Chapter 17: Antidepressant Agents
Depression is categorized as a mood disorder. Overall, mood disorders are classified as:1
(1) depressive disorders
(2) bipolar disorders and
(3) depression which occurs in the context of a medical illness or alcohol and substance abuse.
Depressive disorders do not exhibit manic or hypomanic components characteristic of bipolar disease.
Unipolar major depression ranked fourth among all diseases with respect to disability-adjusted life-years; furthermore, this rank is increasing and may reach second within a decade.1
Depression may occur in association with various medical illnesses.1
Perhaps as many as 1/3 of cardiac patients may exhibit depression; moreover, depressive presentations may be especially associated with unstable (Prinzmetal’s) angina, cardiac bypass surgery, myocardial infarction or heart transplant.1,26
Depression in these settings may inhibit rehabilitation and contribute to enhanced morbidity and mortality.
Variability in heart rate due to reduced autonomic parasympathetic (cholinergic) tone appears may occur with depression.
One category of antidepressants, the tricyclic antidepressants (TCAs), is contraindicated in those individuals will bundle branch blockade; furthermore, TCA-induced tachycardia may exacerbate underlying congestive heart failure.
By contrast, the serotonin specific reuptake inhibitors (SSRIs), a newer class of antidepressants, are not typically associated with either ECG (electrocardiographic) changes or adverse cardiac effects.
Depression and other psychological issues associated with convalescence following myocardial infarction.24
In the 1940s patients often were prescribed a six-month convalescence period to allow recovery from myocardial infarction (MI).
By the 1970s, "early mobilization" was recommended for patients with an uncomplicated hospital course.
For asymptomatic patients with uncomplicated coronary disease resumption of activity was recommended by some following six weeks of convalescence. At present, convalescence following myocardial infarction is often much shorter.
However, at least in the 1970s, many patients, perhaps 50%, remained inactive for an extended period exhibiting reluctance to return to work.
Psychosocial factors such as anxiety, depression, and fear of another infarction were suggested as reasons explaining reluctance to return to work.
A study involving 400 patients involved in cardiac rehabilitation concluded that unwarranted emotional distress with invalidism occurred in about half the patients.25
For those patients remaining unemployed for more than six months, psychosocial difficulties appeared responsible.
For about 50 of the 107 patients remaining unemployable, the reason appeared to be preventable psychiatric problems.
Cancer patients are also likely to exhibit depression; the overall prevalence is about 25%.1
However, with certain cancers, for example pancreatic cancer or oropharyngeal cancer the incidence may approach 40%-50% of patients.
Antidepressant medications in cancer patients may improve quality of life and mood; moreover, short-term depression, pain symptoms, and anxiety may be alleviated using psychotherapeutic management.
In the United States cancer appears responsible for about 25% of deaths, only heart disease exhibits a higher percentage.
Major depressive disorder accounts for about 4.4% of overall disease burden; this contribution is of the same order as noted for ischemic heart disease or diarrheal disease.
Disability Adjusted Life Years (DALYs) for depression may be soon greater than that observed for cancer or HIV-related disease.
Although the overall prevalence for cancer patients exhibiting depression may be about 25% as noted above, prevalence rates of depression in patients with solid tumors range from about 20%-50%.6
This estimate includes all depressive disorders as opposed to only major depressive disorder.6
When considering major depressive disorder, a recent study considering 201 recently diagnosed cancer patients concluded that about 15% of patients likely suffered from major depressive disorder.7
Another estimate of major depressive disorder, considering cancer patients many of whom had inactive disease was about 8%.8
For inpatients with hematological cancer and for breast cancer patients, major depression estimates were about 9%.9,10
Among low-income women with cancer, prevalence rates for major depressive disorder were noted at about 24%.11
Many estimates for major depressive disorder were determined near the time of cancer diagnosis; moreover, additional research is needed to determine depressive disorder prevalence in years following diagnosis.
For example, at time of first breast cancer diagnosis of major depressive disorder was estimated at 22%.12
Women with a diagnosis of early breast cancer exhibited an initial depression and anxiety prevalence of about 33% (and diagnosis), decreasing to 15% at one year but then increasing to 45% following diagnosis of recurrence.12
Another consideration is that there may be errors in estimation of the prevalence of depression in cancer.6
This concern is due to an overlap between symptoms of depression one hand and physiological effects due to cancer on the other.
For example, weight loss, reduced appetite, sleep deprivation and fatigue are symptomatic both of depression and of cancer.
One approach to address this concern has been disregarding certain somatic cancer symptoms as part of diagnostic criteria for depression; an example proposed by Memorial Sloan Kettering Cancer Center would be elimination of anorexia and fatigue from the list of DSM-IV depression presentations.
In that model, the recommendation is to only require four of the remaining seven symptoms for diagnosis. Several other models have also been presented, although the validity of such models remains to be determined.
Culture may also influence symptomatic expression.
One example considers individuals of Asian culture who have depressive disorder but tend to present somatic manifestations more prominently than psychological symptoms.
One of the most frequently reported cancer treatment side effects is fatigue, with the prevalence range reported from 25% to 99%.
Fatigue, also represents an "feeling state" unrelated to cancer treatments.15
Fatigue may be associated with depression in patients undergoing chemotherapy; however, it is frequently taken as depression.
A clinical trial study noted that the antidepressant paroxetine could affect depressive symptoms while not influencing fatigue, a chemotherapy caused effect.16
The study considered cancer patients undergoing chemotherapy for the first time. These patients were assessed for fatigue.16
Following their second chemotherapy cycle, of 704 patients reporting fatigue, 549 patients were randomly assigned either to receive 20 mg oral paroxetine (Paxil) daily or placebo for 8 weeks.
Fatigue and depression assessments were made at chemotherapy cycles 3 and 4. 244 patients treated with paroxetine and 235 patients receiving placebo provided usable data for the study.
No difference was noted in fatigue between the patient groups.16
A difference was noted in the mean level of depression.
Patients with neurologic disorders may also exhibit depressive symptoms.1
Parkinson's disease, dementia, traumatic brain injury, multiple sclerosis and cerebrovascular disorders may be associated with depressive presentations.
In the case of Parkinson's disease is the possibility that the medication L-DOPA itself may induce depression and a small number of patients.26
Depression associated with left-hemispheric stroke involving the dorsolateral frontal cortex may present in 20% of patients.
The "reactive" depression described in the post-myocardial infarction patient discussed above may also be observed in many other medical settings.27
Lesions involving left anterior cerebral anatomy especially of the lateral frontal cortex or basal ganglia appear to correlate with increased frequency and severity of patient depression, at least compared to patients with lesions at other sites.
Right hemispheric lesions did not appear similarly correlated with depression yet appeared associated with an increased incidence of "undue cheerfulness."27
The association between brain lesion location and poststroke depression appears complex.
Furthermore, this complex association does not appear well understood, even though many studies have examined this problem.
Some studies which considered a number of previous results suggest particular relationships between brain injury location and both character and severity of post stroke mood change. In that study, depressive disorders were noted in about 70% of stroke patients with left frontal brain lesions with 15% of variance in depression explained by the degree of intellectual impairment, physical impairment, quality of social support or age; on the other hand, lesion site accounted for 50% of the variance.28
Another retrospective analysis considering 34 primary research studies, however, suggested a different conclusion-that lesion location was not associated with depression.29
Pooled relative depression risk following left hemisphere stroke compared to right hemisphere stroke was 0.93.
Furthermore, these workers noted that even when restricting analyses to "higher-quality" studies or only considering major depressive disorder no association between stroke and depressive disorders were observed.
Results were not sensitive to stratification of time between stroke and assessment of depression.
Therefore, this study result did not support the hypothesis that depression risk following stroke was influenced by lesion location.29
Evaluation of the overall problem of post stroke depression and lesion location suggested several contributing factors which might explain differing conclusions.30
The population source appeared to be a major factor in result heterogeneity; for example, left hemisphere lesion location seem to contribute to poststroke depression and hospital inpatient population studies.
By contrast, right hemisphere lesion location was associated with poststroke depression development in community-based population studies.
Another problem between studies was differences in time since stroke onset and the lack of a standard tool to assess stroke depression.
Problematic statistical analysis likely also contributed to the variousness of findings.30
Several approaches employed in future work may lead to more consistent and possibly definitive findings. 30
development of an appropriate and standardized measure depression
identification of an appropriate population source for the clinical research projects
use of an optimal time since stroke onset for poststroke depression interviews and
the development of more complete predictive causal models of poststroke depression.30
In patients who appear cognitively normal (subclinical manifestations of cognitive dysfunction may be present and might be reflected in biomarker levels) yet exhibit late-onset depression may be at higher risk for an ultimate Alzheimer's disease diagnosis.
Depression of this type may be managed effectively using either SSRI-type drugs or TCA agents.
Monoamine oxidase inhibitors (MAOI) and stimulants may also be efficacious in some individuals.
Patients with diabetes mellitus exhibit depression with a prevalence range of about 8%-27%.1
The severity of depressive state appears to correlate with hyperglycemic extent and presence of diabetic complications.
Some antidepressants in this setting may complicate glycemic control; for example, MAOIs can cause both weight gain and hypoglycemia.
Tricyclic antidepressants (TCAs) administration may predispose to both carbohydrate craving and hyperglycemia.
Although more manageable than MAOIs, serotonin-selective reuptake inhibitors (SSRIs) may reduce fasting plasma glucose.
Depressed mood and memory impairment are characteristics of hypothyroidism.1
Hyperthyroid states at least in geriatric populations may present in a comparable way.
Mood improvement is associated with correction of abnormal thyroid function; however, antidepressant medication may still be required.
Subclinical hypothyroidism may also be associated with depressive symptoms and cognitive dysfunction.
These effects appear to improve with thyroid replacement.
Depression exhibits a lifetime prevalence of about 22%-45% in HIV-positive individuals.1
The relationship between HIV infection and depression is likely multifactorial involving psychological factors, central nervous system disease and immune function changes.
Major depression represents the most common psychiatric disorder in patients with HIV/AIDS.17
HIV disease progression is also associated with an increase incidence of depressive disorders.17
Presentations of depression in HIV patients mirror those seen in non-HIV infected individuals and include as major symptoms:
feelings of worthlessness
weight loss or weight gain
By analogy with depression associated with cancer, a difficulty in diagnosis of depression in the presence of HIV/AIDS is that some symptoms are shared between systemic consequences of HIV infection and depression.17
For example, weakness, weight loss, and fatigue represent presentations that may be due to the HIV infection itself or could be due to depression.
Affective aspects of depression are similar to those of "chronic grieving state" which may be associated with multiple losses that individuals with HIV/AIDS may experience.
Furthermore, neurological impairment secondary to HIV-associated dementia may cause affective changes. HIV-associated hypogonadism may be responsible for fatigue, reduced libido, as well as other symptoms of depression.
In these patients testosterone supplementation may reverse symptoms of depression.
Medications effective in management of HIV/AIDS may themselves be associated with mood changes.
Untreated depression appears to be both a major factor in poor quality of life for HIV-infected individuals and a contributor to noncompliance with HAART (Highly Active Antiretroviral Therapy) drug protocols.17
Lastly, chronic fatigue syndrome and fibromyalgia are associated with depression and anxiety. Some patients appear to benefit from antidepressant treatment.1
Major Depressive Disorder: Diagnostic Criteria based on DSM-IV:2,19
Five (or more) of the following presentations must be noted during the same two week period; furthermore, the presentations should represent a change and that at least one of the symptoms is either reduced interest or pleasure or depressed mood.
Reduced interest or pleasure
Notable weight loss when not dieting or weight gain or a change in appetite
Hypersomnia or insomnia
Psychomotor agitation or retardation
Reduced energy or fatigue
Feelings of worthlessness or inappropriate or excessive guilt
Reduced ability to concentrate or increased indecisiveness
Recurrent thoughts of death or suicide
In addition, presenting symptoms do not meet the criteria for a "Mixed Episode".
Symptoms result in significant distress or impairment in occupational, social or other important functions.
Symptoms are not associated with direct physiological effects of a substance, as might be the case with ingestion of a drug of abuse or medication, and also not associated with a general medical condition, such as those noted above.
Symptoms are not better explained by "Bereavement" following, for example, the loss of a loved one.
Symptoms last longer than two months;
Symptoms are associated with marked functional decline, morbid preoccupation with worthlessness, psychotic symptoms, suicidal ideation, or psychomotor retardation.
Additional Clinical Issues:
Increased risk of suicide is associated with major depressive disorder and physicians should assess risk by direct questioning if patients are otherwise reluctant to discuss this issue.
Factors favoring immediate referral to a mental health care specialist in this setting include patient developing specific suicide plans, prior suicide attempts, profound helplessness, substance abuse, concurrent medical illness or social isolation-with these latter issues constituting significant risk factors.
Near-term increased suicide risk is associated with anxiety, panic, or agitation.
The risk of suicide in depressed patients is about 4%-5%; moreover, most patients will have been seen by a physician within about one month prior to death.
Since many patients who complete suicide have made prior unsuccessful attempts, suicide risk-stratification, which identifies patients at highest risk for suicide attempt recurrence and death, is important.
The method used in attempting suicide may ultimately predict mortality risk.1,20,21
A clinical study in Sweden considered suicide attempts over a nine-year period, 1973 to 1982.20,21
The main outcome measure was completed suicide from 1973 to 2003. Data analysis considered basic demographics, psychiatric diagnoses, level of education, and method of suicide attempt.
The study considered over 48,000 people admitted to hospital following suicide attempt from 1973 to 1982.
About 12% (5740) individuals completed suicide during the 2-3 decade of follow-up surveillance.
The most common method of attempted suicide was poisoning (84%); accordingly, this method was used as a reference for other comparisons.
Patients who attempted suicide by hanging, suffocation, or strangulation had the worst prognosis as 54% of men and 57% of women would later complete suicide.
Of patients in this high-risk group, 87% of those who completed suicide did so within a year of their initial attempt.
Lower-risk methods, similar to poisoning in risk, included piercing, gassing, and cutting.
Intermediate-risk methods, associated with a higher risk of suicide completion compared to poisoning, included drowning, firearm use, or jumping.
Some psychiatric disorders appeared independently associated with suicide.
These included both psychotic disorder and affective disorder. Most patients completing suicide used the same method as in the initial attempt; most common methods used again successfully following the initial attempt were drowning, hanging, firearm use (males) and jumping.20,21
Depression may be a continuous condition, rather than episodic in nature.
Furthermore, the chronic condition may not be connected with either psychosocial dysfunction or changes in the patient's typical life experiences.
Dysthymic disorder refers to a chronic condition lasting at least two years and exhibiting mild depressive symptoms which appear less disabling and severe, compared to those associated with major depressive disease.
Dysthymic disorder and major depression may present concurrently.
Patients exhibiting pessimism, disinterest, low self-esteem may be responsive to antidepressant therapy.
Dysthymic disorder may be present in about 5% of primary care patients.
Also, minor depression may be used to describe individuals experiencing at least two depressive symptoms for about two weeks yet do not meet criteria for major depression.
Minor depression, however, may be associated with disability and significant morbidity and may respond to pharmacological intervention.
The DSM-IV Diagnostic Criteria for Dysthymic Disorder:2,19
Depressed mood for most of the day, four more days than not, as indicated either by subjective account or observation made by others, for at least two years. (In children and adolescents, mood can be irritable and duration must be at least one year).
Presence, while depressed, of two (or more) of the following:
Poor appetite or overeating
Insomnia or hypersomnia
Low-energy or fatigue
Difficulty in decision-making
Feelings of hopelessness
During the two-year period (one year for children or adolescents) of the disturbance, the person has never been without the symptoms in the prior to criteria for more than two months at a time period.
No major depressive episode has been present during the first two years of the disturbance (one year for children and adolescents); i.e., the disturbance is not better accounted for by chronic major depression disorder, or major depressive disorder, in partial remission.
(There may have been a previous major depressive episode provided there was a full remission (no significant signs or symptoms for two months) before development of the dysthymic disorder.
In addition, after the initial two years (one year in children and adolescents) of dysthymic disorder, there may be superimposed episodes of major depressive disorder, in which case both diagnoses may be given when the criteria are met for a major depressive episode.
There has never been a manic episode, a mixed episode, or a hypomanic episode, and criteria have never been met for cyclothymic disorder.
The disturbance does not occur exclusively during the course of a chronic psychotic disorder, such as schizophrenia or delusional disorder.
The symptoms are not due to the direct physiological effect of a substance (e.g., drug abuse, a medication) or a general medical condition (e.g. hypothyroidism).
The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Early onset is described as occurring before the age of 21; late onset disorders described as occurring at age 21 or later.
"Dysthymic disorder" was introduced in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III).2
The intent at the time was to create a diagnostic framework accommodating a heterogeneous set of depressive neuroses disorders.
Prior to the DSM-III publication, analysis in rural primary care patient populations suggested that between about 4%-6% of patients exhibited an intermittent depression with perhaps 10% of patients exhibiting a disorder, including significant depressive components which appeared to fall outside specific depressive disorder categories.
Dysthymic disorder may be one of many disorders that could be described as "subsyndromal mood states."2
Risk factors for the development of dysthymic disorder exhibits a lifetime prevalence in the general population of about 3% include:
familial pattern, since dysthymia presents more commonly among first-degree relatives of individuals exhibiting major depression, compared to the general population.
Dysthymia typically occurs most frequently prior to the age of 45; however, 20% of cases occur after age 65.
Lastly, dysthymia occurrence may be slightly less in African-American individuals compared to whites.
As noted above, the lifetime prevalence of dysthymic disorder in the general population is about 3% which is only slightly less than that reported for major endogenous depression (about 5%).
The 1-month point prevalence rate, as described in the Epidemiologic Catchment Area (ECA) survey for dysthymic disorder is about 3.3% which ranks this disorder second only to phobia and more common than alcoholism and all other assessed mental disorders (see below).2
Depression occurs about twice as often in women as in men; furthermore, in both sexes, increased incidence is observed with age.
Liability to major depression in adult women appears due to genetic predispositions, with this conclusion based on twin studies.
Genetic factors alter an individual’s sensitivity to life's stressful events, given that negative events may contribute to and in some cases precipitate depression.
Precipitation and evolution of depressive episodes appear influenced both by psychosocial and biological factors.
Among stressors, the most potent ones appear to involve death of a relative, substantial marital or relationship problems, or assault.
Unipolar depression usually presents first in early adulthood, recurring episodically thereafter.
The number of past episodes represents the best predictor of future risk.
About half of patients having had a first episode will likely have at least 1 to 2 later episodes.
In some individuals experiencing multiple episodes, subsequent episodes may become both more severe and frequent.
An untreated episode may last from a few months to greater than one year.
The nature of recurring episodes in unipolar depression is often similar with respect to duration, frequency, and presentation.
In a few patients, a severe depressive episode may evolve to a psychotic state.
In elderly patients, depressive symptoms may be linked to cognitive deficits which present similarly to dementia and made described as "pseudodementia."
Depression which exhibits a seasonal dependency is described as seasonal affective disorder, which is more common in women with symptoms including fatigue, weight gain, anergy, hypersomnia and carbohydrate craving.
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