagnosis of major depressive disorder cannot be made when depressive symptoms are due to the direct physiologic effects of a substance or medication.
Persistent depressive disorder (Dysthymia)	Persistent depressive disorder is characterized by a depressed mood, on most days, for at least 2 years. Of note, a patient can be diagnosed with both major depressive disorder and persistent depressive disorder if the diagnostic criteria are met for both disorders.
Premenestrual dysphoric disorder	Premenstrual dysphoric disorder is characterized by the presence of dysphoric mood in the few days before the onset of menses that improves within a few days after the onset of menses. In contrast, no temporal connection is present between the depressive symptoms in major depressive disorder and the menstrual cycles.
Disruptive mood dysregulation disorder	Disruptive mood dysregulation disorder is characterized by severe, recurrent temper outbursts (verbally and/or behaviorally). In between the outbursts, persistently irritable or angry mood, most of the day, almost every day, is present. In contrast, in major depressive disorder, irritability is present only during depressive episodes.
Schizoaffective disorder	Schizoaffective disorderis characterized by major depressive episodes with concurrent active-phase symptoms of schizophrenia, AND presence of hallucinations or delusions for two or more weeks in the absence of a major mood episode, AND major depressive episodes are present for the majority of the total duration of illness. If psychotic symptoms are present exclusively during major depressive episodes, the diagnosis of “Major depressive disorder with psychotic features” is made.
Adjustment disorder with depressed mood	It is characterized by depressive symptoms occurring within 3 months of an identifiable psychological stressor that last <6 months after the stressor has ended. Symptoms should not meet the criteria for a major depressive episode.
Bereavement	Bereavement occurs in response to the loss of a loved one. The symptoms are generally milder than a major depressive episode. Feelings of emptiness and loss are the predominant affective symptoms in bereavement, in contrast to depressed mood and inability to experience pleasure (anhedonia) in major depressive episodes. The dysphoric mood in grief usually decreases in intensity over days to weeks, occurs in wanes, and tends to be associated with thoughts and reminders of the deceased, whereas the depressed mood in major depressive episode that is more persistent and not related to particular thoughts or preoccupations.
Sadness	Nonpathological periods of sadness are characterized by the short duration of few depressive symptoms that are not associated with significant functional impairment or distress.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

The one-year prevalence of major depressive disorder is approximately 7,000 per 100,000 (7%) of the overall population with marked differences by age groups.

• The annual incidence (the number of new cases) of a major depressive episode has been estimated as 1.59% (1.89% in women and 1.10% in men). ^[1]

• The twelve-month prevalence of major depressive disorder is 7,000 per 100,000 (7%) of the overall population.^[1]

• There are marked differences by age groups; for example, the prevalence of major depressive disorder in individuals aged 18-29-year-old is x3 higher than the prevalence in the individuals aged 60-year-old and more. In individuals with the onset of major depressive disorder in early adolescence, the prevalence is 1.5- to 3-fold higher in females than in males. ^[1]

• Major depressive disorder is more common in women. ^[1]

• Depressive disorders are more common among single and divorced individuals compared with married individuals. ^[1]
• There is no association between depressive disorders and socioeconomic status or religion.

• There is no racial predilection to depressive disorders. ^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Risk factors for clinical depression include genetic, temperamental, environmental, and psychological factors. ^[1]

Risk factors for the development of major depressive disorder include: ^{[1] [2]}

• Genetic predisposition:
  • First-degree relatives of patients with major depressive symptoms have two- to four-fold higher risk of developing major depressive disorder than of the general population
• Personality trait (temperament):
  • Neuroticism (also known as Negative emotionality or Negative affectivity) is associated with an increased risk of developing major depressive disorder. Individuals with this personality trait are also more likely to experience depressive episodes in response to stressful life events.
• Environmental factors:
  • Adverse childhood experiences, in particular with multiple and diverse types
  • Stressful life events
• Course modifiers:
  • Major psychiatric disorders increase the risk of developing major depressive disorder. The most common causes include:
    • Substance user
    • Anxiety
    • Borderline personality disorder
  • Chronic or disabling medical conditions increase the risk of developing major depressive disorder. The most common causes include:
    • Diabetes
    • Morbid obesity
    • Cardiovascular diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

According to the U.S. Preventive Services Task Force (USPSTF), screening for major depressive disorder is recommended in children and adolescents 12 to 18 years of age, in older adults, and in pregnant women (at least once during pregnancy and again 4-8 weeks after delivery).

• The U.S. Preventive Services Task Force (USPSTF) does not recommend routine screening for major depressive disorder (MDD) in children 7 to 11 years of age. ^[1]
• The USPSTF recommends screening for MDD in children and adolescents 12 to 18 years of age. ^[1]
  • The Patient Health Questionnaire for Adolescents ([PHQ-A]) and the Beck Depression Inventory for Primary Care ([BDI-PC]) can be used.
• The U.S. Preventive Services Task Force (USPSTF) and American Academy of Family Physicians recommend screening for MDD in the general adult population.
• The USPSTF, American Academy of Family Physicians, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists recommend screening all postpartum women for depression. ^{[1] [2] [1] [3]}
• The USPSTF recommends that all pregnant women should be screened for depression at least once during the perinatal period. It recommends screening at least once during pregnancy and again 4-8 weeks after delivery. ^[1]
  • A validated screening instrument such as the Edinburgh Postnatal Depression Scale or the PHQ-9^[4] can be used.
• In older adults, instruments such as PHQ-2, PHQ-9^[4], Cornell Scale for Depression in Dementia, or Geriatric Depression Scale are appropriate screening tools.
• When any of the screening instruments is positive for possible depression, the diagnosis needs to be confirmed according to the criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th ed.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Common complications of major depressive disorder include alcohol or substance abuse, physical health problems, and suicide.

• People who are depressed are more likely to use alcohol or illegal substances.
• Other complications of depression include:

• Increased risk of physical health problems
• Suicide

Recurrence is more likely if treatment has not resulted in the full remission of symptoms. In fact, current guidelines for antidepressant use recommend 4 to 6 months of continuing treatment after symptom resolution to prevent relapse.

Combined evidence from many randomized controlled trials indicates that continuing antidepressant medications after recovery substantially reduces (halves) the chances of relapse. This preventive effect probably lasts for at least the first 36 months of use.^[1]

Anecdotal evidence suggests that chronic disease is accompanied by recurrence after prolonged treatment with antidepressants (tachyphylaxis). Psychiatric texts suggest that physicians respond to recurrence by increasing dosage, complementing the medication with a different class, or changing the medication class entirely. The reason for recurrence in these cases is as poorly understood as the change in brain physiology induced by the medications themselves. Possible reasons may include aging of the brain or worsening of the condition. Most SSRI psychiatric medications were developed for short-term use (a year or less) but are widely prescribed for indefinite periods.^[2]

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