Table of Contents

Treatment Strategies in Mood Disorders

Treatment of patients with mood disorders should be directed toward several goals. First, the patient\'s safety must be guaranteed. Second, a complete diagnostic evaluation of the patient is necessary. Third, a treatment plan that addresses not only the immediate symptoms but also the patient\'s prospective well-being should be initiated. Although current treatment emphasizes pharmacotherapy and psychotherapy addressed to the individual patient, stressful life events are also associated with increases in relapse rates. Thus, treatment should address the number and severity of stressors in patients\' lives.

Overall, the treatment of mood disorders is rewarding for psychiatrists. Specific treatments are now available for both manic and depressive episodes, and data indicate that prophylactic treatment is also effective. Because the prognosis for each episode is good, optimism is always warranted and is welcomed by both the patient and the patient\'s family. Mood disorders are chronic, however, and the psychiatrist must educate the patient and the family about future treatment strategies.

Hospitalization

The first and most critical decision a physician must make is whether to hospitalize a patient or attempt outpatient treatment. Clear indications for hospitalization are the risk of suicide or homicide, a patient\'s grossly reduced ability to get food and shelter, and the need for diagnostic procedures. A history of rapidly progressing symptoms and the rupture of a patient\'s usual support systems are also indications for hospitalization.

The first and most critical decision a physician must make is whether to hospitalize a patient or attempt outpatient treatment. Clear indications for hospitalization are the risk of suicide or homicide, a patient\'s grossly reduced ability to get food and shelter, and the need for diagnostic procedures. A history of rapidly progressing symptoms and the rupture of a patient\'s usual support systems are also indications for hospitalization. A physician may safely treat mild depression or hypomania in the community if he or she evaluates the patient frequently. Clinical signs of impaired judgment, weight loss, or insomnia should be minimal. The patient\'s support system should be strong, neither over-involved nor withdrawing from the patient. Any adverse changes in the patient\'s symptoms or behavior or the attitude of the patient\'s support system may suffice to warrant hospitalization.

Patients with mood disorders are often unwilling to enter a hospital voluntarily, and may have to be involuntarily committed. These patients often cannot make decisions because of their slowed thinking, negative Weltanschauung (world view), and hopelessness. Patients who are manic often have such a complete lack of insight into their disorder that hospitalization seems absolutely absurd to them.

Psychosocial Therapy

Major Features of Three Psychotherapeutic Approaches to Depression

Feature Psychodynamic Approach Cognitive Approach Interpersonal Approach

Major theorists
Freud, Abraham, Jacobson, Kohut Plato, Adler Beck, Rush Meyer, Sullivan, Klerman, Weissman Concepts of pathology and cause
Ego regression: damaged self-esteem and unresolved conflict due to childhood object loss and disappointment
Distorted thinking: dysphoria due to learned negative views of self, others, and the world
Impaired interpersonal relations: absent or unsatisfactory significant social bonds

Major goals and mechanisms of change
To promote personality change through understanding of past conflicts; to achieve insight into defenses, ego distortions, and superego defects; to provide a role model; to permit cathartic release of aggression
To provide symptomatic relief through alteration of target thoughts; to identify self-destructive cognitions; to modify specific erroneous assumptions; to promote self-control over thinking patterns
To provide symptomatic relief through solution of current interpersonal problems; to reduce stress involving family or work; to improve interpersonal communication skills

Primary techniques and practices
Expressive-empathic: fully or partially analyzing transference and resistance; confronting defenses; clarifying ego and superego distortions

Behavioral- cognitive: recording and monitoring cognitions; correcting distorted themes with logic and experimental testing; providing alternative thought content; homework

Communicative-environmental: clarifying and managing maladaptive relationships and learning new ones through communication and social skills training; providing information on illness

Therapist role-therapeutic relationship
Interpreter-reflector: establishment and exploration of transference; therapeutic alliance for benign dependence and empathic understanding Educator-shaper: positive relationship instead of transference; collaborative empiricism as basis for joint scientific (logical) task Explorer-prescriber: positive relationship-transference without interpretation; active therapist role for influence and advocacy

Marital-family role
Full individual confidentiality; exclusion of significant others except in life-threatening situations Use of spouse as objective reporter; couples therapy for disturbed cognitions sustained in marital relationship Integral role of spouse in treatment; examination of spouse\'s role in patient\'s predisposition to depression and effects of illness on marriage

(From Karasu TB. Toward a clinical model of psychotherapy for depression. I. Systematic comparison of three psychotherapies. Am J Psychiatry. 1990;147:141)

Although most studies indicate—and most clinicians and researchers believe—that a combination of psychotherapy and pharmacotherapy is the most effective treatment for major depressive disorder, some data suggest another view: Either pharmacotherapy or psychotherapy alone is effective, at least in patients with mild major depressive episodes, and the regular use of combined therapy adds to the cost of treatment and exposes patients to unnecessary adverse effects.

Three types of short-term psychotherapies—cognitive therapy, interpersonal therapy, and behavior therapy—have been studied to determine their efficacy in the treatment of major depressive disorder. Although its efficacy in treating major depressive disorder is not as well researched as these three therapies, psychoanalytically oriented psychotherapy has long been used for depressive disorders, and many clinicians use the technique as their primary method. What differentiates the three short-term psychotherapy methods from the psychoanalytically oriented approach are the active and directive roles of the therapist, the directly recognizable goals, and the end points for short-term therapy.

Accumulating evidence is encouraging about the efficacy of dynamic therapy. In a randomized, controlled trial comparing psychodynamic therapy with cognitive behavior therapy, the outcome of the depressed patients was the same in the two treatments.

National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program found the following predictors of response to various treatments: low social dysfunction suggested a good response to interpersonal therapy; low cognitive dysfunction suggested a good response to cognitive-behavioral therapy and pharmacotherapy; high work dysfunction suggested a good response to pharmacotherapy; and high depression severity suggested a good response to interpersonal therapy and pharmacotherapy.

Cognitive Therapy

Cognitive therapy, originally developed by Aaron Beck, focuses on the cognitive distortions postulated to be present in major depressive disorder. Such distortions include selective attention to the negative aspects of circumstances and unrealistically morbid inferences about consequences. For example, apathy and low energy result from a patient\'s expectation of failure in all areas. The goal of cognitive therapy is to alleviate depressive episodes and prevent their recurrence by helping patients identify and test negative cognitions; develop alternative, flexible, and positive ways of thinking; and rehearse new cognitive and behavioral responses.

Studies have shown that cognitive therapy is effective in the treatment of major depressive disorder. Most studies found that cognitive therapy is equal in efficacy to pharmacotherapy and is associated with fewer adverse effects and better follow-up than pharmacotherapy. Some of the best controlled studies have indicated that the combination of cognitive therapy and pharmacotherapy is more efficacious than either therapy alone, although other studies have not found that additive effect. At least one study, the NIMH Treatment of Depression Collaborative Research Program, found that pharmacotherapy, either alone or with psychotherapy, may be the treatment of choice for patients with severe major depressive episodes.

Interpersonal Therapy

Interpersonal therapy, developed by Gerald Klerman, focuses on one or two of a patient\'s current interpersonal problems. This therapy is based on two assumptions. First, current interpersonal problems are likely to have their roots in early dysfunctional relationships. Second, current interpersonal problems are likely to be involved in precipitating or perpetuating the current depressive symptoms. Controlled trials have indicated that interpersonal therapy is effective in the treatment of major depressive disorder and, not surprisingly, may be specifically helpful in addressing interpersonal problems. Some studies indicate that interpersonal therapy may be the most effective method for severe major depressive episodes when the treatment choice is psychotherapy alone.

The interpersonal therapy program usually consists of 12 to 16 weekly sessions and is characterized by an active therapeutic approach. Intrapsychic phenomena, such as defense mechanisms and internal conflicts, are not addressed. Discrete behaviors—such as lack of assertiveness, impaired social skills, and distorted thinking—may be addressed but only in the context of their meaning in, or their effect on, interpersonal relationships.

Behavior Therapy

Behavior therapy is based on the hypothesis that maladaptive behavioral patterns result in a person\'s receiving little positive feedback and perhaps outright rejection from society. By addressing maladaptive behaviors in therapy, patients learn to function in the world in such a way that they receive positive reinforcement. Behavior therapy for major depressive disorder has not yet been the subject of many controlled studies. The limited data indicate that it is an effective treatment for major depressive disorder.

Psychoanalytically Oriented Therapy

The psychoanalytic approach to mood disorders is based on psychoanalytic theories about depression and mania. The goal of psychoanalytic psychotherapy is to effect a change in a patient\'s personality structure or character, not simply to alleviate symptoms. Improvements in interpersonal trust, capacity for intimacy, coping mechanisms, the capacity to grieve, and the ability to experience a wide range of emotions are some of the aims of psychoanalytic therapy. Treatment often requires the patient to experience periods of heightened anxiety and distress during the course of therapy, which may continue for several years.

Family Therapy

Family therapy is not generally viewed as a primary therapy for the treatment of major depressive disorder, but increasing evidence indicates that helping a patient with a mood disorder to reduce and cope with stress can lessen the chance of a relapse. Family therapy is indicated if the disorder jeopardizes a patient\'s marriage or family functioning or if the mood disorder is promoted or maintained by the family situation. Family therapy examines the role of the mood-disordered member in the overall psychological well-being of the whole family; it also examines the role of the entire family in the maintenance of the patient\'s symptoms. Patients with mood disorders have a high rate of divorce, and about 50 percent of all spouses report that they would not have married or had children if they had known that the patient was going to develop a mood disorder.

Vagal Nerve Stimulation ##

Experimental stimulation of the vagus nerve in several studies designed for the treatment of epilepsy found that patients showed improved mood. This observation led to the use of left vagal nerve stimulation (VNS) using an electronic device implanted in the skin, similar to a cardiac pacemaker. Preliminary studies have shown that a number of patients with chronic, recurrent major depressive disorder went into remission when treated with VNS. The mechanism of action of VNS to account for improvement is unknown. The vagus nerve connects to the enteric nervous system and, when stimulated, may cause release of peptides that act as neurotransmitters. Extensive clinical trials are being conducted to determine the efficacy of VNS

Sleep Deprivation##

Mood disorders are characterized by sleep disturbance. Mania tends to be characterized by a decreased need for sleep, whereas depression can be associated with either hypersomnia or insomnia. Sleep deprivation may precipitate mania in patients who are bipolar I and temporarily relieve depression in those who are unipolar. Approximately 60 percent of depressive disorder patients exhibit significant but transient benefit from total sleep deprivation. The positive results are typically reversed by the next night of sleep. Several strategies have been used in an attempt to achieve a more sustained response to sleep deprivation. One method used serial total sleep deprivation with a day or two of normal sleep in between. This method does not achieve a sustained antidepressant response because the depression tends to return with normal sleep cycles. Another approach used phase delay in the time patients go to sleep each night, or partial sleep deprivation. In this method, patients may stay awake from 2 AM to 10 PM daily. Up to 50 percent of patients get same-day antidepressant effects from partial sleep deprivation, but this benefit also tends to wear off in time. In some reports, however, serial partial sleep deprivation has been used successfully to treat insomnia associated with depression. The third, and probably most effective, strategy combines sleep deprivation with pharmacological treatment of depression. A number of studies have suggested that total and partial sleep deprivation followed by immediate treatment with an antidepressant or lithium sustains the antidepressant effects of sleep deprivation. Likewise, several reports have suggested that sleep deprivation accelerates the response to antidepressants, including fluoxetine and nortriptyline. Sleep deprivation has also been noted to improve premenstrual dysphoria.

Phototherapy##

Phototherapy (light therapy) was introduced in 1984 as a treatment for SAD (mood disorder with seasonal pattern). In this disorder, patients typically experience depression as the photoperiod of the day decreases with advancing winter. Women represent at least 75 percent of all patients with seasonal depression, and the mean age of presentation is 40. Patients rarely present over the age of 55 with seasonal affective disorder.\ Phototherapy typically involves exposing the afflicted patient to bright light in the range of 1,500 to 10,000 lux or more, typically with a light box that sits on a table or desk. Patients sit in front of the box for approximately 1 to 2 hours before dawn each day, although some patients may also benefit from exposure after dusk. Alternatively, some manufacturers have developed light visors, with a light source built into the brim of the hat. These light visors allow mobility, but recent controlled studies have questioned the use of this type of light exposure. Trials have typically lasted 1 week, but longer treatment durations may be associated with greater response.

Phototherapy tends to be well tolerated. Newer light sources tend to use lower light intensities and come equipped with filters; patients are instructed not to look directly at the light source. As with any effective antidepressant, phototherapy, on rare occasions, has been implicated in switching some depressed patients into mania or hypomania.\ In addition to seasonal depression, the other major indication for phototherapy may be in sleep disorders. Phototherapy has been used to decrease the irritability and diminished functioning associated with shift work. Sleep disorders in geriatric patients have reportedly improved with exposure to bright light during the day. Likewise, some evidence suggests that jet lag might respond to light therapy. Preliminary data indicate that phototherapy may benefit some patients with OCD that has a seasonal variation.

Pharmacotherapy##

Once a diagnosis has been established, a pharmacological treatment strategy can be formulated. Accurate diagnosis is crucial, because unipolar and bipolar spectrum disorders require different treatment regimens. The objective of pharmacologic treatment is symptom remission, not just symptom reduction. Patients with residual symptoms, as opposed to full remission, are more likely to experience a relapse or recurrence of mood episodes and to experience ongoing impairment of daily functioning.

Major Depressive Disorder

The use of specific pharmacotherapy approximately doubles the chances that a depressed patient will recover in 1 month. All currently available antidepressants may take up to 3 to 4 weeks to exert significant therapeutic effects, although they may begin to show their effects earlier. Choice of antidepressants is determined by the side effect profile least objectionable to a given patient\'s physical status, temperament, and lifestyle. That numerous classes of antidepressants are available, many with different mechanisms of action, represents indirect evidence for heterogeneity of putative biochemical lesions. Although the first antidepressant drugs, the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), are still in use, newer compounds have made the treatment of depression more "clinician and patient friendly."

General Clinical Guidelines

The most common clinical mistake leading to an unsuccessful trial of an antidepressant drug is the use of too low a dosage for too short a time. Unless adverse events prevent it, the dosage of an antidepressant should be raised to the maximum recommended level and maintained at that level for at least 4 or 5 weeks before a drug trial is considered unsuccessful. Alternatively, if a patient is improving clinically on a low dosage of the drug, this dosage should not be raised unless clinical improvement stops before maximal benefit is obtained. When a patient does not begin to respond to appropriate dosages of a drug after 2 or 3 weeks, clinicians may decide to obtain a plasma concentration of the drug if the test is available for the particular drug being used. The test may indicate either noncompliance or particularly unusual pharmacokinetic disposition of the drug and may thereby suggest an alternative dosage.

Antidepressant Medications

Usual Daily Dose (mg), Common Side Effects, Clinical Caveats

NE Reuptake Inhibitors

  • Desipramine: 75–300mg. Insomnia Drowsiness, OSH, agitation
  • Protriptyline: 20–60mg. Drowsiness, Agitation
  • Nortriptyline: 40–200mg. Drowsiness, CA
  • Maprotiline: 100–225mg. weight ↑,Drowsiness anticholinergic.Overdose may be fatal. Dose titration is needed

5-HT Reuptake Inhibitors ###

  • Citalopram: 20–60mg.
  • Escitalopram: 10–20mg.
  • Fluoxetine (Prozac): 10–40mg.
  • Fluvoxamine: 100–300mg.
  • Paroxetine: 20–50mg.
  • Sertraline : 50–150mg.

All SSRIs may cause insomnia, agitation, sedation, GI distress, and sexual dysfunction , Many SSRIs inhibit various cytochrome P450 isoenzymes. They are better tolerated than tricyclics and have high safety in overdose. Shorter half life SSRIs may be associated with discontinuation symptoms when abruptly stopped.

NE and 5-HT Reuptake Inhibitors

  • Amitriptyline: 75–300mg
  • Doxepin: 75–300mg , Drowsiness, OSH, CA, weight ↑, anticholinergic, Overdose may be fatal. Dose titration is needed.
  • Imipramine : 75–300mg. Drowsiness, insomnia and agitation, OSH, CA, GI distress, weight ↑, anticholinergic. Overdose may be fatal. Dose titration needed.
  • Trimipramine: 75–300mg. Drowsiness, OSH, CA, weight ↑, anticholinergic.
  • Venlafaxine (Effexor): 150–375mg. Sleep changes, GI distress, discontinuation syndrome. Higher doses may cause hypertension. Dose titration is needed. Abrupt discontinuation may result in discontinuation symptoms.
  • Duloxetine (Cymbalta): 30–60mg. GI distress, discontinuation syndrome

Pre- and Postsynaptic Active Agents

Nefazodone: 300–600mg. Sedation. Dose titration is needed. No sexual dysfunction.\ Mirtazapine: 15–30mg. Sedation, weight ↑, No sexual dysfunction.

Dopamine Reuptake Inhibitor

Bupropion (Wellbutrin): 200–400mg. Insomnia or agitation, GI distress. Twice-a-day dosing with sustained release. No sexual dysfunction or weight gain.

Mixed Action Agents

  • Amoxapine (Asendin): 100–600mg. Drowsiness, insomnia/agitation, CA, weight ↑, OSH, anticholinergic. Movement disorders may occur. Dose titration is needed.
  • Clomipramine (Anafranil): 75–300mg. Drowsiness, weight ↑ , Dose titration is needed.
  • Trazodone: 150–600mg, Drowsiness, OSH, CA, GI distress, weight ↑ Priapism is possible.

Note: Dose ranges are for adults in good general medical health, taking no other medications, aged 18 to 60 years. Doses vary depending on the agent, concomitant medications, the presence of general medical or surgical conditions, age, genetic constitution, and other factors.

  • CA, cardiac arrhythmia;
  • 5-HT, serotonin;
  • GI, gastrointestinal;
  • NE, norepinephrine;
  • OSH, orthostatic hypotension;
  • SSRI, selective serotonin reuptake inhibitor.

Note: Dose ranges are for adults in good general medical health, taking no other medications, aged 18 to 60 years. Doses vary depending on the agent, concomitant medications, the presence of general medical or surgical conditions, age, genetic constitution, and other factors. CA, cardiac arrhythmia; 5-HT, serotonin; GI, gastrointestinal; NE, norepinephrine; OSH, orthostatic hypotension; SSRI, selective serotonin reuptake inhibitor. anticholinergic: Dry mouth, blurred vision, urinary hesitancy, and constipation.

Administration

Duration and Prophylaxis ##

Antidepressant treatment should be maintained for at least 6 months or the length of a previous episode, whichever is greater. Prophylactic treatment with antidepressants is effective in reducing the number and severity of recurrences. One study concluded that when episodes are less than 2½ years apart, prophylactic treatment for 5 years is probably indicated. Another factor suggesting prophylactic treatment is the seriousness of previous depressive episodes. Episodes that have involved significant suicidal ideation or impairment of psychosocial functioning may indicate that clinicians should consider prophylactic treatment. When antidepressant treatment is stopped, the drug dose should be tapered gradually over 1 to 2 weeks, depending on the half-life of the particular compound. Several studies indicate that maintenance antidepressant medication appears to be safe and effective for the treatment of chronic depression. Prevention of new mood episodes (i.e., recurrences) is the aim of the maintenance phase of treatment. Only those patients with recurrent or chronic depressions are candidates for maintenance treatment.

Initial Medication Selection

The available antidepressants do not differ in overall efficacy, speed of response, or long-term effectiveness. Antidepressants, however, do differ in their pharmacology, drug–drug interactions, short- and long-term side effects, likelihood of discontinuation symptoms, and ease of dose adjustment. Failure to tolerate or to respond to one medication does not imply that other medications will also fail. Selection of the initial treatment depends on the chronicity of the condition, course of illness (a recurrent or chronic course is associated with increased likelihood of subsequent depressive symptoms without treatment), family history of illness and treatment response, symptom severity, concurrent general medical or other psychiatric conditions, prior treatment responses to other acute phase treatments, potential drug–drug interactions, and patient preference.

In general, approximately 45 to 60 percent of all outpatients with uncomplicated (i.e., minimal psychiatric and general medical comorbidity), nonchronic, nonpsychotic major depressive disorder who begin treatment with medication respond (i.e., achieve at least a 50 percent reduction in baseline symptoms); however, only 35 to 50 percent achieve remission (i.e., the virtual absence of depressive symptoms).

Treatment of Depressive Subtypes

Clinical types of major depressive episodes may have varying responses to particular antidepressants, or to drugs other than antidepressants. Patients with major depressive disorder with atypical features (sometimes called hysteriod dysphoria) may preferentially respond to treatment with MAOIs or SSRIs. Antidepressants with dual action on both serotonergic and noradrenergic receptors demonstrate greater efficacy in melancholic depressions. Patients with seasonal winter depression can be treated with light therapy. Treatment of major depressive episodes with psychotic features may require a combination of an antidepressant and an atypical antipsychotic. Several studies have also shown that ECT is effective for this indication—perhaps more effective than pharmacotherapy. For those with atypical symptom features, strong evidence exists for the effectiveness of MAOIs. SSRIs and bupropion (Wellbutrin) are also of use in atypical depression.

Comorbid Disorders ##

The concurrent presence of another disorder can affect initial treatment selection. For example, the successful treatment of OCD associated with depressive symptoms usually results in remission of the depression. Similarly, when panic disorder occurs with major depression, medications with demonstrated efficacy in both conditions are preferred (e.g., tricyclics and SSRIs). In general, the non mood disorder dictates the choice of treatment in comorbid states. Concurrent substance abuse raises the possibility of a substance-induced mood disorder, which must be evaluated by history or by requiring abstinence for several weeks. Abstinence often results in remission of depressive symptoms in substance-induced mood disorders. For those with continuing significant depressive symptoms, even with abstinence, an independent mood disorder is diagnosed and treated.

General medical conditions are established risk factors in the development of depression. The presence of a major depressive episode is associated with increased morbidity or mortality of many general medical conditions (e.g., cardiovascular disease, diabetes, cerebrovascular disease, and cancer).

Therapeutic Use of Side Effects

Choosing more sedating antidepressants (e.g., amitriptyline) for more anxious, depressed patients or more activating agents (e.g., desipramine) for more psychomotor-retarded patients is not generally helpful. For example, any short-term benefits with paroxetine, mirtazapine, or amitriptyline (more sedating drugs) on symptoms of anxiety or insomnia may become liabilities over time. These drugs often continue to be sedating in the longer run, which can lead to patients prematurely discontinuing medication and increase the risk of relapse or recurrence. Some practitioners use adjunctive medications (e.g., sleeping pills or anxiolytics) combined with antidepressants to provide more immediate symptom relief or to cover those side effects to which most patients ultimately adapt.

A patient's prior treatment history is important, because an earlier response typically predicts current response. A documented failure on a properly conducted trial of a particular antidepressant class (e.g., SSRIs, tricyclics, or MAOIs) suggests choosing an agent from an alternative class.

The history of a first-degree relative responding to a particular drug is associated with a good response to the same class of agents in the patient.

Acute Treatment Failures

Patients may not respond to a medication, because (1) they cannot tolerate the side effects, even in the face of a good clinical response; (2) an idiosyncratic adverse event may occur; (3) the clinical response is not adequate; or (4) the wrong diagnosis has been made. Acute phase medication trials should last 4 to 6 weeks to determine if meaningful symptom reduction is attained. Most (but not all) patients who ultimately respond fully show at least a partial response (i.e., at least a 20 to 25 percent reduction in pretreatment depressive symptom severity) by week 4 if the dose is adequate during the initial weeks of treatment.

Lack of a partial response by 4 to 6 weeks indicates that a treatment change is needed. Longer time periods—8 to 12 weeks or longer—are needed to define the ultimate degree of symptom reduction achievable with a medication. Approximately one half of patients require a second medication treatment trial because the initial treatment is poorly tolerated or ineffective.

Selecting Second Treatment Options

When the initial treatment is unsuccessful, switching to an alternative treatment, or augmenting the current treatment is a common option. The choice between switching from the initial single treatment to a new single treatment (as opposed to adding a second treatment to the first one) rests on the patient\'s prior treatment history, the degree of benefit achieved with the initial treatment, and patient preference. As a rule, switching rather than augmenting is preferred after an initial medication failure. On the other hand, augmentation strategies are helpful with patients who have gained some benefit from the initial treatment but who have not achieved remission. The best-documented augmentation strategies involve lithium or thyroid hormone. A combination of an SSRI and bupropion (Wellbutrin) is also widely employed. In fact, no combination strategy has been conclusively shown to be more effective than another. ECT is effective in psychotic and nonpsychotic forms of depression, but is recommended generally only for repeatedly nonresponsive cases or in patients with very severe disorders.

Combined Treatment

Medication and formal psychotherapy are often combined in practice. If physicians view mood disorders as fundamentally evolving from psychodynamic issues, their ambivalence about the use of drugs may result in a poor response, noncompliance, and probably inadequate dosages for too short a treatment period. Alternatively, if physicians ignore the psychosocial needs of a patient, the outcome of pharmacotherapy may be compromised. Several trials of a combination of pharmacotherapy and psychotherapy for chronically depressed outpatients have shown a higher response and higher remission rates for the combination than for either treatment used alone.

Medications for the Treatment of Bipolar Disorders

Each of these medications is associated with a unique side effect and safety profile, and no one drug is predictably effective for all patients. Often, it is necessary to try several so-called "mood stabilizers" before an optimal treatment is found.

  • Aripiprazole (Abilify) Yes (2004) No C
  • arbamazepine XR Yes (2004) No
  • Divalproex (Depakote) Yes (1996) No
  • Lamotrigine (Lamictal) No Yes (2003)
  • Lithium Yes (1970) Yes (1974)
  • Olanzapine (Zyprexa) Yes (2000) Yes (2004)
  • Risperidone (Risperidal) Yes (2003) No
  • Quetiapine (Seroquel) Yes (2004) No
  • Ziprasidone Yes (2004) No

The pharmacological treatment of bipolar disorders is divided into both acute and maintenance phases. Bipolar treatment, however, also involves the formulation of different strategies for the patient who is experiencing mania or hypomania or depression.

Treatment of Acute Mania

The treatment of acute mania, or hypomania, usually is the easiest phases of bipolar disorders to treat. Agents can be used alone or in combination to bring the patient down from a high. Patients with severe mania are best treated in the hospital where aggressive dosing is possible and an adequate response can be achieved within days or weeks. Adherence to treatment, however, is often a problem, because patients with mania frequently lack insight into their illness, and refuse to take medication. Because impaired judgment, impulsivity, and aggressiveness combine to put the patient or others at risk, many patients in the manic phase are medicated to protect themselves and others from harm.

Lithium Carbonate

Lithium carbonate is considered the prototypical "mood stabilizer." Yet, because the onset of antimanic action with lithium can be slow, it usually is supplemented in the early phases of treatment by atypical antipsychotics, mood-stabilizing anticonvulsants, or high-potency benzodiazepines. Therapeutic lithium levels are between 0.6 and 1.2 mEq/L. The acute use of lithium has been limited in recent years by its unpredictable efficacy, problematic side effects, and the need for frequent laboratory tests. The introduction of newer drugs with more favorable side effects, lower toxicity, and less need for frequent laboratory testing has resulted in a decline in lithium use. For many patients, however, its clinical benefits can be remarkable.

Valproate

Valproate (valproic acid [Depakene] or divalproex sodium [Depakote]) has surpassed lithium in use for acute mania. Unlike lithium, Valproate is only indicated for acute mania, although most experts agree it also has prophylactic effects. Typical dose levels of valproic acid are 750 to 2,500 mg per day, achieving blood levels between 50 and 120 µg/mL. Rapid oral loading with 15 to 20 mg/kg of divalproex sodium from day 1 of treatment has been well tolerated and associated with a rapid onset of response. A number of laboratory tests are required during valproate treatment.

Carbamazepine and Oxcarbazepine

Carbamazepine has been used worldwide for decades as a first-line treatment for acute mania. Typical doses of carbamazepine to treat acute mania range between 600 and 1,800 mg per day associated with blood levels of between 4 and 12 µg/mL. The keto congener of carbamazepine, oxcarbazepine, may possess similar antimanic properties. Higher doses than those of carbamazepine are required, because 1,500 mg of oxcarbazepine approximates 1,000 mg of carbamazepine.

Clonazepam and Lorazepam

The high-potency benzodiazepine anticonvulsants used in acute mania include clonazepam and lorazepam. Both may be effective and are widely used for adjunctive treatment of acute manic agitation, insomnia, aggression, and dysphoria, as well as panic. The safety and the benign side effect profile of these agents render them ideal adjuncts to lithium, carbamazepine, or valproate.

Atypical and Typical Antipsychotics

All of the atypical antipsychotics—olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole—have demonstrated antimanic efficacy. Compared with older agents, such as haloperidol and chlorpromazine, atypical antipsychotics have a lesser liability for excitatory postsynaptic potential and tardive dyskinesia; many do not increase prolactin. However, they have a wide range of substantial to no risk for weight gain with its associated problems of insulin resistance, diabetes, hyperlipidemia, hypercholesteremia, and cardiovascular impairment. Some patients, however, require maintenance treatment with an antipsychotic medication.

Treatment of Acute Bipolar Depression

The relative usefulness of standard antidepressants in bipolar illness, in general, and in rapid cycling and mixed states, in particular, remains controversial because of their propensity to induce cycling, mania, or hypomania. Accordingly, antidepressant drugs are often enhanced by a mood stabilizer in the first-line treatment for a first or isolated episode of bipolar depression. A fixed combination of olanzapine and fluoxetine has been shown to be effective in treating acute bipolar depression for an 8-week period without inducing a switch to mania or hypomania. Paradoxically, many patients who are bipolar in the depressed phase do not respond to treatment with standard antidepressants. In these instances, lamotrigine or low dose ziprasidone (20 to 80 mg per day) may prove effective. Electroconvulsive therapy may also be useful for bipolar depressed patients who do not respond to lithium or other mood stabilizers and their adjuncts, particularly in cases in which intense suicidal tendency presents as a medical emergency.

Other Agents ##

When standard treatments fail, other types of compounds may prove effective. The calcium channel antagonist verapamil (Isoptin) has acute antimanic efficacy. Gabapentin, topiramate, zonisamide, levetiracetam, and tiagabine have not been shown to have acute antimania effects, although some patients may benefit from a trial of these agents when standard therapies have failed. Lamotrigine does not possess acute antimanic properties, but does help prevent recurrence of manic episodes. Small studies suggest the potential acute antimanic and prophylactic efficacy of phenytoin. ECT is effective in acute mania. Bilateral treatments are required, as unilateral, nondominant treatments have been reported to be ineffective or even to exacerbate manic symptoms. ECT is reserved for the patient with rare refractory mania or for the patient with medical complications, as well as extreme exhaustion (malignant hyperthermia or lethal catatonia).

Maintenance Treatment of Bipolar Disorder

Preventing recurrences of mood episodes is the greatest challenge facing the clinician. Not only must the chosen regimen achieve its primary goal—sustained euthymia—but the medications should not produce unwanted side effects that affect functioning. Sedation, cognitive impairment, tremor, weight gain, and rash are some side effects that lead to treatment discontinuation.