Depression

Overview

Persons with depression experience and exhibit low mood and low desire for activity. A person may describe transient feelings such as sadness or "the blues" that are considered part of the normal and non-clinical range of human experience. Regarding clinical manifestations of depression, the DSM IV-TR includes a number of types and degrees of depression, all of which include sadness, helplessness, and hopelessness as key emotional factors exerting significant distress. These feelings may periodically break out into periods of crying. Changes in thought content may ensue, most commonly exhibiting a dramatically decreased sense of worth or even persistent thoughts of suicide. Cognitive changes can include impaired memory and cognition. (Sheline, Gado, &Kraemer, 2003) People suffering from depression report such a loss of pleasure in activities that they feel as though they have to force themselves to perform and express themselves despite feeling no motivation to do so. This problem can be as extreme as having inadequate motivation to get out of bed, perhaps for an unlimited period of time, and excessive sleep. Significant changes in physical factors such as level of activity are termed vegetative signs.

Functionally, clinical depression is characterized by extended periods of reduced functioning, threatening the individual\'s family, social, academic, and work roles. Symptoms range from mild to extremely disabling and distressing, and may lead to psychosis or completed suicide in its most severe forms.

Symptoms of depression may occur in disorders other than depressive disorders, such as adjustment disorder with depressed mood. Depression symptoms may be accompanied by fatigue and pain in one or more areas of the body, especially headache or back pain.

Onset and etiology: Depression usually begins early in adulthood, but can occur throughout the lifespan. It may be a consequence of a life circumstance, a traumatic experience, or it may emerge independently of external precursors, but clinical depression is believed to emerge from a combination of genetic (or predisposing) and situational factors. Sustained psychosocial stressors are likely to produce at least some depression. Of particular importance is the triggering of genetic vulnerability by childhood stress, especially when there is a lack of support to buffer such stress. Depression may emerge from conditions involving damage to the brain such as traumatic brain injury and schizophrenia, sometimes after a prolonged period of latency. Persons suffering from depression often have histories of poorly controlled anxiety or agitation. These symptoms may accompany depression as well. Depression is considered to be moderately heritable. (Edvardsen, Torgersen, Roysamb, Lygren, Skre, &Onstad, et al., 2009)

Hippocampal neurogenesis pathology: A variety of models are being explored for depression. It has been observed that stymied hippocampal neurogenesis is implicated, and ongoing antidepressant medication appears to reverse this. (Malberg, Eisch, Nestler, et al., 2000) An important model under development is that reductions in neurotrophic factors that are needed for certain neurons to survive and function lead to depression. (Duman, et al., 1997)

Sickness behavior and the cytokine theory of depression: A number of biological factors have come to be viewed under the rubric of "sickness behavior." This term refers to biochemically induced emotions or feelings and changes in functional state that serve the evolutionary function of increasing the odds of surviving certain illness states, including infection. Cancer and chemotherapy produce sickness behavior and depression.

These feelings, behaviors, and states include:



Of particular interest here is the well-established role of proinflammatory cytokines that act in the brain to cause these sickness behaviors. (Kelley, Bluthé, Dantzer, Zhou, Shen, Johnson, et al., 2003) This pattern is observed in all mammals and birds. Cytokines are small, nonstructural proteins that regulate responses to infection, immune responses, inflammation, and trauma. In contrast to hormones, cytokines are produced by all cells, and are triggered by states rather than the circadian rhythm (daily cycle).

Some cytokines increase diseases symptoms and are referred to as proinflammatory cytokines. Others interfere with this activity and are called anti-inflammatory cytokines. Excessive inflammatory cytokine response, though an attempt to survive infection, can also by harmful or even fatal. Administration of inflammatory cytokines in treatment of illness was found to induce depression and other mood alterations. This led, beginning in the late 1980s, to development of the cytokine theory of depression, which is an aspect of psychoneuroimmunology studies.

A cascade of gene products (chemicals produced when specific genes are activated to express them) that are not typically produced in healthy persons (persons without infection or other triggers of disease or physical trauma response) constitute cytokine-mediated inflammation. It can be induced by infection, physical trauma, ischemia (lack of oxygen to tissues) immune-activated T cells, or toxins. Susceptibility to disease appears to be genetically determined by the balance of pro- and anti-inflammatory cytokines.

An element of sickness behavior that may be the cause of what most people experience as depression in many cases, and an aspect of it in many more, is the lack of motivation for activity. From the perspective of evolutionary psychology, this trait would be of survival value when the conditions that trigger inflammatory conditions occur. For example, an animal with an infection that goes about its normal activities would be less able to escape or defend itself against a predator. One that stays inactive and hidden away long enough to become healthier will be more likely to survive. The immune system has been likened to a "sense" that causes us to react with sickness behavior. Subjectively, we have the universal experience of feeling "under the weather."

It is believed that elements of the inflammatory cascade can become chronic through hypersensitization, and result in or contribute to depression. (Anisman, 2009) Additionally, the triggering of the hypothalamo-pituitary-adrenocortical (HPA) axis by some cytokines may explain additional aspects of depression, including anxiety. This model also may account for cognitive difficulties associated with depression through neurodegeneration explained by factors such as increased oxidative damage. (Maes, Yirmyia, Noraberg, Brene, Hibbeln, Perini, et al., 2009)

Multifactorial generation: Social, psychological, and genetic factors appear to act together in generating depression or in acting protectively against depression. (Ingram, et al., 1998). Of particular interest to psychotherapists is the matter of cognition, especially how meaning comes to be assigned to stressful or traumatogenic life events. On the one hand, cognitive therapists work to identify and correct patterns of interpretation that cause their clients to amplify the negative effect of stressful events. Negative cognitions such as, "I can\'t live without him," are shifted to constructive cognitions such as, "I am a capable woman. Countless people have thrived after breakups, even major ones."

On the other hand, it is noted that factors other than personality or habitual ways of thinking are at play. With changes of physical state, dramatic changes in such thinking can occur. For example, a more positive state that leads to such changes in thought patterns can be triggered by methods such as EMDR, thought field therapy, or various symbolic visualization techniques (the "fast phobia cure" originated by Bandler and Grinder is an interesting example). These techniques can produce very constructive and empowered statements about situations that the client previously seemed intractably committed to seeing in a negative, disempowered light. But this often takes place with negligible cognitive restructuring efforts during the therapy session. These new thought patterns appear to emerge spontaneously in many cases. Sometimes, this shift is so complete, that clients will profess to recall their history of symptoms or trauma as being less serious than what the therapist noted prior to the intervention.

Similarly, the dramatic changes in thought patterns that occur with the emergence of depression are often dramatically divergent from those that characterized the individual prior to onset. This change can go to the point of appearing to be a personality disorder and can even move into delusion and other positive psychotic signs (where positive refers to new psychotic phenomena such as hallucinations).

It is clear that learned patterns from childhood or habits of thought are often very inadequate explanations for depression, despite the view that emerged in early cognitive therapy through theorists such as Aaron Beck. Nonetheless, they are productive targets of intervention in cognitive behavioral therapy. An anxious temperament is associated with heightened vulnerability to producing cognitive patterns that, in turn, produce internal stress and additional external stressful events as the individual engages is excessive efforts to control their environment, which they perceive as the source of their anxiety. This produces problems such as rejection, conflict, and isolation. Chronic anxiety is a risk factor for later depression. More directly germane to depression, thought and behavior patterns that reflect helplessness and passivity tend to compound depression through the results in life that these traits produce. All of the aforementioned traits are targets for cognitive behavioral intervention.

Research and the nature of response to various medications suggests that there are multiple biological pathways to depression (that is, it is a heterogeneous condition; numerous pathologies led to depressive symptoms). This, and the dim outlook for most individuals who do not respond to initial efforts at treatment, mean that great care must be taken in evaluating these patients and that efforts must be intently focused on achieving remission.

Signs and symptoms: Depression as a primary symptoms occurs in most mood disorders. Most mood disorders are classified as being unipolar or bipolar. Bipolar depression alternates depression with mania. Mania is an elevated mood that includes heightened energy and euphoria. Depressive disorders are common in the population, with a lifetime prevalence of 20% for unipolar, and 4% for bipolar depression. Unipolar depression affects twice as many females as males, while bipolar depression is evenly distributed.

Treatment: It is estimated that only 25% of persons suffering from clinical levels of depression seek treatment. Much psychopharmacological treatment is initiated and even maintained by general practitioners, with referrals made to psychiatrists for refractory or complex conditions. Conditions associated with poor treatment outcomes include a higher number of concurrent axis I or III co-morbid conditions, socioeconomic disadvantage, chronicity, and melancholic or anxious mood. (Rush, et. al., 2009)

Psychotherapy has shown to help resolve depression in many cases independently of medication or in combination with medication. Cognitive behavioral therapy is the approach with the greatest research substantiation.

Research on state dependent learning and memory as well as the clinical utilization of techniques that alter the client state suggest that cognitive behavioral therapy can be most effective when strategic management of the client state is incorporated. This is one of numerous "active ingredients" of psychotherapy that have been noted. It is of particular interest in mood disorders, given the vulnerability of such clients to their physical condition.

Masked: Many people do not recognize their own depression, though others are likely to notice changes in the person\'s behavior. This is called "masked depression."

Prognosis: Depression symptoms most commonly pass in time, but many people experience chronic symptoms that require treatment in order to resolve. This treatment may include psychotherapy and medication. Major depression has a poor success rate, and persons with treatment-resistant depression have a particularly low rate of full remission. Approximately two thirds of persons with major depression treated with antidepressants achieve remission. (Maes, Yirmyia, Noraberg, Brene, Hibbeln, Perini, et al., 2009)



Introduction

The DSM-IV-TR defines among various mood disorders the depressive disorders: Bipolar Disorder, Dysthymic Disorder, Cyclothymia Major Depressive Disorder, Depressive Disorder NOS (not otherwise specified). Much of the distinction between mood disorders is how they occur over time in terms of their intensity and other features. In the course of a mood disorder, clients have one or more mood episodes. These are defined as a period of disturbed mood. Episodes may last for weeks, months, or years before there is a period of remission.

Mood episodes include major depressive, manic, hypomanic, and mixed.

Dysthymic Disorder

This disorder falls short of major depression, and does not involve any major depressive episodes. It requires chronic depressed mood that occurs during most of the day, more days than not, and over the course of at least two years (or one for children and adolescents). Symptom-free periods do not last longer than two months. There has been no manic or hypomanic episode.

Periods of depressed mood involve at least two of the following symptoms: changes in appetite, changes in sleep patterns, low energy or fatigue, low self-esteem, poor concentration, difficulty making decisions, and feelings of hopelessness. It is estimated to affect 3% to 6% of the U.S. population and affects women at double the rate of men.

Dysthymia can progress to major depression, and does in roughly 10% of cases. Approximately 10% of cases remit without treatment. When dysthymia and major depression occur simultaneously, this is called "double depression."

Depressive Disorder NOS

When depressive symptoms do not fit the above criteria, this NOS diagnosis may be used. It is a common diagnosis, as many clinical cases of depression do not precisely fit the criteria. For example, the case may not have all five required symptoms for major depression, or symptoms may not yet have been present long enough to meet criteria. The diagnosis may be used pending gathering additional assessment information.

Mood Disorder NOS

This disorder does not involve sufficient depressive symptoms to be a depressive disorder NOS, and it is not yet possible to establish the nature of suspected manic episodes.



Borderline Personality Disorder

This is a condition involving dramatically volatile moods and chaotic interpersonal relationships. Periods of depression or dramatic self expression or suicidality that resembles a depressive disorder can result in a faulty mood disorder diagnosis.

Premenstrual Dysphoric Disorder (PMDD)

PMDD indicates serious premenstrual distress affecting functioning. It involves depressed or labile mood, anxiety, irritability, anger, and other symptoms that occur exclusively during the two weeks preceding menses. The most common primary symptom is irritability. Breast pain and bloating help to differentiate PMDD from major depressive disorder. The DSM-IV requires that the symptoms interfere with occupational and social functioning, in contrast with premenstrual syndrome (PMS). Changes in gonadal hormone levels are suspected to trigger PMDD in some predisposed women. Neurotransmitters, including serotonin, are implicated in PMDD for various reasons, with level changes suspected to occur as a result of cyclic changes in ovarian hormone levels. (Steine &Pearlstein, 2000) Psychosocial, cognitive, and social learning theorists speculate that the meaning and practical inconvenience of menses can trigger or amplify emotional difficulties in some women. The strongest scientific data identify serotonin as the main neurotransmitter affected by ovarian steroid levels, but opioid, adrenergic, and GABA systems are also implicated. While as many as 80% of women have emotional and behavioral premenstrual symptoms, 3-8% have PMDD. Greatest vulnerability to PMDD appears to occur in the late 30s and 40s. Research does not support the concern that suicide risk is increased during the luteal phase (the third phase of the menstrual cycle, prior to the menstrual phase), however, there may be a higher rate of PMDD among women who attempt suicide. (Baca-Garcia, Diaz-Sastre, Ceverino, García, Oquendo, Saiz-Ruiz, et al., 2004)

The following risk factors have been noted:



Adjustment Disorder With Depressed Mood or Anxiety

This diagnosis involves difficulty adapting to or recovering from one or more stressors, and depressed or anxious mood is a significant symptom. However, the degree of mood disturbance does not meet criteria for a mood disorder.

Mood Disorder Due to a General Medical Condition

Numerous medical conditions may result in depression by affecting the regulatory systems of the body or by causing pain. Endocrine and reproductive system disorders are a frequent cause of depressive symptoms. Other common examples include: HIV/AIDS, diabetes, arthritis, strokes as well as neurological disorders such as Parkinson\'s disease, Huntington\'s disease, multiple sclerosis, and Alzheimer\'s disease. Adapting to the challenges such as struggling with disability or social isolation can cause depression.

The required clinically significant depression can be a direct physiological result, or the result of adapting to direct results of the condition. The symptoms cannot be from delirium. It must be specified whether it involves depressive features, a major depressive-like episode, manic features, or mixed features.

Substance-Induced Mood Disorder

Substance use and abuse can produce depression in a variety of ways, including intoxication, side effects, and withdrawal. This can occur during the normal use of prescription drugs or their abuse. A great number of types of drugs may cause depression. Depression can contribute to abuse of drugs, even though it began through appropriate use. The diagnosis of substance-induced mood disorder requires that the onset of depressive symptoms occur in the context of drug use, intoxication, or withdrawal. Not all MDD symptoms need be displayed for this diagnosis.

Bipolar Disorder

This disorder involves swinging between manic and depressive episodes. It is estimated that 1% of the U.S. population suffers from bipolar disorder. It usually develops in late adolescence or early adulthood. This disorder will not be reviewed in detail for this course, but make not of the following types of episodes that are important to recognize in ruling out this condition:

Schizoaffective Disorder

Schizoaffective disorder appears to be a mood disorder that includes psychotic symptoms, rather than a unique illness. Thus, it is slated to be removed or amended on publication of the DSM-V. (Lake, &Hurwitz, 2008)



Overview

Major depressive disorder (MDD) is also referred to as unipolar depression, and is a common psychiatric disorder. Lifetime incidence is 20% in females and 12% in males. The strongest theory for this difference has to do with changing levels of hormones in females. As much as 10% of patients seen in doctors offices have MDD. It results in significant morbidity, mortality, and costs as a major contribution to illness, suicide, drug abuse, and disruption of relationships and productivity. 40% of persons with MDD that are untreated continue to be highly symptomatic after one year.

Persons with major depression are likely to have four episodes of major depression over their lifetime. (Grenyer, Deane, Lewis, 2008)

Major Depression involves one or more major depressive episodes only. There may be no history of any mania. The depressive symptoms must last at least two weeks and involve depressed mood or loss of interest or pleasure in most activities. Also, the symptoms must persist for most of the day, nearly every day, causing problems with social interaction, work, or other activities of daily living needed in order to function.

Major Depressive Episodes are listed with one or more of the following qualifiers:

Chronic: Person meets the criteria for a Major Depressive Episode continuously for the prior two years.

Catatonic Features: Person has a lack of movement or unusual movement patterns, extreme negativism, or mutism.

Melancholic Features: Person exhibits depressed mood, agitation, anorexia (loss of appetite), unplanned weight loss, or excessive or inappropriate guilt. Also, the person does not feel better (even temporarily), in response to something desirable that happens.

Atypical Features: May include exceptions such as mood brightening in response to good news (mood reactivity), weight gain, appetite increase, hypersomnia (excessive sleeping), leaden paralysis (heavy feelings, especially in arms or legs), chronic high sensitivity to interpersonal slights, even in absence of mood disturbance and causing social or occupational impairment.

Postpartum Onset: Within four weeks of childbirth. May include mood fluctuations, truly excessive preoccupation with infant\'s well-being. May include psychotic symptoms.

Seasonal Pattern: At least two depressive episodes occur at a specific time of year. It is also known as Seasonal Affective Disorder (SAD) or winter depression.

Suicide is a leading cause of mortality in the U.S. There are 200,000 annual attempts, with 32.000 completed suicides in 2005. It is especially of concern in adolescents, ranking as the second leading cause of death for this age group. MDD is estimated to play a role in over half of suicide attempts. In all affective disorders, death from suicide exceeds 15%. Recurrence: MDD is recurrent in many people (50-80%). Many people require long-term use of antidepressants rather than achieving initial remission. Guidelines for treatment typically recommend six months of treatment beyond remission.

Cultural differences: The clinician must be aware of cultural differences in expression of MDD. Presentation can be misleading to one unfamiliar with a given presentation. The DSM provides examples of such cultural patterns. For example, Asians may present predominantly with symptoms of fatigue, poor balance, and a combination of exhaustion, irritability, poor concentration, and somatization that may be referred to as neurasthenia in the ICD-10. Neurasthenia, in some regions, is a more culturally acceptable diagnosis, as it was in the early 1900s in the U.S., because it does not bear the stigma of a mental disorder. In Japan, the condition is referred to as shinkeisuijaku, or "nervousness." A popular therapy for this kind of condition, Morita therapy, emphasizes rest and gradual resumption of responsibility and work intensity. As a means of averting stigma, shinkeisuijaku is being used as a substitute for severe mental illnesses such as schizophrenia and MDD, which are much more specific and severe than the actual meaning of shinkeisuijaku. China has a similar term, shenjingshuairuo, written in the same characters as those used for shinkeisuijaku. In China, it is widely believed to result from a depletion of chi, a form of energy described in Chinese folk medicine.

Despite the availability of various treatment options, it an underdiagnosed and undertreated condition. It is often overlooked by primary care physicians, but there is a high percentage of affective disorders, including major depression, in patients seeking medical care.

Pathophysiology: MDD is not well understood in terms of pathophysiology. Research suggests problems with serotonin in the central nervous system (CNS) as a key factor. Also implicated are norepinephrine and dopamine. Serotonin metabolism problems are suggested by the effectiveness of selective serotonin uptake inhibitors (SSRIs) in treating depression. Experimental depletion of the amino acid tryptophan has caused temporary relapse of depression in subjects already in remission. Tryptophan depletion causes a transient reduction of CNS serotonin. It appears that the picture is more complex, however. An additional factor is the regulation of neurons over time that may occur as a response to the availability of the implicated neurotransmitters. Mechanisms of action of antidepressant medication may include 1) inhibiting presynaptic uptake of serotonin or norepinephrin; 2) functioning as an antagonist at receptor sites for serotonin or norepinephrin, thus increasing release of these neurotransmitters; and 3) inhibiting monoamine oxidase, resulting in less breakdown of the neurotransmitters.

Demographics: Depression is less common in blacks and in males. Men have roughly half the prevalence of MDD in women. However, prepubertal children do not have a gender difference in this regard. Clinical depression symptoms increase as age advances, particularly with aggravating situational factors such as illness or institutional care.

Diagnostic Criteria

According to the DSM-IV-TR, Major Depressive Episode requires the criteria shown below.

Note all five of the primary criteria (A through E) are required. Note that criterion A requires that five subcriteria be met within a two-week period.

Affect, Appearance, Physical Findings

No physical findings confirm MDD. History and mental status examination, including observation, are necessary. Observe appearance and affect. Appearance is usually normal, but more severe illness usually affects grooming, hygiene, and weight. Psychomotor retardation (slowing or even loss of spontaneous movement and reaction) may be evident. Flat or less reactive affect is commonplace.

Statements by Client, Mood, Thought Process

Listen for statements reflecting low mood and possibly altered thought processes indicative of MDD, as discussed above.

Bhalla and Moraille-Bhalla (2010) offer the following characteristic disclosures indicative of a "dysphoric mood state:"

Speech in MDD may be normal, or may show the influence of MDD by being slow, robotic, or lacking in spontaneity. Assess for mania or hypomania in the presence of pressured speech, and psychosis when there is disorganized speech.

Feelings of overwhelm or other reactions to situational variables may lead the clinician to believe that the client is merely facing extreme adversity, when the client\'s experience is actually highly altered by MDD, regardless of the actual level of adversity.

Psychosis: Treatment of MDD must, at the outset, take into account whether there are psychotic features. However, clinicians may miss signs of psychosis in client disclosures, because clients with MDD tend to exhibit ruminative thinking and delusions of worthlessness that are congruent with a depressed mood. Therefore, clinicians must get enough disclosures and history to detect delusional thinking or other psychotic symptoms.

Where there are symptoms of psychosis, the clinician must carefully assess for history of bipolar disorder, schizophrenia, schizoaffective disorder, substance abuse, and organic brain syndrome.

Signs of Heightened Risk

The clinician must always assess for indications of suicidality or violence risk, including thoughts, fears, plans, intent, and command hallucinations. History of violence or suicidality is a strong risk factor that must be noted in the history and referral notes. Inpatient treatment may be required during periods of increased risk and must include adequate supervision for the level of risk.

Differential Diagnosis: Bipolar Disorder

There are numerous illnesses that may be mistaken for MDD or overlooked in MDD. Bipolar illness, because of its depressive periods, may be presumed to be another depressive disorder until there is a manic phase, especially if there is no known history of mania. It is very important to assess for a history of mania when assessing persons with depression. Generally, antidepressant medication has no advantages over mood stabilizing drugs for bipolar disorder, and poses a significant risk of inducing mania. There is use of antidepressant medication in some cases of bipolar disorder with severe depression. (Ghaemi, Hsu, Soldani, &Goodwin, 2003)

Cognition, Sensorium

Complaints of poor memory and concentration are common in MDD. (Sheline, Gado, &Kraemer, 2003) Cognitive examination, however, often reveals no significant deficits. When such findings do occur, the clinician must rule out pseudodementia or an underlying organic brain syndrome such as dementia. Fluctuating or depressed sensorium (awareness of sensory input including awareness of identity, location and time) suggests delirium that may have organic causes. In MDD, sensorium is typically unaffected.

Atypical Presentation

Clinicians miss many presentations of MDD when patients do not emphasize the most common MDD symptoms such as low mood. This is especially likely to occur in non-psychiatric medical settings. In such settings, patients are likely to emphasize somatic symptoms such as fatigue, abdominal distress, headache, and changes in weight. Mood may be irritable rather than sad.

In the elderly: Clinicians may assume that a general decline in functioning in the elderly is merely a consequence of old age and non-psychiatric medical conditions, rather than a sign of MDD. In the elderly, MDD may worsen cognitive deficits including those of dementia. A decline in cognitive functioning stemming from MDD is called "pseudodementia" or dementia of depression. It can be distinguished from dementia in that it remits with successful depression treatment. Bear in mind that focal neurological signs indicate that there is an organic syndrome other than depression to be addressed.

Children often present with irritability, a drop in academic performance, or social withdrawal. Depression has been observed to occur as early as preschool.

Associated with other medical conditions: MDD or other affective symptoms and mood disorders may arise from the medical conditions discussed below.

Neurological disorders: Vascular dementias, alzheimer disease, parkinson disease, huntington disease, multiple sclerosis, stroke, and seizure disorders.

CNS lesions resulting from neoplastic disease (cancer, tumors). There may be changes in mood and behavior prior to onset of focal neurological signs.

Inflammatory conditions: Various inflammatory conditions, including systematic lupus erythematosus (SLE), may cause very diverse psychiatric signs and symptoms. Autoimmune brain inflammation (cerebritis) and blood-brain barrier alterations are suspected.

Sleep disorders result in serious medical and psychiatric issues, but are often overlooked. A common cause is obstructive sleep apnea. It is very important that clinicians assess sleep quality over the course of assessment and treatment. The client\'s partner may be aware of sleep issues unknown to the client. Inquire about issues such as daytime sleepiness and snoring. Polysomnography (a sleep study) may confirm the diagnosis.

Infections such as syphilis, HIV, and Lyme disease.

Prescription medications a may produce chronic mood alterations. These include antihypertensive medications, steroids, hormone-related, H2 blockers, sedatives, muscle relaxants, appetite suppressants, and chemotherapy agents.

Substance abuse and addiction: The direct effects of drugs as well as various aspects of abuse and dependence can produce chronic mood alterations. In particular, alcohol, cocaine, amphetamines, marijuana, sedatives/hypnotics, and narcotics are implicated. Non-drug addictive processes such as gambling addiction may be implicated.

Endocrine disorders: In particular, disorders of the hypothalamic-pituitary-adrenal axis or thyroid. These include Cushing disease, hyperthyroidism, hypothyroidism, Addison disease, polactinomas, and hyperparathyroidism.

Axis I or II Mental Disorders: As mentioned, depression may figure or emerge in other psychiatric disorders. In particular, the clinician should assess for depression in the following conditions:

Anxiety Disorders are risk factors for comorbid depressive disorders. Identifying the anxiety as a distinct entity has treatment implications. These disorders include panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, phobia, and generalized anxiety disorder.

Axis I mood disorders: These disorders are largely characterized by depression, but with variations in factors such as course or intensity of illness. Two examples follow, both are unipolar depressive disorders. Assessment Instruments

Assessments such as paper and pencil or automated forms and rating scales cannot substitute for a thorough assessment, but can serve various purposes. These include early detection, supportive documentation, rapid identification of specific factors of depression and harm risk factors, and economical use in primary care settings and emergency care settings in which the determination must be made as to whether a referral for further mental health assessment and care is advisable.

Useful depression screening instruments include the PDQ-9, the Mood Disorder Questionnaire (MDQ), or the more detailed and time-consuming Hamilton test and Beck Depression Inventory.

Psychosocial and Other Contributions to Illness Medical and other situational factors may contribute to initiation and maintenance of MDD. Stress-related substances such as cortisol play a role in depression by providing a neuronal substrate in the CNS for depressed mood. Significant losses, traumatogenic experiences, and other stressors in early life are a vulnerability factor for predisposition to MDD over the lifespan. Medical factors such as pain and disability may initiate MDD, especially in those predisposed to the disorder.



Suicide is a familiar subject to the mental health professional. Tondo and Baldessarini (2001) offer the following statistics: It comprises roughly 10% of psychiatric patient deaths. Life-threatening attempts exceed completed (fatal) suicides. Suicide is the third greatest cause of death for juveniles and young adults, and ranks as the eighth greatest cause across the life span.

Suicide has an extraordinary impact on survivors; including family members, friends, co-workers, and even witnesses who do not know the person. It certainly has an impact on clinicians. Even the specter of liability that suicide risk holds over practitioners can affect judgment and professional satisfaction.

Although a good deal is known about key issues such as risk factors and rates of suicide, there is inadequate information upon which to base clinical judgment, particularly where high risk is involved. Treatment and prevention of suicide and development of public policies concerning suicide are areas that are seriously lacking information. (Tondo &Baldessarini, 2001)

Suicide is notoriously difficult to predict, yet many suicides are predicted but are not prevented despite concerted effort. The majority of suicides result from mental illness and the majority of these are due to mood, psychosis, or alcohol dependence. (Frances, Franklin, &Flavin, 1987) Only a very low percentage of suicides occur among psychologically healthy individuals as a result of stressful life events. However, suicide risk tends to peak over a limited period for nearly all people who experience such risk. This contributes to our understanding of prevention, as limited as it is.

Most cultures confer great shame on suicide, seeing it as a personal or family failure. Unfortunately, moralistic cultural patterns can compound the stress that contributes to suicide, and confound efforts at prevention and treatment. It also suppresses the reporting of suicide statistics, particularly in certain countries. This is an obstacle to the development of social policies and infrastructure that could prevent suicide.

There is substantial incidence of mental disorders in suicidal individuals. Estimates that use the most reliable data are in the range of 22%. Higher estimates (as high as 98%) have been criticized as being too biased in interpreting historical data after suicide was completed.

A Biopsychosocial Perspective: Suicidal behavior stems from numerous factors that include personality, health, and circumstances. Biological, psychological, and sociological views each contribute to our understanding. Risk factors in these domains are discovered through analysis of clinical and epidemiological factors. Suicide is recognized as a public health issue that requires societal resources for a variety of interventions for prevention and treatment. While the presence of psychiatric illness is an ongoing risk, suicide is usually triggered by one or more stressful life events. The highest risk events are losses, separations, and situations that negatively impact self-esteem and confidence.

Highest risk: The most common disorders implicated in suicide are mood disorder and substance abuse. (Clark, &Goebel-Fabbri, 1998) The extreme mood swings of bipolar disorder can cause impulsive suicides. Alternatively, mania or psychotic depression may lead to delusions that contribute to suicidal behavior. While mania does not elevate suicidal risk in mood disorders, there is a much higher risk when there is a combination of dysphoria, excitement, and agitation. (Tondo, Baldessarini, Hennen, Floris, Silvetti, &Tohen, 1998) Depression elevates risk, with major depression posing the most severe risk. More severe forms of mood disorders can double or quadruple the risk of suicide overall. (Bostwick &Pankratz, 2000) Serotonin: Autopsies appear to show that low serotonin levels contribute to suicide. More specifically, disinhibition of impulsive and aggressive behavior appears to stem from the ventral prefrontal cerebral cortex having low serotonergic functioning. (Mann, et al., 2000) This is in keeping with clinical studies suggesting that individuals with previous suicide attempts are more likely to engage in aggressive acts.

It is known that factors such as stress, loss, substance abuse, and even a low cholesterol level can dampen serotonin levels. Thus, a genetic propensity to depression or impulsiveness may combine with trauma history, high chronic stress, or other situational risk factors to create more serious spikes in suicide risk.

This alteration may help explain why a seemingly bizarre act such as killing the children so that they do not become orphans (and other forms of murder-suicide) might seem rational to some suicidal individuals who are not necessarily delusional.

Risk assessment and management: Clinicians are strongly encouraged to learn to assess and manage suicide risk through continuing education and supervision.

Pediatric treatment:

There are insufficient evidence-based treatment guidelines for children, according to Murray, Wong, and de Vries, (2004). The authors express the concern that children experience a more debilitating form of depression than that in adults. Adolescents: diagnosed with MDD have a 50% likelihood of developing bipolar disorder in adulthood. Teens with clinical levels of anxiety have a high risk of developing depression in adulthood. Throughout life, it is important to treat anxiety in order to reduce risk of depression.

In 2004, the FDA determined that antidepressant medications may increase the risk of suicidal thinking and behavior in children and adolescents with depression and other psychiatric disorders. It extended the warning to all antidepressant medications in 2005. (Simon, 2009) The decision to do so is controversial because there are large studies suggesting that suicide risk decreases overall, and because the trials initially used did not reach statistical significance. (Simon) But the features of suicidality that have been linked with antidepressant prescribing for adolescents and children and the poor level of evidence for effectiveness of various antidepressants are motives for warnings. A key concern is that the onset of suicidality appears to be sudden, suggesting that it is not possible to adequately supervise an adolescent on such medication in an effort to prevent suicide. (Simon) It is speculated that more follow up by clinicians may be helpful. There is a very poor rate of follow up in the community for antidepressant medication, and there is a high rate of noncompliance, especially among adolescents. (Simon) Also, it is suggested that clinicians warn parents and clients regarding the actual level of evidence for a given prescription choice. Most antidepressants, as of this writing, have not been proved effective for adolescents or children, and none for depression other than a current major depressive episode. (Simon)

Psychotherapy

Brief psychotherapies, including cognitive behavioral therapy and interpersonal therapy, have proven effective alone or with medication. Psychotherapy can address a variety of factors that may be maintaining depression or creating risk of relapse. Where depression is severe, psychotherapy may not be indicated until there is some degree of improvement in mood and somatic symptoms via medication. The rehabilitative aspect of psychotherapy may be very important in reintegrating the client into activities, relationships, and responsibilities. The psychotherapist should be sensitive to any degree of cognitive difficulties that are not characteristic of the client\'s prior functioning. Recovery of skills affected by negative cognitive signs may be neglected unless the clients and loved ones are sufficiently educated as to the recovery issues involved in the brain dysfunction that can result from serious depression. Antidepressant medication may have a neuroprotective effect in preventing or aiding recovery of brain tissue potentially affected by depression. (Sheline, Gado, &Kraemer, 2003)

Psychotherapists play an important role in educating clients and their families to ensure treatment compliance and following up in taking appropriate action and knowing how to identify signs of relapse. Additionally, they can help to interpret the actions of psychiatrists who may not devote time to reviewing the treatment plan in detail or following up on questions that emerge. The psychotherapist may same psychiatric time by communicating efficiently with the psychiatrist and ensuring that the client and family members understand and follow through.

Psychotherapy has received less study than pharmacotherapy. Existing evidence does not establish overall superiority of pharmacotherapy over psychotherapy, or of any specific psychotherapy over another in the treatment of depression. (Elkin et al., 1989; Thase, 1995)** more current citations? This is from Surgeon General report

Case Management

Communication between those involved in client care is important in ensuring appropriate treatment and in preventing escalation of threat of harm. Observations from the therapist can be especially valuable to psychiatrists because of the additional time therapists typically spend interacting with and observing the client, as well as in communicating with family members or others involved with the client. (Katon, Von Korff, Lin, et al., 1995) The therapist may be the first person to educate the client or family members regarding appropriate support, social services or disability programs that are available. The therapist can provide initial linkage to such help.

Remission as an Objective

Current research indicates that failure to achieve full remission leaves a substantial vulnerability for relapse in depression. Thus, full remission is emerging as an important treatment objective. (Thase, 2003)

Pooled analyses suggest that there are advantages to antidepressants that act on multiple neurotransmitter actions, including venlafaxine, mirtazapine, and duloxetine. They appear to have faster onset, higher remission rates, and greater effectiveness in addressing the somatic symptoms (including pain) that so often occur with depression. (Agency for Healthcare Research and Quality, 2009)

Pharmacotherapy

Overview

All antidepressants currently on the market have shown effectiveness for MDD alone or with psychotherapy. Studies indicate that the more severe the depression, the greater the likelihood of medication being effective. For lower levels of depression, antidepressant medication has been no more effective than placebo. (Fournier, 2010)

Medication typically requires two to six weeks once therapeutic dose level is achieved to realize an observable therapeutic response. Family members and others typically observe these improvements before the client perceives that they are taking place. The most common causes of medication treatment failure are noncompliance with medication, too short duration of treatment, and inadequate dosing. An AHRQ study found second-generation antidepressants to have a 46% rate of remission, while 38% of patients took longer than six to twelve weeks to respond. (Agency for Healthcare Research and Quality, 2009)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs) St John\'s Wort (Hypericum Perforatum) Psychostimulants Atypical Antidepressants Monoamine Oxidase Inhibitors (MAOIs) Tricyclic Antidepressants (TCAs) Atypical Antipsychotics Hormones

Low levels of certain hormones appear to be a factor in depression, but assessment and treatment of hormone levels has not yet gained acceptance as a treatment for depression. (Schmidt, et al., 2005) Hormone fluctuations may explain depression that occurs in pregnancy, advancing age, and the years immediately preceding menopause, in particular. Stress as a mediator of hormone response is also implicated, as many people with depression have high levels of cortisol. (Epperson, et al., 1999) Low thyroid hormone levels may be a factor, and research is showing thyroid hormone supplementation to be helpful in many cases of depression even when levels are already normal. (Agid &Lerer, 2003; Joffe, 2006)

Consumers should be cautioned that there are concerns regarding potential medical complications of self-applied hormonal treatment such as the consumption of over-the-counter DHEA in individuals with certain risk factors. In the case of DHEA, medical supervision that includes assessment of DHEA levels is advised. The rationale for the use of hormone supplementation in literature for consumers is generally based upon observed reductions of these levels with age, and research showing that a variety of health benefits may occur with such supplementation.

Combined Treatment

A combined approach of psychotherapy and medication promises the fastest and most complete and sustained resolution. (Rush, Warden, Wisniewski, Fava, Trivedi, Gaynes, et. al., 2009)

Additional Nonpharmacologic treatments:

Exercise or Activity and Obesity

Physical exercise and activity contribute to recovery from depression. **cite

Some data suggest that obesity may contribute to depression. It is also known that depression contributes to obesity, primarily because of reduced activity, much of which is activity at home that people tend to take for granted. This produces a greater reduction in calorie consumption than one might expect. *8cite

Also, excessive eating may be an attempt to gain more alertness through consuming foods that contain protein. Protein provides amino acids that are precursors for neurotransmitters. People with depression may also consume foods high in carbohydrates in an intuitive attempt to produce more serotonin. Unfortunately, high-carbohydrate foods are high in calories and contribute to overweight. **cite

Diet, Supplements

Coffee: Studies tell us that suicide rates are lower among coffee drinkers. (Kawachi, I., Willett, W. C., Colditz, G. A., Stampfer, M. J., Speizer, F. E. 1996) Epidemiological research indicates that, “coffee consumption may help prevent several chronic diseases, including type 2 diabetes mellitus, Parkinson’s disease and liver disease (cirrhosis and hepatocellular carcinoma).” (Higdon, J. V., Frei, B., 2006) In addition to maintaining neurotransmitter levels through self-applied caffeine, there may be other aspects of coffee that affect depression.

Homocysteine Theory: A variety of nutritional recommendations are springing from the homocysteine theory of depression, in which homocysteine is implicated in, "...cerebrovascular disease, monoamine neurotransmitters, and depression of mood." (Folstein, Liu, Peter, Buel, Arsenault, Scott, et al., 2007) The theory, "is that high homocysteine levels cause cerebral vascular disease and neurotransmitter deficiency, which cause depression of mood." (Folstein, et al.) The recommendations are intended to reduce levels of homocysteine in order to normalize biological functions. Vitamin B-12 and folate have received much interest because of research on their beneficial effect in depression and their connection to the homocysteine model.

Nutrients and dietary patterns: Studies have looked at individual nutrients and overall dietary patterns that may affect depression rates. The evidence for overall diet appears to be confirming the importance of a "whole foods" approach to preventing depression. (Akbaraly, Brunner, Ferrie, Marmot, Kivimaki, and Singh-Manoux, 2009)

Studies have implicated deficiencies in folate, B-12, vitamin D, selenium, and omega-3 fatty acids in depression.

Vitamin D deficiency may be one of the effects of reduced sun exposure during winter months and, as a result, contribute to seasonal affective disorder. The Mediterranean diet can improve folate levels through its emphasis on legumes, nuts, many fruits, and particularly dark green vegetables. It is associated with a variety of health improvements, including a reduction in depression rates. (Sánchez-Villegas, Delgado-Rodríguez, Alonso, Schlatter, Lahortiga, Serra Majem, 2009)

Vitamin B12 deficiencies are difficult to avoid in vegetarian diets. B12 and occurs in all lean and low-fat animal products, including fish and dairy products, including low-fat dairy products. 600 international units (IU) is the recommended intake of vitamin D. Care must be taken to avoid excessive direct sun exposure because of cancer risk inherent in UV light exposure. Selenium can be taken to excess, so food sources are emphasized, including beans and legumes, meat, dairy products, nuts and seeds, seafood, and whole grains.

Sources of omega-3 fatty acids include fatty fish such as anchovy, mackerel, salmon, sardines, shad, and tuna, flaxseed, nuts, canola oil, soybean oil, and dark green leafy vegetables.

Sleep

It appears that sleep hygiene may be important in prevention and recovery from depression.

The connection between sleep and general or mental health has been viewed from various angles through research studies. (Gangwisch, Babiss, Malaspina, Turner, Zammit, Posner, 2010) Sleep can function as a predictor of mood disturbance, as has been shown in a study of healthy pregnant women. In this study, subjective perception of poor sleep affecting daytime functioning was a significant predictor of mood disturbance, while objective measures of sleep quality were only slightly predictive. (Bei, Milgrom, Ericksen, &Trinder, 2010)

Electroconvulsive therapy (ECT)

ECT is very effective and has very little resemblance to outdated stereotypes, such as its use in One Flew Over the Cuckoo\'s Nest. This is due to advances in neuromuscular paralysis and anesthesia that have improved tolerability and safety. ECT is used when a rapid response is needed, when drug treatment has proven inadequate, or based on patient preference or previous successful ECT treatment. ECT is especially helpful in treating delusional depression. Risks of ECT include confusion and, rarely, short-term memory problems.

Light therapy

Broad-spectrum light exposure is established as a treatment for SAD. Emerging evidence suggests that light therapy may also help non-seasonal depression and to augment medication. Authorities recommend an intensity of 10,000 lux for 30 to 90 minutes, preferably early in the day.

This treatment may precipitate a manic episode in individuals who are susceptible.

Transcranial magnetic stimulation

Transcranial magnetic stimulation is being investigated for MDD treatment, and results are promising. This modality does not have the risks and adverse effects of ECT.

Vagus nerve stimulation

Vagus nerve stimulation is showing potential in treatment-resistant depression.

Deep brain stimulation

As of this writing, this approach is considered highly experimental in treatment of depression. However, it is a procedure proven effective and relatively safe (given that fact that it is a highly invasive procedure in that it involves brain surgery) in other conditions, including Parkinson disease and obsessive compulsive disorder. Initial experience is showing that it may have profound benefits from many patients with treatment-resistant depression. (Awan, Lozano, &Hamani, 2009)

Treatment Resistant Depression (TRD)

There is no established definition for TRD, however, chances of remission decrease a great deal after the failure of two trials of treatment. (Shelton, Osuntokun, Heinloth, &Corya, 2010). Once a patient is classified as having TRD, treatment relevant to this condition must be considered. Treatment options include pharmacological and non-pharmacological measures. According to Shelton, Ostuntokun, Heinloth, and Corya (2010), some are considered experimental (including repetitive transcranial stimulation and deep brain stimulation). Vagus nerve stimulation is FDA approved as an adjunctive therapy once there have been four treatment failures, but benefits of this approach occur only after prolonged use.

Pharmacological treatment of TRD may involve "switching" or "combining." The switching approach involves switching from one antidepressant to another while monitoring for improvements in depression. The advantages of switching include avoiding the risks of polypharmacy (combining medications) and lower cost. The combining approach involves adding antidepressant or augmentative medication. The benefit of this approach is that it allows the prescriber to attempt to build upon the benefits of medications used. Switching can be an element of the combining approach, in that a medication that does not appear to be generating significant benefit is dropped in hopes of adding only medications that will contribute to a combined beneficial effect. This way, a medication that might not be considered adequate by itself might be part of an effective regimen that is put together under the combining approach to treatment-resistant depression.

Non-antidepressant augmenting agents that are well-studied include lithium and thyroid hormones, but these are not commonly prescribed. (Shelton, Osuntokun, Heinloth, &Corya) Atypical antipsychotic medication is increasingly used in conjunction with antidepressants for TRD. (Shelton, Osuntokun, Heinloth, &Corya) Alternative compounds are less studied, but are being explored in combination with antidepressants or as monotherapy. The include, "... pindolol, inositol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole and topiramate." (Shelton, Osuntokun, Heinloth, &Corya)

Several experimental pharmaceutical treatment alternatives for TRD are also being explored in combination with antidepressants or as monotherapy. These less studied alternative compounds include pindolol, inositol, CNS stimulants, hormones, herbal supplements, omega-3 fatty acids, S-adenosyl-L-methionine, folic acid, lamotrigine, modafinil, riluzole and topiramate. The hetrogeneity of depression and the urgency of achieving remission are strong incentives for the developments in treating TRD.

Pregnancy and Postpartum Depression

During their childbearing years, many women experience major depression. This can reduce the quality of self care during pregnancy as well as of parenting. Although medication during pregnancy is generally avoided, its use can outweigh the risks when depression threatens pregnancy and early parenting. When severe or involving psychotic symptoms, ECT may be preferred because of its speed and safety.

Postpartum depression is quite common, and potentially very serious. Over 10% experience major depression within their first year after delivery. However, many do not gain medical attention for this. Over 80% of women develop some form of mood disturbance postpartum. Most only experience a temporary problem known as "the baby blues" characterized by periods of tearfulness and changes in mood. Postpartum psychosis is rare, but is most likely in women with a history of psychosis or bipolar disorder.

As of this writing, there is insufficient safety data regarding breastfeeding while taking antidepressants, but there are no warnings in place.

Substance Abuse

Psychiatric disorders, including anxiety and depression, are often comorbid with substance abuse or dependence. Depression can complicate substance abuse, and result in poorer outcomes after treatment. (Subramaniam, 2007; Bovasso, 2001) It can increase the level of disability. Early treatment of individuals with depression or anxiety can lessen the resulting level of disability. (Bovasso, 2001)



The following websites and organizations have excellent resources for the general public regarding depression.



Agid, O. and Lerer, B. (2003). Algorithm-based treatment of major depression in an outpatient clinic: Clinical correlates of response to a specific serotonin reuptake inhibitor and to triiodothyronine augmentation. International Journal of Neuropsychopharmacology, 6, 41-49. Akbaraly, T. N., Brunner, E. J., Ferrie, J. E., Marmot, M. G., Kivimaki, M., and Singh-Manoux, A. (2009). Dietary pattern and depressive symptoms in middle age. The British Journal of Psychiatry, 195, 408 - 413. doi: 10.1192/bjp.bp.108.058925

Agency for Healthcare Research and Quality. (2009). Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression. AHRQ: Agency for Healthcare Research and Quality. Available at http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=7%20&DocID=61.

Anisman, H. (2009). Cascading effects of stressors and inflammatory immune system activation: Implications for major depressive disorder. Journal of Psychiatry and Neuroscience, 34(1), 4-20.

Awan, N. R., Lozano, A., and Hamani, C. (2009). Deep brain stimulation: current and future perspectives. Journal of Neurosurgery. DOI: 10.3171/2009.4.FOCUS0982.

Bei, B., Milgrom, J., Ericksen, J., and Trinder, J. (2010). Subjective perception of sleep, but not its objective quality, is associated with immediate postpartum mood disturbances in healthy women. Sleep, 33(4), 531-538.

Belmaker, R. H., and Agam, G. (2008). Major Depressive Disorder. New England Journal of Medicine. 358(1), 55-68

Bhalla, R. N. and Moraille-Bhalla, P. (2010). Depression. EMedicine Specialties.

Bostwick, J. M., and Pankratz, V. S. (2000). Affective disorders and suicide risk: a reexamination. American Journal of Psychiatry, 157, 1925-1932.

Bovasso, G. (2001). The long-term treatment outcomes of depression and anxiety comorbid with substance abuse. The Journal of Behavioral Health Services and Research, 28(1), 42-57. DOI 10.1007/BF02287233

Clark, D. C. &Goebel-Fabbri, A. E. (1999). Lifetime risk of suicide in major affective disorders. In D. G. Jacobs (ed.), The Harvard Medical School Guide to Suicide Assessment and Intervention, pp.300-310, San Francisco: Jossey-Bass/Pfeiffer.

Duman, R. S., Heninger, G. R., &Nestler, E. J. (1997). A molecular and cellular theory of depression. Archives of General Psychiatry, 54, 597–606.

Elkin, I., Shea, M. T., Watkins, J. T., Imber, S. D., Sotsky, S. M., Collins, J. F., et al. (1989). National Institute of Mental Health Treatment of Depression Collaborative Research Program. General effectiveness of treatments. Archives of General Psychiatry, 46, 971–982.

Epperson, C. N. et al. (1999). Gonadal steroids in the treatment of mood disorders. Psychosomatic Medicine 61, 676-689.

Folstein, M. F., Maiberger, R., McHugh, P. R.(1977). Mood disorder as a specific complication of stroke. Journal of Neurology, Neurosurgery, &Psychiatry, 40, 1018–1020

Folstein, M., Liu, T., Peter, I., Buel, J., Arsenault, L., Scott, T., et al. (2007). The Homocysteine Hypothesis of Depression. American Journal of Psychiatry, 164, 861-867. doi: 10.1176/appi.ajp.164.6.861

Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. Jan 6 2010;303(1):47-53.

Frances R. J. , Franklin J., and Flavin D. K. (1987). Suicide and alcoholism. American Journal of Drug and Alcohol Abuse,(13), 327-341.

Gangwisch J. E., Babiss, L. A., Malaspina, D., Turner, J., B., Zammit, G., K., Posner, K. (2010). Earlier parental set bedtimes as a protective factor against depression and suicidal ideation. Sleep, 33(1), 97-106.

Grenyer, B. F. S., Deane, F. P., Lewis, K. L. (2008). Treatment history and its relationship to outcome in psychotherapy for depression. Counselling and Psychotherapy Research, 8(1), 21 - 27. doi: 10.1080/14733140801889055

Higdon, J. V., Frei, B. (2006) Coffee and health: a review of recent human research. Critical Reviews in F ood Science and Nutrition. 46(2):101-23. Ingram, R. E., Miranda, J., &Segal, Z. V. (1998). Cognitive vulnerability to depression. New York: Guilford Press.

Joffe, R. T. (2006). Is the thyroid still important in major depression? Journal of Psychiatry &Neuroscience, 31(6), 367–368.

Katon, W., Von Korff, M., Lin, E., et al. (1995). Collaborative management to achieve treatment guidelines. Impact on depression in primary care. Journal of the American Medical Association, 273(13), 1026-31.

Kawachi, I., Willett, W. C., Colditz, G. A., Stampfer, M. J., Speizer, F. E. (1996) A prospective study of coffee drinking and suicide in women. Archives of Internal Medicine, 156(5), 521-5.

Kelley, K., W., Bluthé, R., M., Dantzer, R., Zhou, J., H., Shen, W., H., Johnson, et al. (2003). Cytokine-induced sickness behavior. Behavior, and Immunity, Suppl 1, S112-8.

Maes, M., Yirmyia, R., Noraberg, J., Brene, S., Hibbeln, J., Perini, et al. (2009). The inflammatory &neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metabolic Brain Disorders, 24(1), 27-53.

Malberg, J., Eisch, A. J., Nestler, E. J., et al. (2000). Chronic antidepressant treatment increases neurogenesis in adult hippocampus. Journal of Neuroscience, 20, 9104-10.

Mann, J. J., Huang, Y-Y, Underwood, M. D., et al. (2000). A serotonin transporter gene promoter polymorphism (5-HTTLPR) and prefontal cortical binding in major depression and suicide. Archives of General Psychiatry. (57), 729-738.

Murray, M. L., Wong, I. C., de Vries, C. S. (2004). Treating major depression in children and adolescents: research is needed into safer and more effective drugs. British Medical Journal, 328(7438), 524-5.

Nelson, J. C. (1997). Augmentation strategies for treatment of unipolar major depression. Modern Problems of Pharmacopsychiatry, 25, 34-55.

Nelson J. C. and Papakostas, G. I. (2009). Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. American Journal of Psychiatry, 166(9), 980-91.

Rush, A. J., Warden, D., Wisniewski, S. R., Fava, M., Trivedi, M. H., Gaynes, B. N., et. al. (2009). STAR*D: revising conventional wisdom. CNS Drugs, 23(8), 627-47. doi: 10.2165/00023210-200923080-00001.

Sheline, Y. I., Gado, M. H., Kraemer H. C. (2003). Untreated depression and hippocampal volume loss. The American Journal of Psychiatry, 160(6), 1516-1518.

Schmidt, P.J., et al. (2005). Dehydroepiandrosterone Monotherapy in Midlife-Onset Major and Minor Depression. Archives of General Psychiatry, 62,(2), 154–162.

Shelton, R., C., Osuntokun, O., Heinloth, A. N., Corya, S. A. (2010). Therapeutic options for treatment-resistant depression. CNS Drugs, 24(2), 131-61. doi: 10.2165/11530280-000000000-00000

Simon, G. E. (2009). The antidepressant quandary -- Considering suicide risk when treating adolescent depression. Current Opinion in Psychiatry, 355(26), 2722-2723.

Subramaniam, G. A. (2007). Baseline depressive symptoms predict poor substance use outcome following adolescent residential treatment. Journal of the American Academy of Child &Adolescent Psychiatry, 46(8).

SAMHSA. Mental Health: A Report of the Surgeon General. Rockville, MD: HHS, NIH, 1999. Thase, M. E. (2003). Evaluating antidepressant therapies: remission as the optimal outcome. Journal of Clinical Psychiatry, 64(Suppl 13), 18-25.

Thase, M. E., &Rush, A. J. (1995). Treatment resistant depression. In F. E. Bloom &D. J. Kupfer (Eds.), Psychopharmacology: The fourth generation of progress. (pp. 1081–1097). New York: Raven Press.

Tondo, L., and Baldessarini, R. J.. (2001). Suicide: Historical, descriptive, and epidemiological considerations. Medscape, 03/15.

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