Management of Depression
February 4, 2002 28 minutes read
Management of Depression
Author: Karen Broquet, MD, Associate Professor, Division of Internal medicine and Psychiatry, Southern Illinois University School of Medicine, Springfield, Ill.
Editor’s Note—A substantial proportion of primary care patients have a mental illness. At any given time, approximately 7% of a primary care practice will have a depressive disorder. A much larger number (36%) will have symptoms of depression and will rely on their primary provider to identify and treat them. This is an exciting time to take part in the care of individuals with depression. The last several years have brought about an increasing recognition of the prevalence of depression around the world, the cost it extracts in both human and economic terms, and most importantly, treatments that reduce those costs. In the last 2 years, both the Surgeon General and the World Health Organization (WHO) have devoted their annual report specifically to the recognition and treatment of mental illness, including depression. Although third-party recognition and reimbursement for treatment of mental illness has lagged behind the science, there are indications that this is changing, such as the bill mandating parity for insurance coverage of major mental illness that was recently passed by the United States Senate.Treatment options for patients with depression have included psychotherapy, pharmacotherapy, and electroconvulsive therapy. Since 1988, 9 new antidepressant medications have been developed, with more and more specific modes of action. Well-structured research protocols have demonstrated the efficacy of various psychotherapies. Historically, most research on the treatment of depression was done in formal psychiatric settings, leaving us to guess at whether these treatment strategies translate to the primary care setting. An increasing amount of research is being done on the diagnosis and treatment of depression in primary care, demonstrating the efficacy of guideline-based treatment in this setting.
This article will provide an overview of the diagnosis and management of adults with depression in primary care. It begins with a synopsis of the epidemiology, etiology, and risk factors of depression, including a description of depressive disorders. It outlines basic steps in diagnosing depressive illnesses, as well as common comorbid conditions. The next section describes general treatment concepts, including assessment of suicide risk, selection of treatment modalities, and general principles of treatment with antidepressant medication, as well as nonpharmacologic tools available in the primary care setting. The final section reviews specific medications with a brief description of pharmacologic profile and side effects.
Introduction
Few patient problems are as pervasive in a primary care practice as depressive disorders. In recent years, there has been an increasing awareness of the wide-ranging costs of depression. It is associated with the development of stroke and heart disease.1 The WHO estimates that depressive disorders are the second leading cause of loss of disability-adjusted life years for young adults, and the fourth leading cause when all age groups are included.2 In 1993, Greenberg and colleagues assessed the annual cost of depressive disorders in the United States to be $43.7 billion, roughly the same as coronary artery disease. Direct treatment costs accounted for $12.2 billion (28%) of this. The majority (55%) resulted from lost work productivity.3 Some studies have found a reduction of work impairment with adequate depression treatment.4
The depressive disorders include major depression, dysthymia, and the depressed phase of bipolar disorder. For the general population, the lifetime risk of major depression is 12.7% for men and 21.3% for women.5 In a primary care outpatient setting, 4.8-8% of outpatients will have a major depression at any given time, and up to 36% of those with general medical illness have some symptoms of depression.6 The lifetime risk for dysthymia is 6%. It is also twice as prevalent in women as men. Bipolar disorder affects 1% of the population, with an even male-female ratio.7 Depression usually manifests itself in early adulthood. It is a recurrent illness and can affect patients of all ages and socioeconomic backgrounds. When socioeconomic variables are controlled for, rates of depression are similar among Caucasians, African-Americans, and Hispanics. With one episode of major depression, the risk of recurrence is about 50%. The risk after a second episode is 70% and rises to 90% after a third episode.8
Etiology
Depression is a multifactorial disorder influenced by several genetic, biochemical, and environmental risk factors. Biological theories of the etiology of depression date back to the time of Hippocrates. He attributed melancholia to the secretion of black bile from the spleen under the influence of the planet Saturn. In 1621, Burton remarked on the influence of environmental factors such as diet, alcohol, sleep disturbance, and the vagaries of love.
Observations on the psychotropic effects of drugs have provided much of our information regarding the biology of depression. The monoamine oxidase (MAO) hypothesis evolved during the mid 20th century with the recognition that patients on reserpine tended to become depressed and patients treated for tuberculosis with isoniazid saw their mood improve. Reserpine depletes monoamines. Isoniazid inhibits MAO, blocking the metabolism of serotonin, norepinephrine, and dopamine. The precise mechanism of action of antidepressants is still not well understood. All antidepressant drugs enhance serotonergic and/or catecholaminergic systems, by presynaptic reuptake inhibition, blocking catabolism, or receptor agonism/antagonism. The traditional explanation that they work merely by increasing the availability of one or more neurotransmitters is an oversimplification. The clinical effects of antidepressants occur only after days to weeks, indicating that a cascade of events occurs. Down-regulation (reduction) in alpha and beta adrenergic receptors and 5-HT1 serotonergic receptors more closely parallels the time course of clinical response. Changes in neurotransmitter and receptor function may well be secondary effects of other, more primary abnormalities, such as structural abnormalities of the limbic system, or impairments in cellular resilience, neuroplasticity, or intracellular signaling pathways.9
Multiple neuroendochrine peculiarities have been identified in patients with depression. Depressed patients show a blunted thyroid stimulating hormone response to thyrotropin-releasing hormone challenge, as well as a blunted growth hormone response to clonidine. The relationship between stress and depression has long been recognized, and various abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are noted. Although it is not specific to depression, patients with melancholic depression show a lack of cortisol suppression to dexamethasone. Increased levels of corticotropin-releasing hormone (CRH) have been noted in the CSF of drug-free depressives. These decrease with antidepressant treatment. It is theorized that CRH mediates the stress response via the CRH1 receptor and stress-induced CRH inhibits serotonin activity. Antidepressants may act in part via enhancing corticosteroid receptor function and repressing CRH gene activity. A variety of CRH1 receptor antagonists are currently in development as future antidepressants.10
Contemporary psychiatry has entertained multiple psychological explanations for disruptions of mood. The models that seem most applicable currently are those of disrupted interpersonal relationships, learned helplessness, and negative cognitive patterns, which bias a depressed person’s interpretation of life’s events. These 3 models have been incorporated into specific psychotherapies with some level of validation. Although the nature vs. nurture question is incompletely resolved, heredity plays a part, with family history of depression, alcoholism, and suicide all higher in depressed patients as compared to controls.
Risk factors for development of depression have been simpler to identify than a concrete etiology. These include a family history of depression or substance abuse, a personal history of depression or any other psychiatric disorder, female gender, childhood loss or trauma, negative life events, chronic stress, and poor social support system.
Diagnosis
Making a diagnosis of a major depressive episode requires the presence of 5 symptoms for a 2-week period. (See Table 1.) The symptoms must cause impairment in some area of functioning, and one of them must be a depressed mood or loss of interest or pleasure. Depressed individuals may offer multiple vague somatic complaints. Among patients with severe medical illnesses, constitutional symptoms, such as anorexia, fatigue, or sleep disturbance, are not as useful in discerning the presence of a depression. Feelings of worthlessness, guilt, or crying spells are often more diagnostically helpful in this population. It is not uncommon for depressed individuals to describe themselves as feeling empty or numb. Other common symptoms of depression include irritability, hopelessness, reduced libido, and crying spells.
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Subtypes of depression can involve melancholic, atypical, and/or psychotic features. Melancholic depression is characterized by the presence of anhedonia (loss of ability to experience pleasure, even when something good happens), a diurnal variation in mood, with the depressed mood typically worse in the morning, early morning awakening, excessive guilt, or significant weight loss. Melancholic depression is severe and not likely to respond to support or psychotherapy alone. A person with atypical features often has a life-long history of being overly sensitive to rejection by others and may retain the ability to feel brighter in response to positive events. Hypersomnia and an increase in appetite are often seen. Patients with atypical features respond more favorably to serotonergic agents than other antidepressants and often require psychotherapy. Severe depression may be accompanied by psychotic features such as hallucinations or delusions, or by catatonia. Psychotic depression carries a high risk of suicide and generally requires treatment with antipsychotic medication or electroconvulsive therapy (ECT) along with antidepressants.
Dysthymia and major depression differ mainly in chronicity and severity of symptoms. There is a high degree of overlap, and many patients with dysthymia go on to develop a major depression. The concomitant presence of both illnesses is referred to as double depression. Decisions regarding whether and how to treat should be based on symptoms and level of functioning rather than categorical diagnosis.
More than 40% of patients with a major depression will have another psychiatric disorder.11 Substance abuse, personality disorders, generalized anxiety or panic disorders, social anxiety, obsessive compulsive disorder, and eating disorders are common comorbid conditions. In the presence of significant psychiatric comorbidity, treatment of the depression is generally a necessary, but not sufficient, approach to helping a patient to wellness. All patients who present with depressive symptoms should be asked screening questions about comorbid disorders. At a bare minimum, it is vital to inquire about substance use. Substance abuse can markedly increase suicide risk and may often directly precipitate a depressive disorder. Likewise, inquiries about any history of manic symptoms must be made of all depressed patients, as treatment with antidepressant medications in bipolar individuals may precipitate a manic episode. Additional history and physical exam should identify medical problems that may be co-existing or causative. If the onset of depressive symptoms corresponds with the initiation of any medication, a trial off the medication should be arranged if possible. A brief psychosocial assessment should also be done to identify any stresses, losses, or behaviors that may be contributing to the mood symptoms, and to identify the patient’s social supports. If a depressive disorder is present, it can and should be treated even in the presence of identified stressors.
Evaluation of Suicide Risk
The statistics regarding suicide are staggering. In the United States, the suicide rate is 11.4 per 100,000 population. It has increased 3.5% between 1980 and 1995, making it the 8th leading cause of death for all Americans, and the third leading cause for young people ages 15-24. Between 1952 and 1995, the suicide rates for adolescents and young adults have nearly tripled. Caucasian youths overall have a higher rate of suicide, but the rate among minorities is rising. Since 1989, the suicide rate has increased 19% for young white males and an alarming 114% for young African American males in the Midwest.12-14 There is a clear correlation between depression and suicide, in that 45-64% of adults who kill themselves had a depressive illness. The lifetime risk of suicide in all patients with major depression has been estimated to be 2.2-3.5%.15,16 The risk goes up with severity of illness and hospitalization to 10-15%.16 The presence of substance abuse substantially increases the suicide risk, as does recent loss of a relationship, or ever having been hospitalized for suicidality. Other risk factors include being male, adolescent or elderly, or having a chronic illness, family history of suicide, history of impulsive behaviors, or access to firearms. The presence of a well-developed plan has long been considered a robust predictor for suicide, although this has recently been called into question.17
Clinical symptoms associated with suicide risk include severe anxiety or agitation, anhedonia, global insomnia, and the presence of hopelessness and helplessness. (See Table 2: click here.)
The number one cause of suicide is untreated depression. The very act of identifying and appropriately treating our patients’ depression vastly reduces their risk. This is nicely illustrated by Rihmer and associates.18 They reported on a training program on the diagnosis and treatment of depression to all the general practitioners in Gotland, Sweden. Over the following years, there was a significant decrease in the frequency of suicide. A patient with any degree of depressive symptoms must be asked directly about the presence of suicidal thoughts or plans. The presence of significant suicidal ideations warrants immediate treatment.
Approach to Treatment
Establishing Goals of Treatment
Successful treatment of depression is often measured in terms of response or recovery. Response is traditionally defined as a 50% reduction in score on a standardized rating instrument. A patient in recovery or remission no longer meets the criteria for depression on a rating instrument. It indicates wellness. Full recovery means a return to predepression level of functioning, working, and interpersonal relationships. Approximately 65% of depressed patients will have a full recovery, 20-25% will have a response, and 5-10% of patients will continue to have significant symptoms after 2 years of treatment.19 Patients with a longer duration of illness, chronic social difficulties, and significant comorbidity will have lower rates of recovery. For most patients, particularly those with a first episode, full recovery should be the goal.
General Principles of Management
Antidepressant medications are the mainstay of depression treatment in primary care. Twenty-three antidepressants are available in the United States. Usual doses of commonly prescribed drugs are outlined in Table 3 (click here). Antidepressant medications have a response rate of 50-60% in the treatment of depressed primary care patients.20 All have shown efficacy in the treatment of mild-moderate depression. Tricyclic antidepressants (TCAs), venlafaxine, bupropion, and mirtazapine have shown effectiveness in hospitalized patients. Some, but not all studies, have found agents that affect norepinephrine as well as serotonin to be more efficacious in severely ill, melancholic patients than selective serotonin reuptake inhibitors (SSRIs).21-26 Serotonergic agents are more useful in patients with atypical features.
Antidepressant drugs vary widely in their side-effect profiles. These are outlined in Table 4 (click here). Drug selection is based on side effect profile, history of response in the patient or first-degree relative, overdose potential, comorbid illness, potential for drug interactions, and patient preference. Economic factors often play a role. Newer antidepressant drugs are expensive to the individual consumer. However, overall costs for fluoxetine, paroxetine, and nefazodone have been found to be equal to or less than the much less expensive TCAs.27-31 Some antidepressants are priced the same regardless of dosage, so medication costs can often be kept down by prescribing the largest available pill size.
Multiple evidence-based guidelines and treatment algorithms are available for pharmacological treatment of depression.6,20,32,33 Most were developed in psychiatric settings. In their review of the treatment of major depression in primary care practice, Schulberg and colleagues concluded that the efficacy of guideline-based pharmacotherapy transfers from psychiatric to primary care settings.20 Figure 1 outlines a medication algorithm that can be used by a primary practitioner. Once a drug is chosen, patience is required to achieve an adequate dose for a sufficient length of time. A sufficient length of time is generally defined as 4-6 weeks. With severely ill or suicidal patients, medication changes or increases are often made sooner. Use maximal tolerated doses before adding or changing agents, as most medication treatment failures stem from inadequate dosage or duration.
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If a clear improvement in symptoms is seen at 4-6 weeks, continue the medication. If a partial response (less than 50% improvement in symptoms) is seen, significant improvement may follow. Continue the medication at an increased dose or augment. Augmentation of antidepressant medication is more likely to be successful in the face of a partial response than no response at all. Multiple strategies for antidepressant augmentation have been described. Lithium, thyroid hormone, and psychotherapy have been the most well-studied. Methylphenidate, buspirone, and mood stabilizers have been reported as well.34-39 (See Table 5.) Benzodiazepines can be very helpful in relieving anxiety associated with depression but are not useful for treatment of depression or augmentation. If no improvement is noted at 4-6 weeks at an adequate dose, change agents. At this point, reevaluate the diagnosis and reassess for confounding factors, such as substance use, psychosocial problems, etc.
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Reassess at 12 weeks. If a clear improvement in symptoms and functioning is not noted in spite of the earlier changes, augment with a different agent or change medication. When the decision is made to change agents due to lack of response, it makes sense to choose a drug with a different pharmacological effect. For example, rather than changing from one SSRI to another, consider a move to a noradrenergic drug or one with both noradrenergic and serotonergic properties.
For patients who do not respond to trials of any single agent, combinations of antidepressants can be of use. Open-label studies of SSRIs combined with bupropion, desipramine, or mirtazapine40-45 have reported greater improvement than SSRI alone in refractory patients. When using antidepressants in combination with an SSRI, the choice of second drug should be based on pharmacologic action and side effect profile. For example, in a highly anxious patient, the sedating agents mirtazapine, nefazodone, or desipramine would be a more logical choice than the more stimulating bupropion. Titrate the second drug slowly, monitoring for drug interactions and additive side effects. Many SSRIs inhibit the cytochrome P450 IID6 system, which is the primary locus of TCA metabolism. Use one third of the usual TCA dose as well as frequent blood levels.
If a patient is not responding to treatment, the decision to seek psychiatric consultation or referral depends on many factors, including availability of resources, comfort level of the primary practitioner in treating depression, and patient preference. The presence of psychotic symptoms, significant suicide risk, or a history of mania should be indicators for immediate referral. Psychiatric consultation can take multiple forms, such as referral for formal psychotherapy, diagnostic evaluation with recommendations for management by the primary practitioner, or continuing care and treatment by the consulting psychiatrist. When obtaining psychiatric consultation because of lack of response to treatment, it is very helpful to discuss the goals of the referral with the patient and the consulting psychiatrist before the patient is referred.
Once remission has been achieved, medication should be continued for a minimum of 4-9 months, followed by a slow taper with close monitoring for return of symptoms. Re-educate the patient at this point regarding the time course of depression, as it is tempting to stop medications once symptoms are relieved. In the face of multiple depressive episodes or a severe, prolonged episode, maintenance therapy beyond 9 months is warranted. Maintenance antidepressant doses are the same as those for acute treatment.
Nonpharmacological Management
Patients with more severe symptoms need early and frequent follow-up. Valuable psychosocial intervention can be provided in the primary care setting. First and foremost is support and education for the patient and his or her family. This can help reduce feelings of hopelessness, isolation, and guilt, which are often present. Information about medication side effects can improve compliance. Patients need to be aware that antidepressant medications will not exert their effect until 4 weeks or more at a therapeutic dose. It is vital to counsel patients regarding the importance of stress management and the reduction or elimination of alcohol.
Various psychotherapies have been found to be efficacious in the treatment of depression, particularly in the mild-moderate range. Formal psychotherapy is labor intensive, requires referral to a mental health provider, and is not always readily available. Much of the information on the efficacy of psychotherapy comes from trials in psychiatric treatment settings, rather than primary care. In contrast, Mynors-Wallis and associates compared the effectiveness of brief problem-solving treatment in primary care clinics with antidepressants and placebo.46,47 They found the problem solving to be as effective as medication and more effective than placebo. The combination of problem solving and medication was no more effective than either treatment alone. This manual-based psychological intervention, which consisted of an initial hour-long meeting and 6 30-minute treatment sessions over 12 weeks, was delivered by either general practitioners or nurses. Both were equally well received by patients. For patients with mild-moderate levels of depression, "do it yourself" problem-solving materials are available.48 Patients with psychosocial stressors, relationship difficulties, prominent negative thinking patterns, or who prefer not to take antidepressant medication should be considered candidates for psychotherapy referral. A combination of medication and psychotherapy may benefit folks who have not recovered with one or the other. (See Table 6: click here.)
Antidepressant Medications
Selective Serotonin Reuptake Inhibitors (SSRIs). For many clinicians, SSRIs are the first-line medications of choice for depression. Their efficacy in mild-moderate depression has been well established. They also have anti-anxiety and anti-panic properties. They have a large therapeutic window, and a more limited side effect profile than their tricyclic predecessors. SSRIs include fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine. Fluvoxamine is approved by the FDA only as an anti-obsessional drug. In one open-label trial with primary care depressed patients, paroxetine, fluoxetine, and sertraline showed similar rates of effectiveness.49
SSRIs inhibit the presynaptic reuptake of serotonin. They lack any appreciable noradrenergic or anticholinergic effects, and most have negligible alpha adrenergic blockade. Exceptions to this are paroxetine, which is mildly anticholinergic and blocks the reuptake of norepinephrine in vitro at higher doses, and sertraline, which is a mild alpha 1 blocker. The most common side effects are gastrointestinal distress, insomnia, anxiety or agitation, tremor, headache, and sexual dysfunction. Dry mouth, sweating, and dizziness can occur as well. All SSRIs except fluvoxamine can be dosed once per day, generally in the morning with food to reduce nausea. A minority of patients experience sedation and prefer bedtime dosing. Although some patients gain weight, SSRIs do not generally stimulate the appetite. Anorexia is noted more commonly with fluoxetine. Nausea, headache, and agitation tend to improve over time. Unfortunately, habituation occurs less frequently with SSRI-induced sexual dysfunction. Anorgasmia, delayed orgasm, decreased libido, and genital anesthesia have all been reported. The rates of SSRI-related sexual dysfunction range from 1.6-50%.50-52 The assessment of sexual dysfunction is complicated, as it is commonly associated with depression and relationship difficulties. Management strategies are guided more by anecdotes and case reports than good clinical trials. Dose reduction or increased genital stimulation is sometimes helpful. The addition of bupropion, buspirone, or sildenafil has been reported to be useful.53-55 Case reports describe improvement with cyproheptadine or yohimbine.55,56 Switching to nefazodone, bupropion, or mirtazapine, which have less effect on sexual function, can be an option.
SSRIs inhibit multiple subtypes of the hepatic cytochrome P450 system. Fluoxetine and paroxetine are the most potent inhibitors of the IID6 system, followed by fluvoxamine, sertraline, and citalopram. Fluvoxamine is a potent inhibitor of the IIIA4 system and can slow benzodiazepine metabolism. With all antidepressants, the administration of an MAOI can result in a serotonin syndrome, with hyperpyrexia, muscular rigidity, seizures, and mental status changes.
Nefazodone. This drug antagonizes the 5HT2 receptor. Its active metabolite acts as a serotonin reuptake inhibitor, as well as a direct serotonin agonist. Multiple 5HT receptor subtypes have been identified. Stimulation of the 5HT1a subtype is thought to be related to anxiolytic and antidepressant effects. 5HT2 stimulation induces anxiety, insomnia, and sexual dysfunction. Because of the 5HT2 blockade, nefazodone causes less insomnia, sexual dysfunction, and anxiety/stimulation than SSRIs. It does not block muscarinic, H1, or dopamine receptors, nor does it reduce REM sleep. It has a moderate alpha 1 blockade. Primary side effects are sedation, dizziness, nausea, dry mouth, and subjective mental confusion. Weight gain is rare. Nefazodone is useful in the presence of significant insomnia or anxiety, or SSRI-induced sexual dysfunction. The dose range is 300-600 mg. Its short half-life necessitates b.i.d. dosing. It is a potent CYT IIIA4 inhibitor. There have been reports of nefazodone-related liver failure. It should not be used in patients with active liver disease.57
Bupropion. Bupropion has been found to be efficacious in both outpatients and refractory hospitalized patients and is also marketed for smoking cessation. This noradrenergic drug is a weak inhibitor of dopamine reuptake. It has no serotonergic properties and no antagonism of 5HT2, H1, alpha 1, or muscarinic receptors. Bupropion is generally well tolerated. Primary side-effects are nausea and mild agitation. It exhibits little/no sedation, weight gain, anticholinergic effect, orthostasis, sexual dysfunction, or cardiotoxicity. The risk of seizure at doses < 450 mg/d is 0.4%, compared with 0.1% for other antidepressants. Patients at highest risk for seizures are those with a history of convulsions, eating disorder, head injury, or taking doses > 450 mg/d or > 150 mg/dose. It is dosed b.i.d. or t.i.d., depending on the dose. It is also available in a sustained release form (bupropion SR). At doses at or below 300 mg/d, the seizure risk is comparable to other antidepressants. At 400 mg/d, the seizure risk is 0.4%. Doses > 400 mg/d or > 200 mg/dose are associated with increased seizure risk. Bupropion SR can be dosed daily if below 150 mg/d, b.i.d. if above.
Venlafaxine. Clinical trials have found venlafaxine to be efficacious in severely depressed, hospitalized patients and superior to fluoxetine in melancholically depressed patients.58 It has significant anxiolytic effects as well. Pharmacologically, this drug can be considered a 21st century TCA. It inhibits the reuptake of serotonin and norepinephrine and, to a much lesser extent, dopamine. Because it does not block muscarinic, histaminic, or adrenergic receptors, it is relatively free of orthostasis, sedation, weight gain, or anticholinergic effects. Primary side effects are similar to the SSRIs. One study found nonsignificantly lower rates of sexual dysfunction with venlafaxine.52 It is not a potent inhibitor of any cytochrome P450 isoenzyme. An extended release form is available, allowing once-daily dosing. Venlafaxine has a linear dose-response curve. The dose range is 75-225 mg/d, although severely depressed individuals may require higher dosage. At lower doses (< 150 mg), it functions basically as an SSRI. Significant noradrenergic reuptake inhibition is seen at doses > 150-225 mg. Dose-dependent elevations in diastolic blood pressure have been observed with both the regular-release and XR compounds. Monitor blood pressure for patients on either formulation.
Mirtazapine. Mirtazapine is the newest and the most pharmacologically complicated of the available atypical antidepressants. It is a potent blocker of presynaptic alpha 2 autoreceptors. This causes norepinephrine release and subsequent serotonin release. In addition, it blocks 5HT2, 5HT3, and H1 receptors. Nausea, agitation, and sexual dysfunction are minimal. Prominent side effects are sedation, appetite stimulation/weight gain, light-headedness, and dry mouth. Weight gain may present a limitation to the use of this effective antidepressant in some patients. Mirtazapine has been compared to multiple TCAs and venlafaxine in the treatment of severe or melancholic depression and found to be equally effective and better tolerated. Some studies used doses up to 80 mg/d, considerably higher than the 15-45 mg recommended for average use.59 Because it is not cardiotoxic and does not lower the seizure threshold, it is thought to be relatively safe in overdose.60 Significant drug interactions or cytochrome P450 inhibition have not been identified. Montgomery reported a 0.062 incidence of agranulocytosis, compared with 0.014% for placebo and 0.045% for other antidepressants.61 No specific blood monitoring is recommended.
Reboxetine. Currently available only in Europe, reboxetine is a selective norepinephrine reuptake inhibitor, which is awaiting FDA approval. Among severely ill patients, it was found to be equal in efficacy to imipramine. In a comparison trial with fluoxetine, it was found to have similar antidepressant efficacy, with a superior response among severely ill patients. Reboxetine was also associated with greater improvement in social functioning. Side effects are mild, consisting of dry mouth, insomnia, blurred vision, sweating, and constipation.62-65
Cyclic Antidepressants. TCAs are no longer used in the first-line treatment of depression. However, they remain an important ally in the treatment of severe or refractory depression. They block the reuptake of serotonin and norepinephrine to varying degrees and are potent blockers of muscarinic, H1, and alpha 1 receptors. Common side effects include anticholinergic effects, sedation, weight gain, orthostasis, tachycardia, dizziness, and sexual dysfunction. Dose-related cardiac conduction delays and seizures contribute to their high toxicity in overdose. Secondary amines (nortriptyline and desipramine) carry these side effects to a lesser extent than tertiary amines (amitriptyline, imipramine, doxepin) and are generally considered to be TCAs of choice. Tricyclics remain unique among the antidepressants in the availability of clinically useful plasma levels.
Trazodone is a mixed serotonin agonist/antagonist with strong blockade of H1 and alpha 1 receptors. Its high degree of sedation, dizziness, and orthostasis make it difficult for patients to tolerate full antidepressant doses (300-600 mg). It is used more commonly in subtheraputic doses for its sedative and anxiolytic properties. Trazodone is associated with a 0.02% risk of priapism in men. Maprotiline and amoxapine are primarily noradrenergic agents reserved for use in refractory patients. Maprotiline has a significant seizure risk, and amoxapine can cause tardive dyskinesia.
Monoamine Oxidase Inhibitors (MAOIs). MAOIs are reserved for the treatment of refractory patients or severe depression with atypical features, because of the need for a low-tyramine diet and potentially toxic drug interactions. Moclobemide is a reversible inhibitor of MAO-A that is used extensively in Europe and Canada but not yet available in the United States. No dietary restrictions are required with this drug, which does not cause sexual dysfunction.
Special Considerations
With elderly or medically compromised patients, apply the "start low and go slow" rule. Be extra vigilant for drug interactions and comorbid medical conditions. Severely depressed pregnant or nursing patients present a special dilemma in weighing the risk of medication against the risk of an untreated severe depression. Unless patients are severely impaired or suicidal, psychotherapy is generally the preferred treatment. Primary concerns with medication use during pregnancy are fetal loss, congenital abnormalities, and long-term behavioral teratogenicity. No randomized controlled trials are available for obvious reasons. Follow-up studies on women exposed to several TCAs have revealed no significant increase in miscarriage or congenital malformations, although TCA-related irritability and anticholinergic effects have been reported when used immediately before delivery.66 Neonatal seizures have been reported with clomipramine. Chambers and colleagues noted an increased risk of low birth weight and perinatal complications with third trimester exposure to fluoxetine.67 Four studies found no increased rates of teratogenicity with fluoxetine, sertraline, citalopram, paroxetine, fluvoxamine, or venlafaxine.68-71 One study of 135 children exposed to TCAs or fluoxetine found no differences in behavioral or intellectual development compared to controls.72
Other Treatment Modalities—Old and New
Light therapy can be effective in patients with a seasonal pattern of depression. Exposure to 10,000 lux white light for 30 minutes to 2 hours each morning is required. ECT is helpful in the treatment of severely or psychotically depressed patients or in patients who cannot tolerate antidepressant medication. Its onset of action is generally faster than either antidepressant medication or psychotherapy. Even with a complete response to ECT, continued therapy with medication or maintenance ECT is usually required to maintain remission.
Various novel therapies for depression are currently undergoing early clinical trials. Repetitive Transcranial Magnetic Stimulation (rTMS) is a process of depolarizing neurons by applying powerful magnetic fields in rapid flux. Coils of insulated wire carrying an electrical current are held in close proximity to the scalp, inducing magnetic activity. The patient remains awake and conscious throughout the entire procedure. rTMS has been investigated in various neuropsychiatric conditions, but the most promising results have been with affective disorders. Vagal nerve stimulation, available since 1997 for treatment resistant epilepsy, is showing promising results in the treatment of affective illness.73,74
Summary
Patients with depression in its multiple forms make up a significant portion of any primary care practice. Multiple treatment options are available, and for most patients a complete recovery should be the expectation. Accurate diagnosis and prompt and effective treatment can make a profound difference in the lives of these individuals.
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