Special Issues in Prophylaxis of Manic Depressive Disorder

i in prophylaxis of manic-depressive disFirst, when is lifetime, or at least long-term, prophylaxis warranted? After one manic episode? One hypomanic episode? One depressive episode with a strong family history of manic-depressive disorder? There is insufficient empirical evidence with which to make strong recommendations, although a creative study by Zarin and Pass versus observation based on costs and benefits of recurrence risks and drug side effects under several strategies. In clinical practice without clear guidelines, such decisions need to take into account individual and family capability in reporting symptoms, rapidity of onset of episodes, episode severity, and associated morbidity. Clearly, the risks of a wait-and-see strategy would be different in a person who had a psychotic manic episode than in a j who had mild hypomania.

Second, can lithium ever be discontinued? Again, there are no solid to base this decision. However, if lithium discontinuation is , there is evidence that rapid discontinuation (in less than 2 weeks) is more likely to result in relapse than slow taper (2 to 4 weeks), with relapse rates higher in persons with type I compared to type 11 disorder (Faedda, Tondo, Baldessami, Suppes, & Tohen, 1993; Suppes, Baldessarni, Faedda, Tondo, & Tohen, 1993). In those with type I disorder, relapse rate-respectively, 96% and 73%, whereas in those with type II disorder, rates were 91% and 33% (Faedda et al., 1993). There is some theoretical concern, based on a report of four individuals, that those in whom lithium has been discontinued may not be recaptured by resumption of lithium (Post et al., 1992), but these are preliminary observations on a sample from the National Institute of Mental Health that may not be representative of persons with manic-depressive disorder seen in general clinical practice.

Third, treatment options for refractory manic-depressive disorder, particularly rapid cycling, have yet to be established. Persons with rapid cycling represent a treatment dilemma (Bauer, 1994). Withdrawal of antidepressants, which may induce rapid cycling, often leaves the person in a protracted,

Complex treatment strategies may be required, such as anticonvulsants plus doses of the thyroid hormone thyroxine.

Critical Thinking about Treatment Side Effects

All psychotropic medications have side effects. Some are actually desirable (e.g., sedation with antidepressants in persons with prominent insomnia), and specific antidepressants are often chosen on the basis of desired side effects. However, side effects usually represent factors that decrease a person's quality of life and compromise compliance.

Identification of some side effects and attribution to a particular agent are sometimes easy: An antidepressant is started, and within 2 weeks the person develops impotence; a neuroleptic is begun, and within 2 days the eases, doses can be reduced, medications changed, or agents added to manage the side effects.

However, in other cases, the nature of the problem and the solution may not be so straightforward. For instance, it is not uncommon that a person whose manic episode has resolved with lithium treatment will complain of lethargy and a loss of zest for life, without meeting full criteria for a major depressive episode; such symptoms can often markedly compromise social and occupational function, decrease quality of life, and even lead to noncompliance with treatment. Thus, understanding the source of these subsyndro-mal yet clinically significant symptoms can be critical in managing treatment. Several possible sources are commonly encountered in clinical practice, and the astute clinician will consider these types of issues:

• Does this represent a s wing into depression as part of the course of illness? In this case, increasing the lithium dose or treating with an antidepressant may be indicated.

• Is this one of the subtle cognitive side effects of lithium? In this case, it may be prudent to decrease the lithium dose or change to another

• Could the symptoms be lithium-induced hypothyroidism? In this case, thyroid supplementation would be required.

• Could the person be suffering primarily from a substantial blow to his ing the manic episode?

; to having this ; Facing these symptoms is not an ■

Note that, in this last case, idual, thc^ ^"^"more difficult in ,

; to having this ; Facing these symptoms is not an ■

in identifying thefource of these^nore subtle changes, because there is evl dence to support several causes (Gitlin et al., 1989; Goodwin & Jamison, 1990, p, 150; Nilsson & Axelsson, 1989; Weber et al, 1977). In these situa-the psychotherapist plays an important role both in supporting the to develop strategies to cope with the temporary or permanent changes in his or her life.

reviewing at this point. First, side m level of the be to dosage reduction. Other side effects that c i of the offending medication. Side effects or serious toxicity isj

in every exposed i disorder. However, the of mood symptoms within days of exposure to a new drug casts i on that substance as an etiologic agent. Data from an NIMH samthat about 40% of manic episodes occur during

; are that about half of these, or 20% of manic may be caused by antidepressants (Altshuler et al., 1995),

; be as high in other populations (e.g., Altshuler et al, 2001). Fourth, some side effects are particularly relevant to disorder. For example, among neuroleptics it is important to keep that the frequency of tardive dyskinesia, an irreversible movement disorder associated with neuroleptic use, appears to be higher in persons with mood disorders than in those with schizophrenia (Casey, 1984). It is not clear whether this is caused by some particular susceptibility of persons with mon in treating mood disorders (mania leads to neuroleptic 1 lution of mania leads to neuroleptic discontinuation; recurrence of leads to neuroleptic treatment, etc.). Regardless, neuroleptics must be used judiciously in persons with manic-depressive disorder in view of the risk of this irreversible side effect.

As another example, it should be kept in mind that all i sant treatments, including medications, ECT, and light, from depression into mania or hypomania. Rapid cycling can also Thus, initiation of these agents in treatment of the depressed phase of bipolar disorder requires careful monitoring for these effects.

Side Effects Due to Drug Interactions

An but often overlooked, cause of side effects i tat an individual may be taking. G actions with mood stabilizers and their potential clinical i rized in Tables 4.24, 4.25, and 4.26. For more coir psychotropic drug interactions, the reader is referred to work by and coworkers (Callahan, Fava, & Rosenbaum, 1993) and Cozza and Armstrong (2001). It is not uncommon for a person, who had for a long duration without problems, to develop side effects toxicity. For example, thiazide diuretics (a type of "water pill") and nonlevel and produce side effects or even serious toxicity.

However, not all drag interactions are associated with increases in serum levels of the drug of interest. Most drugs circulate in the bloodstream highly bound to plasma proteins; for many drugs, 99% of the circulating drug is

protein-bound. A bound drug is unavailable to caus toxic effects. Thus, the 1% of the drug that is freely circulating is ble for its effects. The addition of a second drug that competes for sites can thus substantially increase the amount of free drug without ful changes in the total serum level. For example, a second drug may the protein-bound fraction of a drug from 99% to 98% by common binding sites. This seemingly small change actually doubling of the amount of free, and active, drug (from 1% to 2%).

Pregnancy and Biological Treatment of Manic-Depressive Disorder

Finally, in terms of side effects, consideration of the teratogenic (propensity to induce birth defects) and perinatal effects of mood stabilizers must be kept treating women of childbearing age. Such considerations are I for lithium, carbamazepine, and valproate in Table 4.27, and can be found for antidepressants and other psychotropics in various specific reviews (e.g., Altshuler et al„ 1996; Iqbal, 1999). Lithium has been thought to increase the risk of cardiovascular defects (Schou, Goldfield, Weinstein, & Villeneuve, 1973). However, reexamination of this issue has suggested that the risk is less than previously supposed (Cohen, Friedman, Jefferson, neural tube defects (Delgado-Escueta & Janz, 1992); folic acid should always be administered to females of ity of neuroleptics or ,

TABLE 4.27 Teratogenetic and Perinatal Effects of Lithium and Commonly Used Anticonvulsants


Associated birth defects

Max risk

Risk (x-Fold)



Ebsteio's anomaly




floppy baby syndrome



Neural tube defects





Neural tube defects




Orofacial malformations



Overall, it is clear that the less fetal drug exposure, the better—for any point of view. Furthermore, the first"trimester appears to be the most sensitive stage of fetal development for most malformations, so avoidance of drug exposure during that period is particularly important. In addition, if the mother is taking medication around the time of birth, the newborn may actually be bom with clinically relevant levels of medication in his or her blood.

However, there are few absolutes in clinical treatment, including in dealing with the potential for teratogenicity when treating a with manic-depressive illness. Many factors must be

ECT. For example, Edlund and Craig (1984), despite risk of birth defects in women exposed to neuroleptic pointed out that these risks must be weighed in light of the increased rates of fetal death in pregnant psychotic women.

Clearly, the risk of teratogenicity must also be balanced against the potential mortality and morbidity of untreated manic-depressive disorder due to the potential for suicide, risk-taking behavior, and drag and alcohol use.

articularly the prescribing clinician, must support the indi-by providing accurate information and support through the decisionmaking process. But decisions regarding such profound matters of life, death, and serious morbidity are ultimately borne by the individual and his or her family.


Psychosocial Treatments for Manic-Depressive Disorder

Psychosocial Trca une n is

depressive disorder. Thus, modulation of these factors, not directly s to medication treatment may improve outcome (reviewed in Johnson et al., 1999). Fourth, social, family, and occupational dysfunctions are the rule rather than the exception. Such functional deficits may persist in the absence of major affective episodes, and even subsyndromal levels of depression appear to be a strong predictor of ongoing functional deficits. Finally, manic-depressive disorder is a costly illness, and it is possible that psychosocial interventions in addition to medical model treatment may reduce costs.

In this chapter, we will consider two broad groups of psychosocial interventions, psychotherapy and what the U.S. National Institute of Mental Health has called the context of care (National Advisory Mental Health Council, 1993). Psychotherapy refers to verbal and behavioral interaction between a clinician and an individual (or group of individuals or the individual with his support system) to relieve the individual's suffering or dysfunction ers a wide ictur

; that specify explicitly how the therapy is to be

• that are more free-form. It is important to keep this distinc-

ach for,

& Gutheil, 2001). This chapter covers a wide range of several that are highly structured and supported by research purposes or evaluates study data.

By contexts of care, we mean the organization of clinical resources to care to individuals with manic-depressive disorder who present for These can be considered along a continuum of intensity (Figure 5.1). There are multiple determinants of the context of care, including, for example, available clinical resources, legislative constraints and incentives, lation by the individual or his or her caregivers (e.g., reimbursement sys-

to push services down the continuum toward lower levels of and cost wherever possible. Thus, it is important both to optimize and to study the impact of various contexts of care along the continuum on clinical and economic outcome. Despite the complexities of this area of have been meticulously described, and a few are being subjected to controlled clinical trials. It is therefore important to review these contexts of care—psychosocial interventions in their own right—in particular with

This chapter is divided into several sections. A brief overview of the various types of psychotherapeutic approaches is first presented. Quantitative studies of the various modalities are then reviewed in detail. Next, a series of for clinicians and researchers looking

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