16.7 MOOD DISORDERS: SOMATIC TREATMENT

INTRODUCTION

Treatment of the mood disorders has entered into a new era of therapeutics based on a variety of factors. There is increasing recognition that mood disorders have a prominent genetic component with well-documented neurobiological alterations that have been elucidated on biochemical, neuroendocrinological, and functional brain imaging measures. The descriptive and diagnostic aspects of the illness have been explicated, and it is recognized that in most cases the mood disorders are recurrent and have the potential for severe morbidity and even mortality. Thus, treatment requires the utmost in clinical management skills.

As knowledge of the classification, course, and mechanisms underlying acute episodes and their recurrences has increased, so also has the array of effective psychopharmacotherapeutic modalities and related somatic treatments. Although single drugs in one or two classes were available for the treatment of depression several decades ago, multiple therapeutic modalities now exist, often with many agents within each class. Thus, the treating physician should be aware of the nuances in the management of patients with acute and recurrent mood disorders so that treatment can be optimized from the outset and the impact of the illness on patients, their lives, and their families can be minimized.

There is also increasing consensus on several new treatment principles. Early recognition and intervention in an acute episode not only may save the patient months of pain and suffering but also may be lifesaving. More careful assessment of the efficacy of an agent at early and regular intervals, with early revision of the treatment modality if it is not optimal, is an important new guideline that applies not only to somatic treatments, but also to psychotherapeutic approaches and combination psychotherapy-pharmacotherapy when treatment is not proceeding optimally.

A large body of evidence supports the efficacy of long-term prophylactic management of recurrent mood disorders. Early institution of long-term prophylaxis is now recognized as a critical approach for the patient with recurrent mood disorders. Such an approach holds promise for reducing the morbidity of the illness and for altering favorably its subsequent course and treatment responsiveness. There is increasing consensus that a patient with a first episode of bipolar disorder is a candidate not only for continuation therapy following the resolution of that episode, but also for long-term prophylaxis, particularly if the patient has a family history of bipolar illness. Correspondingly, in major depressive disorder there is a new appreciation for the recommendation of prophylaxis after the third episode or two closely occurring episodes.

Thus, a variety of factors and guidelines shape the physician's approach to the patient with an acute episode of mood disorder. The illness should be treated with the same respect as is given to the early diagnosis and treatment of a malignancy, with the same skills brought to bear in choosing targeted and, at times, multimodal therapeutics. In a parallel fashion, early and effective intervention may be lifesaving, whereas delayed or inadequate treatment may be associated with considerable

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Major depressive disorder is a common illness, occurring in 7 to 12 percent of male patients and 20 to 25 percent of female patients during their lifetimes. Although bipolar disorder occurs in approximately 1 percent of the population, that percentage translates into 2.5 million people in the United States alone. The bipolar disorders are disabling in the short and long term. For example, it is estimated that the average woman with onset of a bipolar disorder at age 25 will lose 14 years of effective lifetime functioning as a result of the illness. In addition, up to 15 to 20 percent of patients with inadequately treated mood disorders commit suicide. Thus, diagnosis and treatment should be approached with the knowledge that the patient is experiencing a potentially recurrent, disabling medical illness.

HISTORY

Until the middle of the 20th century the available treatments for mood disorders were largely supportive and palliative. Electroconvulsive therapy (ECT) then emerged as efficacious treatment for major depressive disorder. In the following decades, the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants were introduced. Today, second- and third-generation treatment modalities are available. The latter preparations include drugs with novel structures, different mechanisms of action, and more benign side-effect profiles than the original agents. Those agents include the serotonin-specific reuptake inhibitors (SSRIs) (fluoxetine [Prozac], sertraline [Zoloft], paroxetine [Paxil], fluvoxamine [Luvox]), the mixed serotonergic-noradrenergic drug venlafaxine (Effexor), and the dopaminergic-noradrenergic agent bupropion (Wellbutrin). The emergence of a new range of acute antidepressant psychopharmacological agents raises important treatment issues for the clinician, particularly when those agents must be chosen on the basis of an inadequate literature on potential clinical and biological markers of responsiveness to a given drug in a given person. There is general consensus in the field that, with the possible exception of ECT, no antidepressant modality is more effective or more rapid in onset than another. Thus, agents may be chosen based on their side-effect profile, acceptability in long-term prophylaxis, and clinical lore regarding possible syndromal selectivity of response.

A similar revolution has occurred in the treatment of bipolar disorder. In the first half of the 20th century no adequate treatment for bipolar disorder was available, whereas in the second half lithium (Eskalith) emerged as a wonder drug for the acute and prophylactic management of the disorder. It is noteworthy, however, that there were marked oscillations in the assessment of the efficacy and utility of lithium, and it was initially abandoned as unsafe (until adequate monitoring of blood levels was devised so as to eliminate cardiovascular and central nervous system [CNS] toxic effects). After many decades of use, the limitations of lithium are better recognized. As many as 50 percent of patients do not show adequate response to lithium even when conservative criteria for clinical response, such as one episode of illness during a two-year follow-up, are employed. Fortunately, as the limitations of lithium were increasingly recognized, a variety of other treatment modalities became available, particularly the anticonvulsants carbamazepine (Tegretol) and valproate (Depakene, Depakote). However, as is the case of matching treatment to patient in the depressive disorders, there is even less evidence in the bipolar disorders for clinical and biological predictors of acute and long-term responsiveness to the mood-stabilizing agents.

In treating patients with bipolar disorders the clinician often has to resort to educated guesses and to systematic, sequential clinical trials to delineate optimal responsivity. Even with the availability of new treatment modalities, episodes of illness can emerge through otherwise partially successful pharmacoprophylaxis, necessitating adjunctive measures. The role of combination therapies is well recognized in many branches of medicine; for example, it is central to the treatment of congestive heart failure, tuberculosis, and most malignancies. By comparison, research on combination therapies in the mood disorders has lagged behind clinical practice, and clinicians are often left to their own devices without the aid of controlled studies as a guide for determining the optimal algorithm in cases refractory to standard treatments.

This section reviews the knowledge base gleaned from both systematic controlled clinical trials and anecdotal observations, and delineates novel treatment interventions that may be employed when patients fail to respond to first-, second-, and third-line treatment options. Although many of the specific recommendations may change in the years to come as the results of new, more systematic research are reported, the principles enunciated here should provide useful guidelines for physicians formulating optimal treatment options for acute and long-term prophylaxis for patients with mood disorders.

INITIAL DIAGNOSTIC AND THERAPEUTIC APPROACHES

IMPEDIMENTS TO ACUTE AND LONG-TERM TREATMENT

Although the mood disorders are treatable, several illness-related variables complicate access to treatment and the ability of the patient to follow through. It is estimated that as many as 25 percent of patients with major depressive disorder do not receive treatment. Depressed patients often do not recognize their constellation of symptoms as a medical illness, and the symptoms of depression, such as motor retardation, apathy, inertia, and hopelessness, may preclude the patient's becoming involved in treatment. Thus, the patient's family, acquaintances, and medical physician may have to play active roles in encouraging the patient to initiate treatment.

Treatment must be conducted against the backdrop of the patient's distorted depressive cognitions, sense of hopelessness, and view of the untreatability of the illness. Patients should be informed that such beliefs and feelings are symptoms of the illness and that a positive response to treatment is likely, based on the literature and the physician's own experience with the illness. However, the physician's empirically based hope for recovery should be conveyed to the patient without the promise of immediate results. The physician should also explain that lags in onset of treatment efficacy are expected so that the patient does not misinterpret such delays as confirmation that the illness is untreatable. Finally, the risk for suicide during each phase of a depressive illness must be continually reassessed.

Similar impediments to the effective treatment of manic patients exist. For example, in the early stages of hypomania the sense of well-being and increased productivity may lead the patient to ignore more severe consequences of the illness, including irritability, intrusiveness, insomnia, poor judgment,

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There are important roles for the family in both the diagnostic evaluation and the ongoing treatment of a patient with a bipolar disorder. Family participation may be needed to assist the patient in confronting the denial of illness and the thought disorder that are associated with hypomania and mania and that can be just as great impediments to adequate treatment as are the apathy and hopelessness of depression. Therefore, therapeutic activism, engagement of the family, and early and aggressive treatment of mood disorders are important. The patient and family should receive immediate and regular information about the medical aspects of the illness, its course, and its response to treatment. The long-term goals of education are to increase compliance and destigmatize the illness. Compliance and destigmatization may become focal issues later in therapy when the physician considers recommendations for long-term prophylaxis; at that time society's negative attitudes toward taking psychotropic medications may have to be addressed. The conceptualization of mood disorders as medical illnesses that deserve the same attention and respect as other medical disorders may be important to the patient and family in choosing and committing to a long-term treatment option.

Thus, a variety of societal, attitudinal, and illness-related variables may interfere with appropriate help-seeking and maintenance behavior in the various phases of treatment of mood disorders. During each of the successive phases--acute care, continuation treatment, and long-term prophylaxis--the patient and family should be assisted in their evaluation of the medical data and the potential impact of the disorder on the patient. The variables affecting treatment should be addressed sequentially as they arise in each phase of the illness rather than in aggregate at the start of treatment. For example, the importance of continuation therapy, which should have a duration of four to nine months following the resolution of acute symptoms, should be discussed once the patient has begun to respond to treatment, rather than being raised with the acutely depressed patient, who may feel hopeless about ever achieving a therapeutic outcome.

Similarly, education on the importance of long-term treatment, with appropriate provision of data to the patient and family, may be critical for achieving an optimal outcome. Patients taking medications long term for any reason may decide to test the need for therapy by discontinuing the medication. As an example, even with an illness such as juvenile diabetes, in which it is unequivocally demonstrated that the patient cannot survive without adequate insulin treatment, many adolescents nevertheless feel compelled to test the long-term need for insulin and consequently experience periods of marked hyperglycemia that often lead to hospitalization. In parallel fashion, it should be anticipated that patients with bipolar mood disorders are likely to be tempted to discontinue their recommended treatment, all the more so because data on the potential lethality of the regimen or its morbid consequences may be less well delineated. Consequently, the treating clinician has the educational responsibility of providing patients and families with information on the high likelihood of a recurrence in a relatively short time in patients with several prior episodes and with information on the ability of a variety of antidepressant agents and bimodal mood-stabilizing agents to prevent recurrences of major depressive disorder and bipolar disorder, respectively.

After several prior episodes of major depressive disorder, the likelihood of a new episode after successful, acute antidepressant treatment and placebo substitution is approximately 50 percent in the first year and increases with time. Maintenance treatment can reduce that rate by more than half. Although often a helpful adjunct, long-term psychotherapy cannot substitute for pharmacotherapy in the prophylaxis of either major depressive disorder or bipolar disorder.

In bipolar disorder the high likelihood of relapse (80 to 90 percent) following lithium discontinuation is widely recognized. In addition, although it had previously been assumed that if a well-treated patient experienced a relapse following drug discontinuation, the patient would readily respond again once treatment was reinstituted, several reports of lithium discontinuation-induced refractoriness have been noted. After long periods of successful lithium treatment, the patients discontinued the drug, experienced a relapse, and did not re-respond once treatment was restarted at similar or higher doses. Other patients may not respond as rapidly as they did to the first treatment sequence. Several studies suggest that lithium may be less effective in patients who experienced more than three or four episodes prior to lithium initiation than in those in whom lithium is initiated earlier in the illness sequence. Thus, in recommending long-term preventive therapy, the physician should consider not only the potential morbidity and mortality of an episode recurrence, but also the possibility that new episodes could affect the subsequent course of the illness and its pharmacological responsivity.

PSYCHIATRIC HISTORY

A thorough history and medical examination is paramount. Because several medical conditions may mimic both manic and depressive syndromes, the diagnosis should be approached from the perspective that a medical cause may exist for the illness until proved otherwise. Throughout the history taking and physical examination, attention should be paid to obvious and subtle hallmarks of associated pathology. The physician should be alert to the signs and symptoms indicative of CNS neuropathology, underlying endocrinopathy, and associated medical illness. Although aggressive in exploring those themes with the patient and family, the physician should directly state that the patient's somatic and vegetative symptoms are most likely indicative of a typical depressive process.

Thus, even the earliest parts of the history taking can be used not only for diagnostic purposes but also to begin educating the patient about the types of symptoms that are characteristic of mood disorders, the likely course of remission of episodes, and the likely response to somatic and pharmacological interventions. Simultaneously, the physician should be isolating the target symptoms for future assessment of the efficacy of psychological and pharmacological interventions and constructing a framework for longitudinal monitoring of the patient. The same symptoms are likely to appear in future recurrences and thus may provide an early warning system to aid in early detection and the aggressive institution of treatment. The medical history and examination should also look for evidence of glaucoma (a relative contraindication to anticholinergic antidepressants) and cardiac, renal, and thyroid abnormalities that may preclude certain treatments.

A detailed family history of medical and psychiatric illness is crucial to the initial diagnostic assessment of the patient. It is recommended that a formal family tree be graphically constructed and information recorded on the potential diagnosis, course of illness, and response to therapy of each first-degree relative, as that information may provide a guide to current treatment of the patient. Patients with a positive family history

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Graphing the course of illness

The author suggests developing a graphical representation of the patient's prior depressive and manic episodes (Figures 16.7-1 through 16.7-4 ). A formal graphical representation of the patient's longitudinal course of illness is useful for several reasons: (1) It provides a clear-cut picture of the earlier course of illness (which appears to be the best predictor of the future pattern of episodes). (2) It clarifies medication responsiveness (by indicating the efficacy of previous treatments, if any) and helps in the medicalization of the history taking and management process (with regard to current and future prescriptions). (3) It encourages the patient to collaborate and thus may enhance the doctor-patient relationship by bringing the patient into the process as an active rather than passive participant. (4) If a number of past recurrences are uncovered in the history, that information may help in determining the subsequent long-term approach to the illness and in identifying the patient's willingness to comply with prescribed regimens. (5) Graphing the course of illness often uncovers important psychosocial events and possible precipitants of the illness; unique characteristics of the illness, such as seasonal variation and relation to anniversaries; and other patterns that cannot be discovered easily without systematic and graphical representation of the prior course. Elucidation of periods of increased vulnerability to illness provides a template for future intensification of observation and augmentation of therapeutic modalities as appropriate.

With a little practice the course of an illness can be graphed easily. It is suggested that graphing be done as part of the initial intake session and be the primary mode of history taking, rather than a verbal account that is later converted to graphical form. A graphical rather than verbal representation immediately and systematically focuses the patient and physician on the longitudinal course of the illness and its variation over time. The graphical approach and its associated temporal landmarks can also facilitate recall of important events, dates, and episodes that would otherwise be obscured or forgotten.

Levels of Severity

Physicians can devise their own ways of plotting the longitudinal course of illness or can adopt a system like the one the author and his colleagues have used successfully over the past decade. That consists of graphing three levels--mild, moderate, and severe--of mania or depression, based on the degrees of associated functional incapacity, and can easily be assessed retrospectively (Figures 16.7-1 and 16.7-2) .

MILD LEVEL

The mild level is one in which the patient or family notes a distinct change from the patient's usual behavior without a notable impairment in the patient's functional status. This state is readily discerned by depressed patients and may represent the baseline of double depression from which more severe episodes erupt. Hypomanic patients, however, may deny a mild state, and the physician may have to obtain additional information from family members and relatives. (That observation underscores the utility of an initial nonanalytic approach

Figure 16.7-1 Graphing the course of affective illness: Prototype of a life chart.

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Figure 16.7-2 Carbamazepine prophylaxis maintained with optimal management of dose titration against side effects.

Figure 16.7-3 Evolution of cycle frequency in a male patient with bipolar II disorder.

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Figure 16.7-4 Response to acute and prophylactic treatment with carbamazepine in a lithium nonresponder.

MODERATE LEVEL

Moderate levels of depression and mania can be graphed at the next level to represent illness with distinct functional impairment. Patients have difficulties continuing their social or employment responsibilities, showing absences from work or performance deficits on routine social tasks.

SEVERE LEVEL

The third or severe level of impairment is graphed when patients are functionally incapacitated and are unable to perform consistently in their usual roles (that is, they are no longer able to go to work or to perform socially). Hospitalization can be indicated by shading in the severe manic or depressive episode. When an episode has occurred in the past but its precise timing is not available, it can be indicated on the life chart with dotted lines.

Earlier Psychopharmacological Interventions

Superimposed on this template of mood fluctuations can be the history of prior psychopharmacological interventions, which is plotted above the mood disorder episodes, as illustrated in Figure 16.7-1 (life chart schema) and in Figures 16.7-2 and 16.7-3 (case examples). When plotted in this fashion, the efficacy of earlier treatments is often reclassified. A treatment previously deemed ineffective may, on careful reexamination, be shown to be partially effective (that is, a decreased frequency or severity of prior episodes compared with the pretreatment baseline may emerge). If that is the case, the reassessment may suggest supplementing this partially effective treatment rather than abandoning it. Previous psychotherapeutic interventions should also be included so that their impact on the illness and patient satisfaction can be assessed. Important psychosocial events (for example, anniversaries, suicide attempts) and other notes about drug side effects, dosages, reasons for discontinuation of medications, and the like can be noted below the mood graph (Figure 16.7-1) .

Descriptive Symptoms

The anamnestic account of symptomatology provides a basis for following clinical improvement during an acute episode and possible subsequent episodes. The clinician should develop a sense for the major symptoms that are the best descriptors of a patient's episodes. In some patients impaired sleep with early morning awakening may be the major symptom; in others it may be inability to concentrate, decreased energy or increased agitation, isolation, anxiety, a change in appetite, or weight gain. The sequential ebbing of symptoms during a treated episode may be a clue to the duration of maintenance treatment required and to the earliest symptoms that may recur during a subsequent episode. Should the more difficult or residual symptoms emerge during prophylaxis, or should they recur or become more profound as medication is tapered, they can be used as indicators for renewed, more aggressive management of a potential episode.

Similarly, clinicians should decide on and make a contract with their patients in advance about specific symptoms that may

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Prospective Charting

For patients with recurrent major depressive disorder, and definitely for patients with multiple episodes of bipolar disorder, the author suggests that some elements of the life chart process be continued prospectively. That can be done quite easily in a number of ways. As an example, the patient can be asked to keep a nightly calendar and record a number from 0 to 100, with 0 representing most depressed ever, 50 representing normal or usual self, and 100 representing most activated or manic ever. The patient's record can later be converted to life chart episodes based on functional incapacity following discussion with the clinician.

By nightly recording on a simple scale, patients can systematically track their mood fluctuations in a manner that is unobtrusive and takes only seconds to complete. In an analogy to the urine glucose self-assessments of diabetic patients, systematic mood ratings by mood-disordered patients may provide an important measure of how well the illness is responding to a given treatment modality or of dose-side effect titration. It is worth reemphasizing that the morbidity and mortality of the mood disorders can be no less severe than those of many medical illnesses in which a great deal more attention is paid to the longitudinal and systematic monitoring of fluctuations in symptoms, biochemistry, and underlying pathology. Patients should be encouraged to help in the life chart process, if they are amenable to it, and should receive copies of the ongoing or completed chart, as it may be helpful in any future transfer of medical care, orientation of hospital staff, or consultation should they move or experience future episodes requiring review of treatment.

Subjective and objective differences

Asking patients to make a calendar and rate their moods with a specific number from 0 to 100 has an additional, secondary benefit: It addresses the possibility of becoming attuned to the major subjective or objective differences in the assessment of a patient's illness. Many patients with major depressive disorder can detect mood changes and side effects before the therapist observes them. Conversely, many patients with bipolar disorder show remarkable objective improvement in major symptom areas, including sleep, appetite, energy, spontaneity, and sociability, without any subjective sense of clinical improvement attending those changes. If patients do not recognize that their depression is improving, it may lead to further therapeutic pessimism and may increase the possibility of suicide as the patient may have more energy to carry out such a plan while still convinced that improvement is not imminent. Moreover, return to previous levels of social and occupational functioning may lag even further behind the patient's objective and subjective appreciation of symptomatic improvement, and the patient should be adequately supported and encouraged during that time.

Time frame of education

Although a hopeful perspective on the treatability of a patient's episode should be maintained, the patient should also be told that more than one drug may have to be tried before the best treatment regimen is found. The evaluation of a treatment response often requires three to six weeks, and a given agent's lack of efficacy should be regarded as additional information about the patient's illness rather than as an indication that the illness is not responsive. At the start of treatment the availability of different effective treatments, with many drugs in each class, should be brought to the patient's attention. That puts possible treatment sequences in their proper perspective and emphasizes to the patient that a lack of response to or intolerance of a drug does not portend a negative therapeutic outcome.

Those points should be reemphasized throughout the entire therapeutic process, particularly in light of the different temporal perspectives of the therapist and the patient. The therapist is aware not only of the many treatment alternatives but also of the extended treatment course that may be necessary to achieve optimal efficacy. From the patient's perspective the current mood-disordered state may be overwhelming in its immediacy and desperation. Particularly for the depressed patient, pain and hopelessness can override the realities of the situation and increase the risk of suicide before a positive treatment outcome is established.

Reassurance without promising an immediate therapeutic effect is therefore an important part of treating a depressed patient. A similar but inverse process may be required for the manic patient, who also may see only the immediate time frame and not the longer-term perspective. The therapist should encourage and help supply the ego for the longer-term view in both cases. Thus, supportive, interpersonal, cognitive, and behavioral approaches to the psychopharmacotherapy of the mood disorder may be essential. The patient should be counseled not to make important long-term decisions on the basis of a distorted view of himself or herself during an acute manic or depressive episode.

Stressing the time frame of possible improvement and the need to evaluate a given treatment over a matter of weeks to months may not only aid in maintaining patients' and families' morale but may also be helpful in obtaining adequate informed consent and avoiding malpractice litigation. In regard to the latter, it is important to indicate the possible side effects of each drug treatment so that they are seen as expected and not worrisome or, conversely, can be recognized as out of the ordinary and something that merits a call to the physician.

Hospitalization

The decision to hospitalize severely depressed or manic patients depends on a variety of clinical and pharmacological issues. Hospitalization is often indicated for the acutely suicidal patient, but it may also be considered for a patient with associated medical problems or one who needs close management and monitoring of complicated or novel psychopharmacological regimens. For the knowledgeable patient with a supportive family, it may be possible to institute psychopharmacological approaches on an outpatient basis, particularly if there is close coordination between patient and physician regarding dosage, titration, side effects, and the like. Despite societal criticisms of ECT, that modality should be given higher than usual priority when the physician is faced with an extremely suicidal patient, one with associated medical illnesses, one whose profile of side effects from routine psychopharmacological agents precludes use of those agents, or one in whom other medical and psychological situations pose a therapeutic emergency necessitating the most rapid treatment response available.

For the patient with recurrent, severe episodes of mania, who

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PSYCHOTHERAPY AND PHARMACOTHERAPY

Depression is a serious, potentially life-threatening medical illness, and patients and their families deserve much support. The author emphasizes the importance of combining psychosocial and pharmacological approaches in a majority of patients, not only because of evidence of the efficacy of both treatment modalities, but also because of the potential for mutual interaction and support of the patients and their social system in the context of ongoing pharmacotherapy.

Although psychotherapy may not be considered an appropriate primary treatment modality for severe depression, it may behoove the clinician to use combined treatment, for several reasons. Not only does initial evidence suggest that the two types of therapy may target different symptoms, but the therapeutic process may provide support for the patient before the psychopharmacological interventions are effective, especially if several agents must be tried before a successful one is found. Psychosocial issues and stresses not only may play important etiological roles in the onset and amelioration of some types of depression, they may also indicate the need for more aggres-sive pharmacological management during a period of high vulnerability.

Frequent meetings with the patient may also help in assessing the progress of pharmacotherapy, titrating the dose against blood levels and side effects, and facilitating compliance in the face of pessimism. Finally, if a depressed patient experiences severe pain and suffering, frequent meetings may encourage the physician to apply maximum clinical and therapeutic leverage and to revise regimens as appropriate within the shortest time frame (generally two to four weeks) if improvement is not forthcoming in optimal fashion. Combined treatment may also be helpful in instances of only partial response to extensive pharmacotherapy, if an episode is very protracted, or if there is poor interepisode recovery of function, associated personality disorder, or the presence of acute psychosocial stressors.

THEORETICAL ASSUMPTIONS AND RATIONALE:NEUROTRANSMITTER THEORIES

Because most of the effective treatments for mood disorders were discovered by serendipity or empiricism, the effectiveness of somatic treatments has propelled theoretical formulations rather than vice versa. Neurotransmitter theories of the basis of depression and the transmitters involved have included serotonergic (5-hydroxytryptamine [5-HT]), noradrenergic (NE), cholinergic (ACh), dopaminergic (DA), and gamma-aminobutyric acid (GABA)-ergic theories, each based on presumed mechanisms of effective pharmacotherapeutic interventions. For example, the findings that several drugs (which acutely potentiated catecholamines and indoleamines) were antidepressants and that reserpine (Serpasil) (which depleted these neurotransmitters) could exacerbate depression and treat mania led to the amine hypotheses of deficiencies in depression and excesses in mania.

Insofar as relatively selective manipulations of each of several different neurotransmitter systems (5-HT, NE, DA) appear to be associated with antidepressant effects (Table 16.7-1) , a critical psychopharmacological question is raised as to whether a patient may respond to one type of treatment targeting one neurotransmitter system but not to another that targets an alternative system. Because definitive studies that would answer that question are lacking, the sequential use of drugs that act differently within or among classes of agents may be appropriate (for example, changing from a relatively more serotonergic drug to a relatively more noradrenergic tricyclic reuptake blocker or from a tricyclic to an MAOI to lithium). Because relatively few validated clinical or biological markers of responsivity to given treatment agents exist, the clinician must move through various treatments or adjuncts for a patient with a refractory condition until an effective one is found, with the process largely being trial and error. In mania, a similar strategy of using agents with different mechanisms of action may also be warranted.

TREATMENT OF DEPRESSIVE DISORDERS

ACUTE AND CONTINUATION THERAPY FOR MAJOR DEPRESSIVE DISORDER

The drugs of choice may vary for an agitated, retarded, or psychotic depression. Because clinical trials of many weeks' duration are needed to evaluate the clinical efficacy of any individual drug, before switching treatment modalities the physician might attempt to potentiate a specific drug treatment once adequate blood levels have been reached. Thus, thyroid or lithium potentiation warrants earlier emphasis in the treatment sequence than do multiple trials with single alternative agents (Figure 16.7-5) .

Once a detailed history from the patient and, perhaps, a friend or relative has revealed no prior personal or family history of mania, the acute and prophylactic treatment of a patient with major depressive disorder proceeds very differently from that for a patient with bipolar disorder. The acute approaches form a backdrop to continuation treatment and longer-term prophylaxis of either recurrent major depressive disorder or bipolar disorder. When an antidepressant treatment modality is found to help alleviate an acute episode of major depressive disorder, treatment should be continued for six to nine months--a period during which vulnerability to relapse is high. The presence of residual symptoms (such as minor sleep disturbance, anergy, lack of concentration, or minor early morning awakening) suggests continued and more aggressive treatment with higher doses or potentiation. Minor increases in depression after a gradual reduction in dosage may also suggest the need for continuing the therapy. (Tapering of cyclic and MAOI antidepressants may also help in avoiding minor drug withdrawal symptoms, which include sleeplessness, nausea, vomiting, and irritability, as well as rapid eye movement [REM] rebound with the MAOIs.)

Although more research is needed on biological predictors of treatment response, initial data suggest that the failure to normalize on the dexamethasone suppression test may be associated with a higher risk of relapse. Thus, a positive test may point to continuing antidepressant treatment even though the patient is clinically asymptomatic. Some evidence indicates that the sleep electroencephalogram (EEG) may remain abnormal for a long time after remission, although that test does not appear to be a practical marker for continuation therapy. The course of an episode may best be predicted from scrutiny of past episodes. Therefore, if the history reveals earlier, protracted episodes with some evidence of relapse before medication was stopped, the treatment of the current episode should be extended.

Serotonin-specific reuptake inhibitors

Fluoxetine, sertraline, and paroxetine are available in the United States for the treatment of acute and recurrent depressions, and fluvoxamine is likely to be approved soon. Fluoxetine is one of the leading

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Figure 16.7-5 Maximizing and potentiating antidepressant treatment.

Sertraline has a shorter half-life than fluoxetine and does not have a long-lasting metabolite. Despite those differences, sertraline shares most of the side effects seen with fluoxetine, including GI distress and sexual dysfunction. In contrast to fluoxetine, sertraline exhibits first-order kinetics (that is, it does not inhibit its own metabolism). Further, some patients intolerant of fluoxetine may respond to and tolerate sertraline. It does not increase the blood levels of other drugs. The most prominent side effects are GI effects (nausea, diarrhea, dyspepsia) and sexual effects (anorgasmia).

Serotonin nonselective reuptake inhibitors

Venlafaxine is a mixed serotonin, norepinephrine, and, to a lesser extent, dopamine reuptake inhibitor with a novel phenylethylamine structure. Unlike the specific SSRIs fluoxetine, sertraline, and paroxetine, venlafaxine provides substantial inhibition of norepinephrine reuptake. Like other antidepressants, venlafaxine decreases locus coeruleus firing. A single dose in rats produces down-regulation of beta-adrenergic receptors, suggesting the possibility of more rapid onset of action than with existing agents, although clinical data are inconclusive. Unlike many older antidepressants, venlafaxine lacks significant binding to adrenergic, serotonergic, dopaminergic, histaminergic, and cholinergic receptors. That may explain why venlafaxine therapy is less likely to yield the orthostasis, sedation, weight gain, tachycardia, dry mouth, and constipation seen during therapy with older-generation antidepressants.

The mixed serotonergic, noradrenergic, and dopaminergic action of venlafaxine makes it a potentially useful agent in the treatment of patients with depression who are refractory to agents that affect only one of those monoamine systems. A 40 percent response rate to venlafaxine has been reported in patients who have failed adequate trials of other treatments, including MAOIs and ECT. MAOIs (which also affect all three monoamine systems) have been found effective in treating refractory depression, but side effects, dietary restrictions, and drug interactions have limited their utility.

Venlafaxine has a plasma elimination half-life of about five hours, requiring administration two or three times a day. Its principal metabolite, O-desmethylvenlafaxine, is active and has a half-life of about 11 hours. Venlafaxine is metabolized by and is a weak inhibitor of the cytochrome P-450 2D6 isoenzyme, so that pharmacokinetic interactions with other drugs (including some antidepressants) metabolized by that system may occur. Knowledge of the pharmacokinetic interactions of venlafaxine with other psychotropic agents is preliminary.

Venlafaxine is generally well tolerated, with a side-effect profile similar to that of the SSRIs. The most frequent side effects include nausea, weight loss, sweating, sedation, dry mouth, and sexual dysfunction. Except for nausea, side effects appear to be dose-related, and most attenuate over time or with a decrease in dosage. Infrequently, they require discontinuation of the medication. Increases in supine diastolic blood pressure have been reported with venlafaxine. Such increases are generally mild, but are more common with higher doses (mean increase of about 7 mm Hg at 375 mg a day). About 3 percent of patients develop a rash that requires discontinuation of the drug. Approximately 0.25 percent of patients develop seizures, an incidence similar to that seen with other antidepressants. In addition, about 1 in 200 patients experience hypomania or mania while taking venlafaxine.

The recommended dosage titration in the clinical treatment of depression includes starting with 25 mg three times a day (75 mg a day) and increasing by 75 mg a day at four-day intervals until the dosage reaches 125 mg three times a day (375 mg a day), if necessary.

Heterocyclics

The antidepressant properties of bupropion do not involve potent effects on brain 5-HT. Bupropion does increase levels of dopamine in the nucleus accumbens and striatum. Preliminary reports in patients with bipolar disorders suggest that it may have prophylactic effects without increasing the risk of mania in those patients. A positive effect on motor retardation has been reported. Bupropion has few anticholinergic side effects, and its administration is not associated with weight gain. The risk of seizures is increased at doses above 450 mg; the dose should be divided and generally should not exceed 150 mg at a given time.

Despite sporadic claims to the contrary, there is little convincing evidence that one particular antidepressant works more rapidly than another. That statement remains true for the newer second- and third-generation heterocyclic (tetracyclic and bicyclic) antidepressants. Although further research may uncover some exceptions to the rule, clinicians should be familiar with several different antidepressants in the heterocyclic class and their dose-response and dose-side effects characteristics. The clinical response profiles and side effects of heterocyclic and other antidepressants are summarized in Table 16.7-1 . Given the relatively uniform incidence and time of onset of efficacy, the side-effect profile may be the deciding factor in the choice

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Thus, for the first antidepressant, a second- or third-generation antidepressant compound with a relatively benign side-effect profile or a secondary amine tricyclic antidepressant might be selected over the better studied but less well-tolerated primary amine compounds. One possible exception to that general recommendation is the use of clomipramine (Anafranil) in the patient with comorbid obsessive-compulsive disorder, as clomipromine, unlike desipramine (Norpramin), is highly effective in the treatment of obsessive-compulsive disorder.

Monoamine oxidase inhibitors

MAOIs may be started shortly after the termination of tricyclic antidepressant therapy, but the converse is not recommended, as MAO inhibition can persist for two weeks or more after cessation of treatment. Treatment with an MAOI should not be started until five weeks after termination of fluoxetine therapy because of the possibility of a lethal serotonergic syndrome. The lag in onset of relief with the MAOIs is similar to that of the heterocyclics. Consequently, three to six weeks may be required to assess the treatment's effectiveness. Doses in the higher range (phenelzine [Nardil], 60 to 90 mg; tranylcypromine [Parnate], 30 to 60 mg) should be given to achieve adequate MAO inhibition in the absence of clinical response and side effects at lower doses. Antidepressant effects may be more closely associated with inhibition of MAO type A (MAO_A ) (clorgylinelike), primarily affecting NE (and 5-HT). Thus, high doses of MAO type B (MAO_B )-selective agents such as L-deprenyl (30 to 60 mg), may be required to achieve antidepressant effects. Phenelzine and tranylcypromine are A,B nonselective. The potentiation of antidepressant efficacy during MAOI therapy has also been reported for both L-triiodothyronine (T₃ , liothyronine) (Cytomel) and lithium carbonate.

Side effects

Conventional wisdom suggests using initial minor selection criteria to choose one agent over the next. For example, among the tricyclics the clinician might consider protriptyline (Vivactil) or desipramine for a patient with retarded depression and a more sedating drug, such as amitriptyline (Elavil) or doxepin (Adapin, Sinequan), for a patient with agitated depression. In general, the tertiary amine antidepressants, such as amitriptyline, imipramine, trimipramine (Surmontil), and doxepin, tend to be more sedating than the secondary amines desipramine, nortriptyline (Pamelor), and protriptyline (Vivactil).

The SSRIs fluoxetine, sertraline, and paroxetine, and bupropion, venlafaxine, desipramine, and possibly trazodone (Desyrel) may be considered for the overweight depressed patient or one with a history of weight gain during previous tricyclic administration, as preliminary evidence suggests that those drugs may be less likely to induce weight gain than most tricyclics. Bupropion and the SSRIs may even be associated with weight loss rather than gain. Isocarboxazid (Marplan), which is no longer generally available, was thought to be less likely to cause weight gain than tranylcypromine and phenelzine.

Anticholinergic effects (dry mouth, blurred vision, sweating, constipation, urinary hesitancy and retention, delayed ejaculation) tend to be more prominent with the tertiary amine tricyclics and less so with trazodone, desipramine, amoxapine (Asendin), maprotiline (Ludiomil), and the MAOIs, SSRIs, and lithium.

Orthostatic hypotension, particularly in the elderly, may be associated with the administration of imipramine, amitriptyline, desipramine, trazodone, and the MAOIs but less frequently with the SSRIs, bupropion, nortriptyline, amoxapine, maprotiline, and doxepin (or lithium and carbamazepine). The heterocyclics amoxapine, maprotiline, and trazodone, touted for their less sedating and possibly less anticholinergic and less cardiotoxic profile, are not consistent in that regard.

Orthostatic hypotension may become more prominent in the second and third weeks of MAOI treatment. Salt loading, the use of pressure stockings, and fludrocortisone (Florinef) administration may prove effective in the treatment of MAOI-induced hypotension. MAOIs can be given in a single morning dose or in divided doses. If marked insomnia occurs, nighttime doses of trazodone have been recommended by some authorities. Bouts of daytime drowsiness and sedation may also become problematic. The clinician might attempt to titrate the dose against side effects, as variations in dosage or timing of administration may be helpful.

The necessity of restricting substances that release tyramine or catecholamines and can produce hypertensive crises during MAOI treatment should be emphasized to the patient. Hypertensive crises may be clinically manifested as explosive headaches, flushing, palpitations, perspiration, and nausea. Immediate treatment with a slow infusion of phentolamine (Regitine), 5 mg given intravenously in an emergency room, is the recommended treatment (Tables 16.7-2 (Table Not Available) through 16.7-4 (Table Not Available) ).

TABLE 16.7-2 -- Instructions for Patients Taking Monoamine Oxidase Inhibitors (MAOIs)
Table from D L Murphy, T Sunderland, R M Cohen: Monoamine oxidase-inhibiting antidepressants: A clinical update. Psychiatr Clin North Am 7:549, 1984. Used with permission.

(Not Available)

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Blood levels

Blood levels of tricyclics above 450 mug/m l may be cardiotoxic, and doses of tricyclics equivalent to 2,500 mg or more of imipramine may be fatal. Electrocardiographic (ECG) monitoring should be considered in patients on high-dose tricyclic therapy (above 300 mg a day). The risk of seizures increases with increasing dosages of many cyclic antidepressants, especially maprotiline (above 225 mg a day). Maprotiline should therefore be avoided in patients with an abnormal EEG or a family history of epilepsy. Many of those guidelines are based on anecdotal evidence and may not stand the test of time and careful clinical research evaluation.

As a general rule, blood levels among patients treated with the same dose of a tricyclic or heterocyclic agent vary widely. Thus, giving all patients doses within the conventional range will leave some with subtherapeutic blood levels and others with very high levels. That may be important for nortriptyline, for which there is evidence of an inverted U-shaped curve (that is, there is a therapeutic window for clinical improvement below and above which patients do not do well). Thus, with the exception of nortriptyline, it appears clinically useful to increase doses slowly, titrating against side effects with blood level monitoring at (maintenance) doses in patients who do not show an adequate therapeutic effect. During nortriptyline treatment with a moderate to a high, but ineffective, dose, one might decrease the dose to bring blood levels back into the therapeutic range, which is highly variable across studies.

It may be useful to assess the blood level of a heterocyclic agent in a patient who fails to show adequate therapeutic response to conventional doses of the drug. Evaluation may be done once steady-state blood levels have been reached and a clinical response can be expected, generally two to three weeks after initiation of the drug. Blood levels may also be helpful in assessing the patient with substantial side effects at the lower dosage ranges. Finally, a single blood level determination in the well-maintained patient may be prudent, as a score of medicolegal cases are pending in which massive blood levels of tricyclic antidepressants were associated with sudden death. Although general blood level guidelines for some agents are given in Table 16.7-1 , the clinician should remember that blood level-response relations are obscure for most drugs and that laboratories may differ widely in the accuracy of the determination and in the agreed-upon therapeutic range. Nonetheless, blood levels may be helpful in the general assessment of the nonresponsive patient and may provide an opportunity for discussing issues such as fast metabolism and noncompliance when unexpectedly low levels are ascertained. In contrast, blood level monitoring may be less important for the SSRIs.

Time frame

With the traditional tricyclics and other antidepressants, initial improvement in sleep in the first weeks of treatment is not necessarily predictive of subsequent clinical outcome. Nevertheless, the patient may be comforted by the fact that sleep is improving. Antidepressants often require two to four weeks to produce substantial effects and four to eight weeks to produce maximal effect; however, gradual improvement often begins in the first and second weeks of treatment. Thus, there may not be an absolute lag in time to onset of clinical efficacy, only in time to onset of substantial or maximal change.

Potentiation

Because antidepressants have to be administered for several days to weeks before the response can be evaluated, the clinician should consider antidepressant potentiation in either the first or second antidepressant trial before switching antidepressants, even if the category of agents seems to lack efficacy in the patient under treatment. Thus, if a patient is

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TABLE 16.7-5 -- Approaches to Refractory Depression

Level of Refractoriness	Therapeutic Strategies
I Failure to respond	Optimize dosage; assess blood levels
II Failure to respond to adequate trial of first agent	Consider potentiation or switch to new antidepressant with different mechanism of action, or to one in a new class
III Failure to respond to second agent	Potentiate with T3 . If no response, discontinue and potentiate with lithium Switch to a third agent Strongly consider an MAOI Add or revise psychotherapy
IV Failure to respond to third agent	Definitely consider an MAOI, with or without potentiation with T3 and lithium Consider ECT, depending on severity and suicidality Add or revise psychotherapy Consider consultation and reexamination of compliance and diagnosis, especially previously unrecognized physical, psychiatric, or substance abuse comorbidity If comorbidity is present, treatment should be better targeted to that comorbid condition (i.e., medical therapy, revised pharmacotherapy, and adjunctive group work such as Alcoholics Anonymous, a related "12-step" program, or a self-help group)
V Failure to respond to numerous clinical trials of agents with different mechanisms of action, MAOIs and ECT	Consider novel therapies, including extreme doses of MAOIs (80-120 mg tranylcypromine) carbamazepine or valproate with or without an adjunct antidepressant such as bupropion (especially if recurrent or rapid cycling) alprazolam (especially if increased anxiety) bromocriptine (dopamine-acting, especially for retarded depression) TCA plus MAOI (in this but not reverse order) MAOI plus stimulant (pemoline, amphetamine, methylphenidate). Use stimulant or MAOI only with great care and after appropriate informed consent has been obtained adjunctive folate

There is a sizable literature on the efficacy of thyroid potentiation in converting antidepressant nonresponders to responders, but only in some 20 to 30 percent of patients. This appears to be independent of an initial clinical thyroid status or any evidence of hypothyroidism. A response to the addition of T₃ (25 to 50 mug a day in the morning) may occur within days and usually occurs within the first week or two of treatment. If no response to antidepressant potentiation occurs during that time frame, the clinical trial of T₃ can be exchanged for other options. Side effects are unusual but may include tachycardia, hypertension, anxiety, and flushing.

A second option is potentiation with lithium carbonate. An extensive literature, including several controlled clinical trials, reveals that the addition of lithium carbonate to a variety of antidepressant modalities, including tricyclic, heterocyclic, and MAOI antidepressants and carbamazepine, is often accompanied by a rapid clinical improvement in 50 to 60 percent of patients. Improvement may begin within 24 to 48 hours but may be slower in onset and stretch over the first week to 10 days. Doses of lithium that are slightly lower than those conventionally used for monotherapy are generally effective (that is, 600 to 900 mg in a single dose taken at bedtime may be sufficient). When lithium is used in that fashion, its side-effect profile appears to be quite benign. Lithium potentiation may be effective in all subtypes of depression. The initial reports of estrogen potentiation of antidepressant response do not appear as promising as those of either thyroid or lithium potentiation.

Drug sequence

The clinician might consider exchanging one type of antidepressant for another should unacceptable side effects appear before adequate blood levels or clinical response have been achieved. If an adequate dose and adequate blood levels have been achieved but the clinical response is inadequate, the clinician may switch to a drug with a different biochemical profile within the same class or to a different class altogether, such as an MAOI.

APPROACHES TO DEPRESSIVE SYMPTOMS AND SUBTYPES

Comorbid anxiety disorder and panic disorder

DSM-IV notes the existence of a mixed anxiety-depressive disorder among the anxiety disorders. It is not known whether patients with significant symptoms of both anxiety and depression are affected by two different disease processes or by one disease process that produces both kinds of symptoms.

If panic disorder coexists with a depressive disorder, an SSRI, tricyclic antidepressant, or MAOI should be tried initially, as those drugs are among the best for treating primary panic disorder. If symptoms of panic or anxiety remain prominent despite apparently adequate antidepressant treatment, the physician might consider the acute adjunctive use of a benzodiazepine-active agent such as alprazolam (Xanax) or the less well-studied clonazepam (Klonopin), which has also been reported to be useful in treating primary panic disorder. Those benzodiazepine agents may also have a role in the first weeks of tricyclic treatment, when anxiety symptoms occasionally increase. Alprazolam should be used with caution in patients with borderline personality disorder as it may be associated with an increased incidence of dyscontrol acts. Patients with panic or marked anxiety symptoms have often been reported to respond to MAOIs, with or without lithium potentiation. Trazodone and bupropion should be avoided as first-line treatments as they are ineffective in patients whose primary diagnosis is panic disorder or anxiety disorder. Trazodone should be avoided in male patients because of the risk of irreversible priapism that requires surgical intervention.

The new antianxiety drug buspirone (BuSpar) has recently been reported to produce moderate to marked antidepressant effects in 50 percent of patients with depressive disorders without melancholic features, although it had no effect on those with melancholic features, and responses were not associated with

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The early literature suggested a response to MAOIs in atypical depressed patients with rejection sensitivity, leaden paralysis, hypersomnia, and hyperphagia, although a recent study reported characteristics of typical depression as predictive of a positive response to tranylcypromine. Those characteristics included greater initial severity of depressed mood, psychomotor retardation, weight loss, but less middle and late insomnia (early morning awakening). Thus, the MAOIs should be considered for patients in whom multiple agents have failed, regardless of the subtype of clinical presentation. Five to six weeks must elapse following the discontinuation of fluoxetine before an MAOI is initiated.

Psychosis

A growing literature suggests that if a patient's depression has reached psychotic proportions and delusions are present, the adjunctive use of low to moderate doses of antipsychotics may help produce an antidepressant response and alleviate delusional symptoms. Preliminary evidence also suggests that lithium carbonate may be useful and that a triple drug regimen consisting of a heterocyclic agent, an antipsychotic, and lithium may be needed in some patients. When using antipsychotic potentiation in delusional depression, the physician should taper and discontinue the antipsychotics as early as possible in the continuation phase in order to lessen the risk of tardive dyskinesia. Amoxapine may also be considered for agitated, delusionally depressed patients as it has some inherent antipsychotic (dopamine receptor-blocking) properties that may be advantageous, although it, too, has been associated with the development of tardive dyskinesia.

ECT is more likely to be successful in treating delusionally depressed patients and has a more rapid onset than most psychopharmacological regimens. Thus, ECT may be considered earlier for depressed patients with delusions rather than as a treatment of last resort after psychopharmacological trials have failed. An absolute contraindication to ECT is the presence of a cerebral aneurysm or increased intracranial pressure, but a recent myocardial infarction is only a relative contraindication. Additional indications for implementing ECT may include severe medical or suicidal risk, cardiac problems (which make tricyclics dangerous), and, possibly, severe mood episodes associated with pregnancy.

Insomnia

Persistent insomnia may accompany an inadequate antidepressant response but should begin to resolve as the treatment begins to take effect. Giving more sedating antidepressants in a once-a-day evening dose is usually an effective strategy for the insomniac depressed patient because of the long half-life of most cyclic antidepressants. That regimen makes positive use of the sedation at bedtime and increases the likelihood of compliance with a single nighttime dose. Acute adjunctive treatment with a benzodiazepine may be warranted in rare instances of severe sleep loss, although the physician should be cautious about prescribing benzodiazepines and related sedatives on a long-term basis because of the possibility of habituation and addiction. Benzodiazepines should not be used as the primary antidepressant modality, as is still common in many general practice settings. The physician may also consider adjunctive nighttime medication with such agents as nortriptyline or buspirone in the patient experiencing insomnia while taking SSRIs.

Paradoxically, sleep deprivation may be an adjunctive procedure, whether or not there is severe sleep loss. An acute but transient antidepressant response to one night of sleep deprivation has been consistently reported in studies from different laboratories. Although many patients relapse after one night's recovery of sleep, sleep deprivation may be used in combination with more traditional tricyclic antidepressant or lithium carbonate treatment. Lithium may help sustain the sleep deprivation response. Moreover, preliminary evidence suggests that deprivation of sleep in the last half of the night (from 3 to 7 am) may be just as effective as total sleep deprivation and thus may be more convenient for clinical use in outpatient treatment. The rapid onset of effects achieved in approximately one half of severely depressed patients is different from the slower but sustained effects following selective deprivation of REM sleep, which is not amenable to easy clinical induction.

Lethargy and retardation

Extreme morning lethargy and retardation may be an indication for the use of SSRIs, bupropion, venlafaxine, or secondary amine tricyclic antidepressants. In the face of unsuccessful drug trials, including T₃ and lithium potentiation, the short-term supplementation of cyclic antidepressants (not MAOIs) with psychomotor stimulants has been recommended by some until there is an adequate antidepressant response to the other agents. Small doses of methylphenidate (Ritalin, 5 to 10 mg) or an amphetamine in the morning may help the otherwise incapacitated, severely retarded depressed patient face the day with more energy. Stimulants as a primary antidepressant modality in elderly depressed patients have been recommended by some authorities but remain relatively understudied.

For depressed patients with decreased appetite and associated decreased nutritional intake, the physician may consider potentiating with folic acid supplements, as a folic acid deficiency has been reported to cause refractory depression in patients receiving anticonvulsants and, presumably, could also occur because of decreased dietary intake. Moreover, intracellular deficits can occur in the setting of apparently normal plasma levels.

Obsessive-compulsive symptoms

The associated occurrence of marked obsessive-compulsive symptoms may lead to the consideration of clomipramine, which has been reported to be highly effective in adults and children with primary obsessive-compulsive symptoms when more traditional antidepressants are ineffective. Fluoxetine and the other SSRIs may share that positive effect on obsessive-compulsive symptoms.

Double depression

It is important to assess the possible occurrence of a double depression, defined by DSM-IV as the condition in which major depressive disorder is superimposed on dysthymic disorder. As the patient's superimposed depressive symptoms are alleviated, a core of chronic, minor depression may be left. In such a case the physician may erroneously conclude that the superimposed episode has not been successfully treated. Psychopharmacological approaches to the baseline level of the double depression have not been adequately delineated, but the physician might consider drugs used for the cyclic mood disorders (for example, lithium) in addition to the more traditional antidepressant agents and the SSRIs. Psychotherapy may also be indicated for some patients.

Atypical depressive features

The occurrence of atypical features or reverse or vegetative symptoms, such as hypersomnia, carbohydrate craving, and weight gain, suggests a careful reevaluation for the possible bipolar II disorder and seasonal affective disorder (SAD) (called mood disorder with seasonal pattern in DSM-IV). The atypical features may be effectively targeted with the SSRIs, bupropion, venlafaxine, and the MAOIs.

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APPROACHES TO REFRACTORY DEPRESSION

A sequence of treatment reevaluations and options for different levels of refractoriness is outlined in Table 16.7-5 . During each sequence the physician should consider optimizing a given regimen by appropriately maximizing the dose and titrating blood levels against the emergence of side effects, and using appropriate augmentation strategies. Switching among different classes of antidepressants or, within the heterocyclic class of agents, among drugs with different mechanisms of action appears most appropriate, although occasionally response to one but not another of the SSRIs may be observed. A trial of an MAOI should definitely be considered in a patient in whom multiple previous trials have failed. Venlafaxine also has a relatively positive response profile in patients who have not responded to multiple previous clinical trials. With increasing levels of refractoriness the physician should reevaluate the diagnosis (with careful assessment of possible physical, psychological, and substance use comorbidity) and should consider consultation, psychotherapy revision, ECT, and combination modalities.

Clinical trials have suggested some antidepressant efficacy of the direct dopamine agonist bromocriptine (Parlodel), which is used to treat parkinsonian patients. One double-blind study indicated that bromocriptine was equally as effective as imipramine. A related dopamine agonist, piribedil (Trivastal), has also been effective for the occasional patient with treatment-refractory depression. Dopamine-active drugs had been reported to be more effective in patients with low cerebrospinal fluid (CSF) levels of the dopamine metabolite homovanillic acid (HVA). Whether that relation holds for bupropion, with its ability to increase dopamine levels in the nucleus accumbens and striatum, remains to be explored. A similar relation between low levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and a better response to the serotonin-active compounds clomipramine and sertraline has been reported. The results are inconsistent as to whether urinary levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) can predict the response to noradrenergically active antidepressants, such as desipramine, maprotiline, and venlafaxine. Consistent endocrine or other biochemical markers of antidepressant response have not yet been found.

Although the acute antidepressive effects of lithium have been repeatedly reported, especially in patients with bipolar disorders, they remain controversial; nonetheless, consideration of lithium for patients with unresponsive major depressive disorder, particularly in augmentation trials, appears reasonable. The lag in onset to full antidepressant response is often two to four weeks or longer when lithium is used as monotherapy. Combination treatment with a tricyclic antidepressant and an MAOI has been advocated by some for patients with treatment-resistant major depressive disorder, although the superiority of that combination regimen to single-agent treatment remains controversial and virtually unstudied in a systematic fashion. If used (under extreme circumstances), both drugs can be started together (at low doses), or the MAOI can be added later. The reverse order should be avoided. The tricyclic nortriptyline may have a better safety record than imipramine or protriptyline.

Carbamazepine has been reported to be effective when used acutely and prophylactically in some patients with major depressive disorder in whom multiple trials with traditional antidepressants have failed, especially those with a history of head trauma or EEG abnormalities. For patients with treatment-refractory bipolar disorder the anticonvulsants carbamazepine and valproate may be used in combination with bupropion. Those and other combination treatments for the patient with refractory depression warrant further systematic research to provide adequate statistical and sequence-ordering guidance for the clinician.

OTHER ANTIDEPRESSANT MODALITIES

A host of studied but unproven antidepressant modalities have been reported; many are unavailable in the United States and are not generally accepted treatments. Among them are S-adenosylmethionine (SAM), beta-noradrenergic agonists, GABA agonists (such as progabide [Gabrene]), the opiate agonist buprenorphine (Temgesic), the alpha₂ antagonist idazoxan, very high parenteral doses of reserpine, anticholinergics, thyrotropin-releasing hormone (TRH), melanocyte inhibitory factor (MIF-1), vasopressin, and circadian-phase interventions.

Because of the rapid onset of effects of SAM in a high percentage of patients and the relative absence of side effects in a large number of controlled studies, that agent warrants further clinical and theoretical investigation. In double-blind studies SAM in doses of 400 mg a day produced rapid effects.

Compounds active in the dopamine biosynthetic pathway--phenylalanine, tyrosine, and levodopa (Larodopa, Dopar)--have each been reported effective in small groups of depressed patients. Levodopa may be more activating in retarded depressed patients with low CSF HVA levels, but its effectiveness is limited by increases in agitation, psychosis, and the switch into mania in patients with bipolar disorders. The precursors of 5-HT, tryptophan and 5-hydroxytryptophan (5-HTP), also have been reported to have antidepressant effects. Surprisingly favorable results in 12 of 14 studies have been reported with 5-HTP in 53 percent of a total of 547 depressed patients. The status of those agents remains in considerable doubt, however, especially in light of a reported association with malignant eosinophilia.

PHARMACOPROPHYLAXIS

Although ongoing interpersonal psychotherapy may delay the onset of subsequent episodes in patients with recurrent major depressive disorder, only maintenance, standard-dose pharmacotherapy appears highly effective in preventing subsequent relapses and the emergence of new episodes. There is a high rate of relapse in depressed patients who have been entered into controlled studies after having had two or more previous episodes (Table 16.7-6) . When effective treatment with an antidepressant agent has been followed by placebo substitution, the rate of recurrence of depressive episodes has averaged 55 percent by one year, 74 percent by two years, and 85 percent by three years. Double-blind maintenance of the original effective treatment reduced the rate of relapse by more than half at each of those time points. Statistically significant results have been obtained using a variety of treatment agents, among them the tricyclics imipramine and amitriptyline, the SSRIs fluoxetine, sertraline, and paroxetine; noradrenergic selective agents, such as maprotiline (whose effects were shown to be dose-dependent); and other agents,

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Given those data, the physician should strongly recommend pharmacoprophylaxis to patients with recurrent major depressive disorder who have had three or more prior episodes or several closely occurring episodes in the past two years. Prophylaxis should be strongly considered for the patient with two prior depressive episodes in the past five years. The strength of the recommendation should be highly integrated with a variety of other factors, including prior episode severity, refractoriness, degree of incapacitation, and the likelihood of suicidal risk if another depressive episode should occur. The recommendation should be strengthened if there is a family history of mood disorder.

Investigators in the field have observed the phenomenon of lithium-induced discontinuation refractoriness when effective prophylactic treatment was stopped in patients with bipolar disorder (Figure 16.7-6) . Though the question of whether a similar phenomenon could occur in the treatment of major depressive disorder has not been systematically examined, it is at least possible that repeated depressive episodes after discontinuation of effective treatment with an antidepressant might lead not only to the reemergence of new episodes (Table 16.7-6) but also, in some percentage of patients, to refractoriness. Repeated episodes, in addition to carrying their own morbidity and potential for mortality (through suicide), may affect the subsequent course of illness. Thus, recurrent episodes could render the patient more vulnerable not only to subsequent relapses, but also to the possibility of decreased responsiveness to medications.

Patients should be specifically educated about the known risks for recurrence on a percentage basis (Table 16.7-6) , and their negative attitudes concerning prophylaxis should be addressed and discussed. Negative attitudes include viewing the need for long-term prophylaxis as reflecting weakness, lack of effort, a character defect or flaw, and the like. Those attitudes need to be explored and countered. Societal stigma against open recognition of psychiatric illness and its short- and long-term treatment should also be addressed.

The risks of recurrence should be weighed against the relative lack of evidence of long-term side effects when the agents are used for prophylaxis, acknowledgment of the few potential side effects that can occur (such as the effects of lithium on the kidney and thyroid), and evidence for the lack of habituation

Figure 16.7-6 Loss of drug responsiveness following lithium discontinuation--a fatal outcome.

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If the patient chooses to discontinue prophylaxis, it is recommended that the drug treatment be very slowly tapered. Slow tapering avoids withdrawal insomnia and may serve other functions as well. If minor episodic symptoms begin to reemerge, treatment can be reinstituted early, before a full-blown episode has occurred and gained a momentum of its own. Thus, a specific contract should be made with the patient to contact a physician should symptoms reemerge. Reminding the patient of the long time frame to clinical response in prior episodes and his or her associated despair and incapacitation may also help the patient arrive at the decision for prophylaxis. In analogy to a fully loaded tanker, it is much easier to deal with a depression before it gains a full head of steam than to try stopping it once it has gained full speed and a momentum of its own.

Regular psychiatric visits during the prophylactic phase are recommended at intervals ranging from one to four months, depending on a variety of ancillary circumstances, including completeness of response, lack of psychosocial crises, excellent history of compliance, lack of ambivalence about the process, absence of side effects, and the financial constraints and wishes of the patient. In addition to periodic assessment of all of those issues, regular treatment visits are recommended to assess separately the potential risks of suicide, independent of the occurrence of discrete episodes. Periodic assessment of suicidal risk is particularly important if there is a family history of suicide or if other risk factors are present, among them male sex, older age, comorbid alcohol abuse, and prior suicide attempts (particularly if they were severe). One study of maprotiline, for example, indicated that although patients showed a substantial and highly significant ( P < 0.0001) decreased likelihood of recurrence of depressive episodes during treatment with that agent compared to placebo, there was a small but statistically significant increased likelihood of suicide attempts in the patient group that remained on active treatment. Thus, suicidal impulses and acts may not always vary directly with either severity of depression or reemergence of a full-blown episode that requires hospitalization, and the assessment of such risks should be part of the ongoing clinical assessment of each patient in all phases of the illness and treatment. A specific contract for communicating with the clinician on reemergence of suicidal thoughts should be considered for patients with some of the risk factors described above.

TREATMENT OF BIPOLAR DISORDER

ACUTE MANIA

Lithium carbonate

Lithium remains the paradigmatic treatment for acute mania. In comparative studies with antipsychotics, it demonstrates better overall improvement in all aspects of manic symptomatology, including psychomotor activity, grandiosity, manic thought disorder, insomnia, and irritability.

The typical clinical profile of the manic patient most responsive to lithium carbonate consists of (1) a classic presentation and euphoric mania rather than severe or dysphoric mania, (2) a pattern of mania followed by depression and then a well interval (MDI) rather than DMI (depression-mania-well interval) or continuous cycling, (3) a history of few prior episodes and no rapid cycling illness (defined as four episodes a year), and (4) a positive family history of primary mood disorder in first-degree relatives. Lithium doses should be administered to achieve blood levels between 0.8 and 1.2 mEq/L. Although a high-dose strategy (to 1.5 mEq/L) is advocated by some investigators, the author has not seen many patients who, after failing to respond at more typical blood levels of lithium, responded well when the dosage was pushed to higher, potentially toxic levels. Dose-limiting side effects may include GI disturbances, particularly diarrhea, and neuropsychiatric syndromes, including tremor, confusion, and myoclonic twitches. For the inadequate responder the author recommends potentiation with other agents rather than increasing lithium to toxic levels. Blood levels of lithium achieved at a given dose may also increase further if the patient switches from mania to depression, thus leading to greater side effects.

Lithium's antimanic action may take several weeks to manifest, even with aggressive dosing, and so, for acutely deteriorating, aggressive, or psychotic manic patients, lithium may need to be supplemented in the early phases of treatment. In a recent collaborative study that used the liberal criterion of 50 percent improvement in manic severity, only 50 percent of patients treated with lithium (or valproate) had improved at the end of the three-week monotherapy trial in an intent-to-treat analysis. That figure speaks to the frequent need for combination strategies, particularly as short stays and rapid discharges from inpatient units are increasingly mandated by managed care. Augmentation has traditionally been accomplished with antipsychotics, including the phenothiazines and butyrophenones, such as haloperidol (Haldol). Because of growing evidence of the acute antimanic efficacy of carbamazepine and valproate, it is suggested that those agents or the high-potency benzodiazepines be used for initial supplementation (rather than an antipsychotic), for reasons discussed below.

Double-blind controlled evaluations reported from different laboratories have indicated that the onset of antimanic efficacy is often as rapid with carbamazepine as it is with traditional antipsychotics, including chlorpromazine (Thorazine), thioridazine (Mellaril), pimozide (Orap), and haloperidol. As of 1994, 19 double-blind studies of carbamazepine in acute mania had indicated clinical efficacy. Fewer controlled studies have been performed with valproate, but those available, including a recent large collaborative study, also indicate acute antimanic efficacy. Because initial acute antimanic response may be a guide to subsequent prophylaxis (the major focus of therapeutics in bipolar disorders), the author encourages the investigation of an individual patient's response to those alternative anticonvulsant agents. Antipsychotics can be employed later in the sequence if there is a lack of clinical response to the mood stabilizers.

Antipsychotics

Long-term maintenance treatment with traditional antipsychotics should be avoided, if possible, in patients with bipolar disorder, as they are reported to have an increased risk for tardive dyskinesia. The strategy of rapid tranquilization with suprathreshold doses of antipsychotics should clearly be avoided. Many double-blind evaluations of that high-dose strategy in acutely psychotic and manic patients have shown it to be no more efficacious than traditional dose regimens, and it may be associated with toxic effects. Particularly

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Carbamazepine

Several preliminary studies have suggested that some of the variables associated with a poor response to lithium may be associated with a good antimanic response to carbamazepine. Thus, the drug should be considered for lithium-nonresponsive manic patients.

Typical doses of carbamazepine to treat mania have ranged between 600 and 1,600 mg a day and are associated with blood levels ranging from 6 to 12 mug/mL. However, within that dose and blood level range, there does not appear to be a clear relation to the degree of clinical response across patients.For an individual patient, however, clinical response and side effects are typically dose-related. Thus, it is important to individualize dose administration, as there is wide variability in the dose and blood level at which side effects occur.Increasing the dose to achieve a clinical effect while titrating the increases against the emergence of side effects is an appropriate strategy for a drug with such wide dose-response variability.

Valproate

Typical dose levels are 750 to 2,000 mg a day, to achieve blood levels between 50 and 120 mug/mL. Oral loading with 20 mg per kg a day from the outset is likely to be well tolerated and rapidly effective. In several case series patients with more typical manic syndromes and fewer schizoaffective symptoms appeared to show a high frequency of response. Dysphoric manic patients and rapid cyclers may also be responsive. Carbamazepine and valproate have been used in combination to treat epilepsy, and preliminary evidence for the efficacy of that combination in the acute and prophylactic management of the patient with refractory bipolar disorder is available. Valproate may act by enhancing GABAergic tone, although it also has actions shared by carbamazepine and lithium. Typical side effects are listed in Table 16.7-7 .

Clonazepam and lorazepam

Benzodiazepine anticonvulsants that have been studied in acute mania include clonazepam and lorazepam (Ativan). The sedating side effects of clonazepam may be problematic in some outpatients but may be useful in the management of inpatients or for bedtime medication for severely insomnic manic patients. The two anticonvulsants work at the central-type benzodiazepine receptor; in contrast, carbamazepine is not active at that receptor and appears to act at the peripheral-type benzodiazepine receptor. Classic central-type benzodiazepine receptors are associated with GABA receptors and surround the chloride ionophore through which chloride influx mediates neuronal inhibition. In contrast, the peripheral-type benzodiazepine receptor appears to be more closely associated with calcium fluxes and neurosteroid biosynthesis. Those findings may have ramifications for a possible differential clinical response between the two classes of anticonvulsants.

Calcium channel antagonists

A series of preliminary reports suggest that the calcium channel antagonist verapamil (Calan), and possibly also nifedipine (Procardia) and nimodipine (Nimotop), have acute antimanic efficacy. The clinical utility of the calcium channel antagonists appears promising but needs to be more systematically documented.

TABLE 16.7-7 -- Comparative and Differential Clinical and Side-Effect Profile of Lithium Carbonate, Carbamazepine, and Valproate

	LithiumCarbonate	Carbamazepine	Valproate
Clinical Profile
Mania (M)	+ +	+ +	+ +
Dysphoric	±	(+ +)	+ +
Rapid cycling	+	+ +	+ +
Family history negative	±	+	±
Depression (D)	(+)	(+)	(+)
M D prophylaxis	+ +	+ +	+ +
Epilepsy	0	+ +	+ +
Pain syndromes	0	+ +	0 (+ +)
Side Effects
White blood cell count	*		-
Diabetes insipidus	*		-
Thyroid hormones (T3 , T4 )
TSH	*	-	?
Serum calcium			?
Weight gain		(-)
Tremor		-
Memory disturbances	()	()	()
Diarrhea, GI symptoms	()	()	()
Teratogenic	(?)	()	()
Psoriasis	()	-	-
Pruritic rash	-		-
Alopecia	-	-	()
Agranulocytosis	-	()	-
Aplastic anemia	-	()	-
Thrombocytopenia	-	()	()
Hepatitis	-	()
Hyponatremia, water intoxication	-		-
Dizziness, ataxia, diplopia	-		(+)
Hypercortisolism, escape from dexamethasone suppression	-		-
Key: Clinical efficacy:    Side effects:   0 = None      = Increase   ± = Equivocal     = Decrease   + = Effective     ( ) = Inconsistent or rare + + = Very effective     - = Absent   ( ) = Ambiguous or insubstantial data base   * = Effect of lithium predominates in combination with carbamazepine

Other anticonvulsants

The clinical utility of other anticonvulsants, such as the GABA agonist progabide or the traditional anticonvulsant phenytoin (Dilantin), also requires further evaluation. Acetazolamide (Diamox) has been reported to be effective in patients who were not responsive to lithium or carbamazepine, especially those with atypical psychoses associated with dreamy confusional states occurring premenstrually or in the puerperium. The efficacy of the newly approved anticonvulsants felbamate and gabapentin and those about to be approved, such as lamotrigine, remains to be studied.

Electroconvulsive therapy

Older clinical observations and recent controlled clinical trials have demonstrated the efficacy of ECT in acute mania. Bilateral treatments are necessary; unilateral, nondominant treatments have been reported to be ineffective and to exacerbate manic symptoms in some studies. Because of the many effective pharmacological treatments that are available, assessing their usefulness for long-term preventive therapy, based on their acute antimanic efficacy, should be emphasized. ECT may then be reserved for the rare refractory patient or one with medical complications, extreme exhaustion, lethal catatonia, or malignant hyperthermia. Otherwise, after a

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Antiadrenergic drugs

Several other nonanticonvulsant compounds with some neurotransmitter selectivity have been reported to be effective in the treatment of mania. Clonidine, an alpha₂ -adrenergic receptor agonist, is used to treat hypertension. It acutely inhibits the firing of the noradrenergic locus ceruleus and has been reported to have acute antimanic efficacy in some, but not all, controlled trials. However, response in the first few days of treatment may not be associated with the ultimate outcome. Another agent that inhibits noradrenergic function is the beta-adrenergic receptor antagonist propranolol (Inderal). Because very high doses of propranolol in either the d- or l-isomer form have been effective, it is not known whether the beta-antagonist properties or some other membrane-stabilizing effects of the drug account for its acute antimanic efficacy.

Cholinomimetics

Intravenous administration of the indirect-acting cholinergic agonist physostigmine (Antilirium, Eserine) has an almost immediate antimanic effect. Physostigmine inhibits acetylcholine esterase function, making more acetylcholine available at the synapse. Although intravenous administration can produce rapid decreases in manic symptoms, physostigmine also has a short half-life and can be associated with marked increases in dysphoria and other side effects such that its long-term utility is doubtful. The success of attempts to increase cholinergic function chronically through other methods, such as lecithin, deanol, or direct acetylcholine agonists, has not been adequately delineated.

Overview of antimanic agents

The ability to achieve rapid antimanic effects with intravenous physostigmine suggests that, with appropriate pharmacological intervention and pharmacokinetics, there is no theoretical reason why an acute antimanic response cannot be achieved extremely rapidly, even though most of the other antimanic treatments have a moderate delay in onset. Manipulations of a variety of neurotransmitter systems (inhibition of noradrenergic and dopaminergic systems, but potentiation of cholinergic, benzodiazepinergic, GABAergic, and, perhaps, serotonergic systems) are all capable of inducing antimanic effects. The antipsychotics block dopamine receptors; clonidine and propranolol appear to decrease alpha- and beta-noradrenergic function, respectively; lithium, ECT, and carbamazepine each alter DA, NE, and GABA function, among others. Reserpine, which depletes catecholamines and indoleamines, has also been reported to have antipsychotic and antimanic effects. The literature on tryptophan-induced altered serotonergic function in relation to antimanic efficacy is ambiguous. Awareness of the multiple neurotransmitter approaches to the treatment of mania not only may be clinically useful in changing treatments that target different systems in non-responsive patients, but it also suggests the current weakness of any hypothetical single neurotransmitter defect in mania.

Alterations in endogenous neuropeptide function also have been postulated in mania. Although manipulations of opiates or cholecystokinin (CCK) have not produced consistent results in psychotic schizophrenic patients, calcitonin has been reported successful in treating excited psychotic states including mania. Preliminary evidence suggests that other calcium-active treatments may also be effective in treating acute mania. The clinical efficacy of calcitonin and other peptide interventions in mania remains to be confirmed but is mentioned because peptides could represent the next generation of antimanic treatments, particularly in light of increasing evidence that peptide neurotransmitters coexist in the same neurons with the more classic neurotransmitter substances that have been indirectly linked to the manic syndromes.

MAINTENANCE TREATMENT OF BIPOLAR DISORDER

Lithium prophylaxis

Lithium carbonate originally appeared to be effective in some 70 to 80 percent of bipolar patients, but current estimates suggest that even with adjunctive use of antidepressants and antipsychotics, a figure of 40 to 50 percent efficacy in many lithium clinics is more accurate.

Although early studies indicated the need for blood levels between 0.8 and 1.2 mEq/L, some case studies have suggested that lower levels, in the range of 0.5 to 0.8 mEq/L might also be effective in maintenance treatment. However, a recent controlled study found that the lower levels of side effects are achieved at the cost of a three-times-higher relapse rate when a low lithium level range (0.4 to 0.6 mg/L) is used in comparison to higher levels (0.8 to 1.0 mg/L). Monitoring of trough levels (performed in the early morning, before the morning dose is given) at one- to two-month intervals, or more frequently if the patient's course is unstable, is recommended.

Because of the overwhelming data on long-term efficacy, it is important to consider preventive treatment after a single severe episode of mania particularly if there is a family history of mood disorder. The development of a life chart, outlined above, so that the frequency, severity, and interval between episodes can be accurately assessed, may also assist in arriving at the decision for prophylaxis. If previous episodes were severe--that is, socially incapacitating and requiring hospitalization, or associated with extremely adverse events for the patient and family--the physician should consider prophylaxis earlier rather than later, despite moderately long well intervals between episodes. Those factors should be discussed with the patient during a euthymic interval so that the appropriate risk-benefit ratios can be weighed intelligently and adequate informed consent can be obtained. New data from several studies indicate that a history of more than three or four prior episodes is associated with a poor response to lithium prophylaxis; therefore, a delay in instituting prophylaxis may have consequences not only for morbidity during recurrence but also for ultimate treatment response.

Lithium-induced side effects

The profile of lithium-induced side effects has proved to be generally benign even in the long-term maintenance treatment of patients over several decades. Several of lithium's effects deserve comment, however.

THYROID FUNCTION

Lithium can impair thyroid function by several different mechanisms, and it has even been used to treat hyperthyroidism. Lithium lowers T₃ and T₄ levels circulating in the plasma and, in some patients, increases the production of thyroid-stimulating hormone (TSH). TSH increases above normal can be indicative of the hypothalamic-pituitary-adrenal axis working overtime to maintain normal levels of thyroid hormones. Thus, thyroid replacement with T₄ might be considered when TSH levels are substantially elevated, even when thyroid hormone indices are still within the lower limits of normal. Thyroid function should be assessed at six-month intervals, and more frequently if there is a breakthrough of depressive symptoms during otherwise adequate lithium maintenance treatment. Treatment of underlying hypothyroidism can, in those

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RENAL FUNCTION

By the 1980s, the scare regarding the possible high incidence of long-term adverse consequences of lithium on the kidneys had largely dissipated. Original reports of severe nephrotoxicity and pathology induced by lithium were in part related to the absence of an age-matched control group of psychiatric patients not treated with lithium. Thus, although lithium impairs vasopressin function at the level of adenylate cyclase and often produces a syndrome of diabetes insipidus, it is less consistently associated with other evidence of renal toxicity. Preliminary data suggest that less renal toxicity may occur with single nighttime dosing, which produces higher peaks but lower nadirs than conventional dosing regimens. Single nighttime dosing may also facilitate compliance.

Current practice suggests that frequent monitoring of renal function is not indicated. It is important, however, to obtain baseline measures of renal function, including the creatinine clearance rate, before beginning lithium treatment, particularly in patients with a history of renal alterations. Because of the induction of diabetes insipidus syndrome related to the blockade of antidiuretic hormone actions, patients must have adequate fluid intake to maintain an appropriate fluid and electrolyte balance. Several cases have been reported in which high levels of lithium during intoxication were associated with irreversible cerebellar toxicity. Thus, lithium levels, fluid and electrolyte status, or both should be monitored closely during periods of febrile illness, decreased fluid intake, or greater than ordinary fluid loss (such as during extreme athletic stress or GI illnesses accompanied by vomiting or diarrhea). Amiloride (Midamor, 5 to 10 mg) has been useful in the treatment of lithium-induced diabetes insipidus. If diuretics (furosemide [Lasix] or thiazide [Diuril]) are used, lower doses of lithium may be indicated.

TREMOR

Tremor can be problematic for a small but substantial percentage of patients treated with lithium. Tremor is frequently exacerbated by social stress. When the tremor persists at doses at the lower end of the therapeutic range or at the minimum doses necessary for therapeutic efficacy, attempts can be made to treat it symptomatically. Some investigators find that 10 to 40 mg of the beta-blocker propranolol in divided daily doses may reduce lithium tremor. Relief may occur within 30 minutes and may last from four to six hours.

GASTROINTESTINAL EFFECTS

GI side effects (diarrhea and indigestion) can be problematic for many patients but may be attenuated by reducing the dose or giving it at meal times (for indigestion). Antidiarrheal agents should be restricted to acute treatment.

MENTAL EFFECTS

Patients may express concern about the effects of lithium on their memory, spontaneity, and creativity. Although impairment can be objectively delineated on some, but not all, types of detailed neuropsychological testing, most patients either do not experience that effect or do not find it unduly impairing. In fact, productivity and creativity may, overall, be enhanced during lithium treatment because it prevents unproductive manic and depressive episodes. Though no adequate approach to measuring the subjective cognitive effects of lithium has been reported, it is important to rule out associated causes for cognitive impairment, including possible hypothyroidism or an inadequately treated coexisting depression, and to consider a careful dose reduction. Many so-called drug-related side effects occur during placebo treatment and thus appear to be more closely associated with illness-related variables than with a particular psychopharmacological treatment. That perspective on lithium maintenance treatment needs to be explored with the patient to avoid premature discontinuation of treatment or noncompliance.

WEIGHT GAIN

Lithium-induced weight gain is a problem in a small percentage of patients. If there is a reactive hypoglycemic component, carbohydrate restriction may help avoid the problem. Thyroid indices should be rechecked and the patient reminded not to use calorie-containing beverages to maintain the necessary increased fluid intake associated with diabetes insipidus. The role of bupropion for weight loss in the context of antidepressant augmentation remains to be studied systematically.

Dose reduction

Dose reduction may be a first maneuver in treating a variety of lithium-induced problems (for example, tremor, weight gain, thirst, urinary frequency, diarrhea, and psychomotor slowing). If lower doses are not adequate for prophylaxis, combination or alternative treatment, especially with carbamazepine (which has a different side-effect profile) or valproate, may be indicated. Other lithium-related effects during combination treatment with carbamazepine are discussed below. Because the renal clearance of lithium appears to decrease with age, a lower dose may be adequate and necessary in the older patient on lithium maintenance therapy. The calcium channel blockers may be effective in lithium responsive patients, yet avoid most lithium-related side effects.

Treatment of depressive breakthrough episodes during lithium prophylaxis

The treatment of a depressive episode in an untreated patient with bipolar disorder or of an episode emerging during lithium prophylaxis is very different from the treatment for major depressive disorder. Although SSRIs, cyclic antidepressants, and MAOIs are the mainstays of treatment of major depressive disorder, they should be used cautiously in patients with bipolar disorder. Some studies have reported an increased incidence of switches into hypomania or mania during tricyclic or MAOI therapy, above that expected for the patient's natural course of illness (Figures 16.7-3 and 16.7-7) . Although it is unknown whether the increased incidence of switching is sufficient cause to reduce the use of unimodal antidepressants in patients with bipolar disorder, it is clear that treatment with those compounds can speed up the rate of cycling in rapid-cycling patients. Thus, a depressive episode may be shortened at the cost of more rapid onset of the subsequent manic episode. Withdrawal of antidepressants has also attenuated cycle frequency in some patients.

Some uncontrolled observations implicate tricyclics and related compounds in the development of continuous cycling phases (that is, successive episodes without a well-interval) (Figures 16.7-3 , 16.7-7 , and 16.7-8) . Continuous cycling is difficult to treat and tends to be refractory to lithium. There is anecdotal evidence (requiring further investigation) that bupropion may not be associated with the same tendency toward cycle induction as are other antidepressant modalities (Figure 16.7-3) . The SSRIs (or venlafaxine) may have the same effect on the switch phenomenon and on cycle induction as the tricyclics, but that conjecture requires further investigation.

Once a switch has been observed while the patient was taking

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Figure 16.7-7 Prophylactic response to valproate in a nonresponder to lithium and carbamazepine.

Figure 16.7-8 Loss of prophylactic efficacy in a woman with rapid-cycling bipolar II disorder.

Therefore, the unimodal antidepressants should be used with caution in treating the depressive episodes of bipolar disorder, particularly if there is a history of drug-induced switches. In addition, other options should be considered, such as adding another mood stabilizer (for example, lithium, carbamazepine, or valproate). Women appear to be particularly predisposed to heterocyclic- and antidepressant-induced cycling. If unimodal antidepressants are used for a bipolar depressive episode, they should be tapered and discontinued as soon as possible to avoid the potential for drug-induced switches and cycle acceleration. Lithium and other mood stabilizers may not be able to prevent those phenomena entirely. Several case reports suggest that alprazolam may induce switches into hypomania and mania even in nonpredisposed patients.

The MAOIs in general may be less likely to induce switches than the tricyclics (Figure 16.7-7) . They should be given relatively greater consideration, especially for anergic, hypersomnic, hyperphagic patients with bipolar disorders. A substantially higher rate of antidepressant response has been reported in one controlled series for tranylcypromine (81 percent) compared with imipramine (48 percent) in patients with bipolar disorder. Clorgyline, a selective MAO type A inhibitor that is not yet clinically available, has been reported to slow the cycling frequency. The efficacy of other type A-selective drugs,

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CARBAMAZEPINE

One alternative to traditional unimodal antidepressants for depressive breakthroughs during lithium prophylaxis is the addition of carbamazepine (Figure 16.7-8) . Although evidence of the overall clinical benefit of carbamazepine when used as sole treatment in primary depression is scanty, in conjunction with the emerging literature on the efficacy of carbamazepine prophylaxis for both manic and depressive episodes, it raises the priority of using carbamazepine as a supplement to lithium in depressive breakthroughs, particularly of the rapid-cycling variety. Although only one third of acutely depressed patients responded in one study, responders tended to be patients with greater initial severity of depression and histories of discrete episodes rather than chronic depression. An abnormal EEG and increased psychosensory symptoms did not predict an acute response to carbamazepine in that series. When antidepressant response to carbamazepine was observed, it tended to exhibit the typical lag observed with other agents, so that only minor improvement was noted in the first and second weeks of treatment, whereas considerable improvement was observed after the third and fourth weeks.

In a small series of patients who responded inadequately to carbamazepine alone, one half showed a rapid onset of antidepressant effect with lithium augmentation. Thus, the combination of carbamazepine and lithium appears to be helpful for a subgroup of patients with treatment-refractory conditions. Whether the combined efficacy of the two agents is sufficient to block tricyclic- and MAOI-induced switches into mania or hypomania is unknown.

VALPROATE

In uncontrolled studies valproate, alone or in addition to lithium, has been reported to be successful in the long-term treatment of a subgroup of previously lithium-refractory patients. The antidepressant efficacy of valproate is less well delineated than its antimanic efficacy, and the utility of valproate in the treatment of an acute depressive episode remains to be further elucidated. Nonetheless, valproate, alone or in combination with lithium, offers another option in the long-term management of patients with bipolar disorder who do not respond to lithium alone. A response to one anticonvulsant may not predict response to another, and positive long-term effects of valproate plus lithium have been noted in patients not responsive to lithium or carbamazepine prophylaxis (Figures 16.7-7 and 16.7-9) .

BUPROPION

Bupropion in combination with a mood stabilizer has shown promise in the acute and prophylactic management of patients with bipolar disorder, including rapid cyclers. Although bupropion may be added to lithium or valproic acid prophylaxis without major pharmacokinetic interactions, when used with carbamazepine its blood levels are markedly decreased and those of its metabolites are increased.

THYROID HORMONE

Although thyroid hormone potentiation similar to that observed in major depressive disorder can be attempted, treatment with greater than suppressive doses should be approached with caution. Medical toxic effects have been reported with high-dose thyroid treatment, and long-term prophylaxis was inadequate unless other agents were used concurrently. Thus, T₃ , because of its short half-life, is recommended for acute augmentation strategies, whereas T₄ is recommended by some for long-term maintenance during prophylaxis. However, the addition of T₃ to T₄ in nonresponders has been reported to be helpful.

CALCIUM CHANNEL BLOCKERS

Although the calcium channel blockers, especially verapamil, have been reported effective in the treatment of acute mania in most, but not all, controlled clinical trials, their effectiveness in depression has received little attention. Recently, the dihydropyridine L-type calcium

Figure 16.7-9 Prophylactic response to valproate in a carbamazepine nonresponder.

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Among those showing responses, confirmed with the use of blind off-on-off-on (placebo-drug-placebo-drug) designs, were those with bipolar refractory depression, rapid and ultradian cycling, and recurrent, brief episodes of major depressive disorder. All of the patients with bipolar disorder who responded to nimodipine failed to respond to verapamil, but did respond to the dihydropyridine isradipine. Studies on the use of nimodipine in combination with lithium or carbamazepine for inadequate responders to those agents alone are promising.

SPIRONOLACTONE

Spironolactone (Aldactone) was reported to be effective in six lithium-intolerant patients. It has received no further systematic study.

FOLIC ACID

A single investigation reported that folic acid supplementation in the dose range of 300 to 400 mug a day significantly reduced affective morbidity, compared with results in a placebo group maintained on lithium. The promising result and the benign nature of folic acid treatment suggest that it be considered while awaiting further clinical investigation.

ELECTROCONVULSIVE THERAPY

ECT may be useful for bipolar depressed patients who do not respond to lithium and adjunctive agents. Whether ECT would help abbreviate recurrent depressive episodes in rapid-cycling patients and whether it would be useful in long-term prophylaxis are questions that await further investigation.

Treatment of manic breakthroughs during lithium prophylaxis

A wide range of drugs is available for breakthrough manic episodes occurring during lithium treatment. They include the entire spectrum of drugs indicated for the treatment of acute mania, and particularly carbamazepine and valproate because of their longer-term prophylactic efficacy. Clonazepam or lorazepam may also be useful acute alternatives to antipsychotic supplementation even though the benzodiazepines (and antipsychotics) appear to have a lesser role in the long-term management of bipolar disorders than does carbamazepine or valproate.

Other approaches to the manic breakthrough include the judicious use of antipsychotics at minimal doses and for the shortest period of time. The use of clozapine for refractory bipolar and schizoaffective patients (that is, those unresponsive to lithium, carbamazepine, and valproate) appears promising in light of preliminary reports of its efficacy and its lack of induction of tardive dyskinesia.

Lithium augmentation with carbamazepine or valproate

Supplementing the clinical effects of lithium with anticonvulsants such as carbamazepine and valproate is often more effective than using the anticonvulsant alone. Because lithium treatment is continued, evaluation of the anticonvulsant's efficacy is not confounded by a lithium withdrawal-induced episode, and time may be saved in the assessment of one clinical trial of the combination rather than two sequential trials (the anticonvulsant alone and then the combination). For patients who are unable to tolerate lithium carbonate, carbamazepine or valproate alone may be useful in preventing both manic and depressive episodes when given as long-term maintenance treatment. The literature on open clinical trials with carbamazepine is substantial, and several double-blind studies support the preliminary evidence of its long-term efficacy. Most of the data on valproate are based on clinical case series. The choice of carbamazepine or valproate may depend on the development of better clinical predictors or on the current assessment of their relative side-effect profiles.

Side Effects During Combination Therapy

HEMATOLOGICAL EFFECTS

The side-effect profile of carbamazepine tends to be quite different from that of lithium or valproate (Table 16.7-7) . As a rule of thumb, whenever lithium and carbamazepine act on a common target system, the effects of lithium tend to override those of carbamazepine. In almost every instance that is a clinical disadvantage except in terms of white blood cell (WBC) count suppression: The ability of lithium to increase the WBC count and override the count-suppressing effects of carbamazepine may be useful. Lithium is effective only against carbamazepine's benign suppression of the WBC count, and its effects are doubtful if there is evidence of more problematic interference by carbamazepine in hematological function in other cell lines, such as platelets or red cells, indicative of a pancytopenic or aplastic process. If levels of those other blood elements are normal, potentiation with lithium to reverse the benign WBC count suppression of carbamazepine may be attempted. Valproate has been associated with thrombocytopenia; the potential impact of lithium on that syndrome has not been reported.

VASOPRESSIN FUNCTION AND ELECTROLYTES

Because carbamazepine appears to act as a vasopressin agonist, either directly or by potentiating vasopressin effects at the receptor, it is not sufficient to reverse lithium-induced diabetes insipidus, which occurs by an action of lithium below the receptor level at the adenylate cyclase second-messenger system. Lithium may counter the hyponatremic effects of carbamazepine, however. To the extent that the minor cognitive impairments of lithium are, in part, related to its ability to impair vasopressin function in the brain, those data suggest not only that carbamazepine would be less likely to cause that side effect but that during combination treatment the side effects of lithium would override those of carbamazepine. Carbamazepine tends to induce a benign hypocalcemia that is generally not associated with bone demineralization. In contrast, lithium often produces a transient increase in serum calcium levels.

THYROID FUNCTION

Not only does carbamazepine tend to decrease T₄ , free T₄ , and T₃ levels, as does lithium, but, when the two drugs are given in combination, the decreases are potentiated. However, during carbamazepine treatment there is a negligible incidence of clinical hypothyroidism or above-normal increases in TSH. Consequently, thyroid supplementation of carbamazepine is rarely needed, but when the two drugs are used in combination, lithium's effect on TSH will override that of carbamazepine and the patient may require thyroid supplementation.

ALLERGIC RASH

Carbamazepine induces an allergic rash in 5 to 15 percent of patients treated. In most instances the drug should be discontinued. However, if carbamazepine has shown efficacy and other available agents have not, prednisone (40 mg a day) has been reported to be effective in suppressing uncomplicated carbamazepine-induced rashes.

HEPATITIS

There are extremely rare cases of carbamazepine-induced hepatitis. Routine monitoring for that side effect does not appear to be indicated.

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Valproate has been associated with reports of severe hepatitis in the neurological literature; most of the fatalities have been in children, particularly those under the age of 2 years and on polytherapy. Few serious hepatic side effects have been reported in the adult psychiatric patients so far studied with valproate, but liver function should be monitored periodically when that agent is used, and the patient should be warned to report symptoms that might be referable to hepatitis, such as fever, right upper quadrant pain, malaise, nausea, anorexia, and jaundice. Benign elevation of values on liver function tests (to two or three times normal) can be followed without drug discontinuation, however. Selenium vitamin supplements may be helpful in avoiding valproate-induced hepatitis-pancreatitis.

NEUROTOXICITY

There have been occasional reports of neurotoxicity when lithium and carbamazepine were used together. Because both agents can cause neurotoxic effects at or below clinically accepted dose ranges, they may occasionally occur from the combination treatment as well. In most studies the combination appears to be well tolerated, without producing side effects greater than those seen with either agent alone. Many of the side effects reported in the literature appear to have been caused by starting with relatively large doses of carbamazepine (rather than increasing the dosage slowly) in combination with other agents and assuming that the side effects were related to the combination treatment rather than to carbamazepine alone. Lithium and valproate are generally well tolerated in combination, but effects on tremor or GI distress may be additive.

PHARMACOKINETIC INTERACTIONS

There do not appear to be major pharmacokinetic interactions between carbamazepine and lithium. However, that is not the case with carbamazepine and haloperidol, as haloperidol blood levels are markedly reduced by carbamazepine. Nevertheless, most studies report improvement with carbamazepine supplementation, which suggests that carbamazepine might potentiate antipsychotic effects because of its action on systems not involving dopamine receptor blockade.

Agents commonly employed in medical practice can markedly increase carbamazepine levels and produce attendant toxicity. The most frequent dose-related toxic manifestations are dizziness, drowsiness, ataxia, diplopia, and confusion. Those effects may occur in a patient who may tolerate carbamazepine well until another agent is added. Erythromycin, troleandomycin, isoniazid (but apparently not other MAOIs), and the calcium channel blockers verapamil and diltiazem (Cardizem) (but not nifedipine or nimodipine) increase blood levels of carbamazepine. Less marked increases occur during cotreatment with propoxyphene (Darvon), fluoxetine and fluvoxamine, and, transiently, cimetidine (Tagamet). Carbamazepine lowers the blood levels of various agents (especially oral contraceptives, so that higher-dose formulations or other contraceptive strategies are indicated) and interfere with some tests that are dependent on protein binding.

In contrast to the multiple pharmacokinetic interactions between carbamazepine and other drugs--in large part owing to carbamazepine's metabolism by and its ability to be an inducer of hepatic P-450 enzymes--valproate is largely without those effects. If carbamazepine and valproate are used together, the clinician should consider reducing the dose of carbamazepine (because valproate displaces carbamazepine from protein-binding sites, increases levels of free drug, and increases levels of the -10,11-epoxide metabolite) and increasing the dose of valproate (because carbamazepine lowers levels of valproate).

TERATOGENIC EFFECTS

Cardiac and great vessel (Ebstein's) anomalies have been reported to occur with a higher frequency than expected in patients treated with lithium during pregnancy. However, recent retrospective and prospective studies have indicated that the risk may be only minimally greater than in control patients not exposed to lithium and in the normal population. In light of those data and the substantial risk of episode recurrence and its possible effects on the subsequent course of illness should lithium be stopped, routine discontinuation of lithium in all patients wishing to become pregnant should be reevaluated.

Lithium may be safer than valproate or carbamazepine for the patient with prior frequent, severe, psychotic, or suicidal episodes that might render discontinuation inadvisable. If lithium is to be discontinued for a planned pregnancy, discontinuation should be done so slowly, since a taper is less likely than rapid discontinuation to be associated with episode re-occurrence. Recently, an increased risk of inducing minor congenital malformations and developmental delay has been reported for carbamazepine. A substantial and increased risk of spina bifida has been reported for valproate. The risk is only slightly lower with carbamazepine, and use of those mood-stabilizing agents should be avoided in pregnancy if possible.

Using the lowest effective doses and supplementing with folic acid should be considered in patients who need those agents during pregnancy. Consultation with a specialist for fetal monitoring and assessment of possible defects with ultrasound and other techniques is also recommended. Persisting biochemical alterations have been found in some animal studies of fetal exposure to antipsychotics, but have not been assessed systematically in follow-up studies in humans. ECT may have the lowest risk to the fetus among the somatic treatments, but risks to the fetus from maternal seizures have not been adequately elucidated.

SENSITIZATION EFFECTS ON THE MOOD DISORDERS

Early clinical observations and more recent systematic controlled studies suggest that recurrent major depressive disorder and bipolar disorders may undergo a transition from initial episodes that are often precipitated by psychosocial stressors to later episodes that tend to occur more spontaneously. The transition often occurs in the context of an overall pattern of cycle acceleration with decreasing well intervals between successive episodes. It has been postulated that psychosocial stressors and recurrent episodes of mood disorder themselves not only may cause acute biological perturbations but also may leave behind residual biological memory traces, based on their ability to alter gene expression. It is thought that, following stress- and episode-induced changes in neurotransmission, a cascade of neurobiological effects takes place that includes not only short-term adaptations but also longer-lasting alterations initiated by a variety of transcription factors, including immediate early genes such as c-fos and c-jun. Those transcription factors are then capable of inducing changes in the long-term regulation of transmitters, receptors, nerve growth factors, neuropeptides, and possibly even in the microstructural synaptic organization of the brain, as demonstrated in many models of learning and memory.

If that conceptualization proves to be correct, it suggests the potential twofold importance of preventing episodes of mood disorder. Not only would the associated morbidity and potential mortality be prevented, but the longer-lasting neurobiological

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Treatment efficacy may vary as a function of the stage or severity of evolution of illness. For example, pharmacotherapies such as lithium may be more effective in initial and midphases of the illness, but with the emergence of rapid and ultrarapid cycling, alternative and adjunctive treatments with the anticonvulsants may be required. Similar treatment alterations may be necessary in patients with major depressive disorder, for whom psychotherapy may be effective in the early, milder forms of the illness, but, with major recurrent episodes (and particularly melancholic and psychotic syndromes), aggressive acute and maintenance pharmacotherapy may be mandatory. Adjunctive interpersonal, cognitive, and behavioral psychotherapeutic techniques may also play important roles in the late and severe stages of illness as problem-solving, remoralization, and suicide prevention techniques and in facilitating compliance with prescribed pharmacological regimens.

If two or more episodes of major depressive disorder have occurred, the clinician should strongly consider recommending long-term pharmacoprophylaxis, whether or not the patient is in ongoing psychotherapy, as recent data unequivocally support the long-term efficacy of a variety of antidepressant agents. In contrast, psychotherapy appears to be of only minor utility in delaying the onset of the next episode.

The mood disorders involve multiple areas of brain dysfunction and affect a variety of organ systems, producing alterations not only in mood but also in motor, cognitive, sleep, appetite, reward, and other somatic systems. Neurobiological alterations are evident at the level of endocrine dysfunction, as reflected not only in alterations in the regulation of glucocorticoids, corticotropin-releasing hormone, TRH, and somatostatin, but also in the size of the pituitary and the adrenals. Brain imaging has revealed alterations in blood flow and glucose utilization reflecting hypofrontality in primary and secondary depression in many studies in direct proportion to the severity of the depressive syndrome. Thus, patient and clinician should be reminded of the wealth of evidence indicating that the mood disorders are grave, potentially life-threatening, medical illnesses not different from those that afflict other major organ systems of the body and as such should be treated with equal respect.

SUGGESTED CROSS-REFERENCES

Biological therapies are discussed in Chapter 32 . Obsessive-compulsive disorder is covered in Section 17.3. The range of psychotherapeutic modalities and techniques useful in treating depressed patients is discussed in Section 16.8. The rest of Chapter 16 can be consulted for other aspects of mood disorders.