Research has made m j o r contributions to our scient$c knowledge of mood disorders, but the treatment of depression and mania is still a therapeutic art.

Psychotropics: The Drug Treatment of Mania and Depression Richard Finn

Once a therapist has decided that treatment for a depressed or manic patient will include antidepressant and mood-stabilizing drugs, the therapist will have to make and evaluate a series of decisions about those drugs until the episode remits-and even later for some patients. In this chapter, I categorize depres- sions suitable for drug treatment as unipolar or bipolar depressions, using the DSM-I11 classifications major depression, single episode; major depression, recurrent; and biplar disorder, depressed. I categorize manias by the two DSM-I11 classifications bipolar disorder, manic and bipolar disorder, mixed. I divide drug treatment for each of these categories into three phases: trial period, continuing treatment, and prophylactic treatment. The trial period starts when psychotropic medicines are first prescribed, and it ends when they suppress the symptoms, starting a drug-induced remission. Continuing treat- ment begins then and ends when the illness goes into spontaneous remission. Prophylactic treatment begins after spontaneous remission. The term mainte- nance is sometimes used for the continuing treatment phase and at other times for the prophylactic phase. In this chapter, I will use the term only for the pro- phylactic phase. This chapter is not a minitextbook of psychopharmacology. The clinical use of antidepressants and mood-stabilizing drugs is a large and

R . A. Munoz (Ed.). Thnopculic Potmtzol ofMood Dirorclnr Clinics New Directions for Mental Health Services, no. 23. San Francisco: Jossey-Bass, September 1984. 33

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complex issue. Instead, the aim of this chapter is to explain the basic concepts and principles of drug treatment of depression and mania.

Anyone who is clinically involved in prescribing or evaluating the use of such drugs on patients with affective disorders must work to keep up to date. A handy, quick reference library for this purpose will include Gilman and others (1980), Perry and others (1981), Johnson (1980), Jefferson and others (1983), Hansten (1979), Berkowitz and others (1981), “Mediphor Drug Interaction Facts,” a PDR and an over-the-counter PDR. Time spent familiarizing oneself with these books is a wise investment. No one can expect to remember all the details.

Despite twenty-five years of clinical experience and an enormous amount of research, the drug treatment of affective disorder remains a thera- peutic art. That will be the focus of this chapter, which is written for those who conduct such treatment or who must evaluate its effect as they conduct other parts of the total treatment program.

History of Drug Treatment of Affective Disorder

There was no effective drug treatment for depression or mania until the mid 1950s. Many drugs had been tried, and many drugs had relieved some of the symptoms, but none could stop an episode, shorten its duration, or reduce its severity. From this frustrating experience came both our knowledge of the natural history of untreated depression and the 10 to 15 percent suicide rate among those so afflicted and our knowledge of the natural history of untreated mania and its 14 percent mortality rate (McCabe, 1976). Treatment was cus- todial and aimed at protecting the depressed patient from suicide and the manic patient from infection and exhaustion.

In the 1950s, electroconvulsive therapy (ECT), which had been intro- duced as a treatment for schizophrenia, began to be used as the treatment of last resort with depressed and manic patients. The results were spectacular. A course of eight such treatments ended an episode in 80 percent of the patients who met the description of endogenous depression, retarded or agitated. Exogenous or neurotic depressives were unaffected or became more sympto- matic. Two or three electroconvulsive treatments a day were a life-saving pro- cedure for severe manics, and an extended course of such therapy could pro- duce a remission. But, many patients relapsed within six months. Moreover, many patients disliked the primitive, unmodified treatment method then used and refused the further ECT needed to produce a remission. Nevertheless, even the relative success of electroconvulsive therapy showed that an illness which seemed to be psychological in nature could be treated physically, and after World War 11, research was started to find a more acceptable treatment. The pharmacological revolution had started, and research turned to drugs.

The first drug group to be studied was the opiates. The effectiveness of morphine in making depressed patients accessible to the moral treatment prac-

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ticed in the retreats and asylums of Victorian England and America had been known for a hundred years. Nothing came of this research. However, our two current major classes of antidepressants did come serendipitously from other research started at this time. The tricyclic antidepressants and their analogues came from the search for better antihistamines, and the monoamine oxidase inhibitors (MAOIs) came out of the search for more effective drugs for the treatment of tuberculosis.

Monoumine Oxiduse Inhibitors. The elevating effect on mood and activity of tubercular patients observed during research on an experimental drug called iproniazid (Marsilid) was considered a serious unwanted side effect, and research on this drug was stopped. Then, in the mid 1950s Nathan Kline recalled this effect and successfully tried iproniazid on depressed patients. It became the first antidepressant. Unfortunately, this MA01 was highly toxic to the liver. Less toxic MA01 drugs replaced it. In two dimensions, their chemical formulas resembled those of amphetamines and other related mem- bers of the drug group called central nervous system stimulants. For this rea- son, the MAOIs were first called psychic energizers, and for some a double antidepressant-stimulant action was postulated. However, when the MAOIs were studied with larger groups of patients, they did not have the results hoped for: Only 50 percent of the patients responded-not much better than a two- or three-week stay in a hospital without treatment. Thus, it was asked whether these drugs were actually placebos. It was not known for some time that acetyl transferase, an enzyme in the body, inactivates MA01 antidepressants. Fifty percent of Americans have high levels of this enzyme. These individuals are called fast acetylators, and they inactivate MA01 drugs so rapidly that the drugs have little or no therapeutic effect when they are used in the usual dose range. The problem created by an as yet unidentified limiting factor relegated MAOIs to the backseat long before the so-called cheese reaction was identified in the mid 1960s. The cheese reaction is an acute and sometimes fatal hyper- tensive crisis triggered in patients on these drugs by eating aged cheese or any food or drug that contains large amounts of a class of natural and synthetic chemicals called sympathomimetic amines. MAOIs inactivate monoamine oxidase, the enzyme that inactivates sympathumimetic amines, which leaves the body with no protection against the blood pressure-elevating effect of these amines. For this reason, patients taking MAOIs must watch their diet and medications. If they do, they have little trouble. However, it is difficult to identify the amines in every bite of food and in every tablet of medicine taken, and it is not easy to remain continuously alert, so the MAOIs had become a second- or third-line or even a last resort treatment for most clinicians by the start of their second decade of use. However, clinical research aimed at increas- ing the safety and effectiveness of these drugs continues.

Tricyclic A ntidepressunts. The second class of antidepressants to be developed consisted of the tricyclics. Tricyclic antidepressants can elevate the mood of depressed individuals until there is spontaneous remission. Such

remission occurs for 70 to 80 percent of the patients who take tricyclics at opti- mal doses. (An optimal dose is the maximum dose that a patient can take before side effects become intolerable.) Although the tricyclic antidepressants have many troublesome and a few dangerous side effects, they have proved to be one of the safest classes of drugs ever synthesized.

Imipramine (Tofranil), the first tricyclic, was tested by Swiss psychia- trist Roland Kuhn in the mid 1950s. He apparently tried it on all the patients in his sanatorium, no matter what their illness was. He found that imipramine helped in one illness, “vital depression,” which corresponds to the American concept of retarded depression. Kuhn (1970) reported that imipramine had a remarkable effect in vital depressives and only in them.

Imipramine was introduced into this country in 1957, but no one paid much attention to Kuhn’s findings. The drug was used with every kind of depression, and the overall results were disappointing. Here, too, it was asked whether imipramine was only a placebo. Imipramine was the only tricyclic available for five years. Then, amitriptyline (Elavil) began to be marketed, and a differential treatment quickly developed: nonsedating imipramine for retarded depression, sedating amitriptyline for agitated depression. The clini- cal effectiveness of tricyclic antidepressants was soon established.

Amitriptyline was introduced at about the time of the thalidomide pho- comelia disaster. The Food and Drug Administration (FDA) responded to that disaster by slowing the process of introducing new drugs to a snail’s pace. Only a few more tricyclics were marketed in the mid 1960s, and no more were approved for almost fifteen years. The tricyclics marketed before the FDA freeze constitute the first-generation tricyclics. They were assigned to the sedating or the nonsedating group, Protriptyline (Vivactil) and desipramine (Norpramin, Pertofran) were grouped with imipramine, and nortriptyline (Aventyl, Pamelor) and doxepin (Sinequan, Adapin) were grouped with amitriptyline.

There was no scientific basis for the selection of a particular tricyclic. All seemed to be equally effective if the difference in their potencies was ac- counted for by altering the dose. The cost of treatment was the same before they were produced in generic forms. Imipramine and amitriptyline were most often prescribed. The others were chosen to meet a patient’s need for more or less sedation or for less autonomic side effects. Of drugs in the non- sedating group, protriptyline was chosen for its lack of sedation and desipra- mine for its lower autonomic activity. Of drugs in the sedating group, nor- triptyline was chosen for lower autonomic activity and doxepin for its increased sedation. We still cannot predict which drug is best for a particular patient.

Tricyclic Blood Levels. During the second decade in which tricyclics were used, two important research findings helped to improve clinical use of these drugs, and those findings remain significant to this day. The first was that, in a large group of people taking the same dose of tricyclic, blood levels vary by as much as a factor of twenty or more. While most people will get a

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similar blood level from a similar dose, some people get a high blood level, while others get a low blood level. This finding means that dosage is important only for the blood level obtained. The second finding was that patients who have a high blood level do not get the desired therapeutic effect; they may even experience a reversal and feel worse instead of better. Such a reversal is known as going through the therapeutic window. While this research has not been repeated for each and every tricyclic, it is hard to believe that these findings would not hold for every member of a class whose constituent drugs seem so similar.

But, are they that similar? Recent research has raised the possibility of clinically significant differential drug effects. During the past decade and a half, much research has been done on the biochemical basis of depression. Theories have emerged that associate depression with a disturbance in func- tion of a neurotransmitter in the brain. One theory, the catecholemine hypoth- esis, centers on norepinephrine, while other theories point to serotonin or dopamine. Drug manufacturers began to emphasize their products’ differentid effects on brain neurotransmitters. These effects will not be described here, because there is no generally available, accurate way to diagnose depressions associated with the different neurotransmitter disturbances. Nevertheless, the therapist needs to keep up to date on the different neurotransmitter effects of the antidepressants, especially for the second-generation drugs. These drugs have yet to prove any more effective than the first-generation drugs, but they are indicated for patients who have not responded satisfactorily to first- generation drugs or who cannot continue them because of side effects.

Trazodone (Desyrel) is useful because of its lower level of anticholin- ergic activity, one of the major causes of side effects in these drugs. However, it is irritating to the gastrointestinal tract, and it is also quite sedating. Trimi- pramine (Surmontil), a first-generation drug whose marketing was delayed, is sedating. Trimipramine is the antidepressant analogue of levomepromazine (Levoprome), an antipsychotic phenothiazine that can be used in this country only as a central analgesic given by injection. The possibility of analgesic activity in trimipramine must be kept in mind. Two other later-generation antidepressants are currently available: maprotiline (Ludiomil) and amoxa- pine (Ascendin). The starting dose of maprotiline must be low, and doses must be increased with caution, because rapid dose increases have caused con- vulsions in some patients. Amoxapine also has a problem: Some patients metabolize it into loxapine, an antipsychotic with neuroleptic activity, dopa- mine blockade, which is associated with the long-term side effect tardive dys- kinesia. Patients on amoxapine can develop the acute extrapyramidal syn- dromes produced by antipsychotics. The problem is that there is no way to know whether all patients susceptible to tardive dyskinesia will develop these acute side effects.

Other Drugs. Antipsychotic drugs have been widely used to treat affec- tive disorders. They are used in psychotic depressions to suppress delusions until antidepressants elevate the mood enough to stop delusion formation, at

which point the antipsychotics should be discontinued. Antipsychotics were used to take the edge off imipramine in agitated patients when imipramine was the only available tricyclic. After amitriptyline was introduced, the anti- psychotic perphenazine (Trilafon) was added to it, and the resulting combi- nation was marketed as Triavil or Etrafon. These combinations became very popular in general medical practice because of their rapid effect on agitation. Without a rapid effect, patients would not continue taking antidepressants alone. It was not known that tricyclic antidepressants and phenothiazines interact to slow each other’s metabolism, so that the blood level of each is 50 to 75 percent higher than one would expect for the same dose of each drug alone, nor was it known that using an antipsychotic in this way for a full course of treatment placed the patient at unnecessary risk for tardive dyskinesia. Because of this hazard, a new combination, Limbritol, made up of amitriptyline and the antianxiety drug Librium, was marketed. Librium has no known inter- actions with tricyclics and no known risk of tardive dyskinesia. While Librium and the older benzodiazepine antianxiety drugs have no known antidepressant activity, a new member of this class, alprazolam (Xanax), has shown some antidepressant activity in early tests. Further work is needed because of the risk of suicide in untreated depression.

Antipsychotic drugs are important in the treatment of mania. The phenothiazines can control a manic’s disruptive behavior, although they cannot shorten or stop an attack, Haloperidol (Haldol) produces much better control and much less sedation. However, sudden cycles into depression not previously seen with phenothiazines became apparent with the use of haloperidol. Since lithium became available as this problem began to surface, haloperidol received little further attention.

Lithium. Lithium carbonate or lithium citrate and carbamazepine (Tegretol) are mood-stabilizing drugs. The effects oflithium were first observed more than thirty years ago by Cade in Australia. Carbamazepine’s effect was only recently shown, and the FDA still has to allow its use in mood disorders. It is no exaggeration to say that lithium revolutionized the treatment of bipolar mood disorders. It is the only drug that can terminate a manic attack. It can terminate or suppress a bipolar depression. It is very effective in preventing recurrence of mania, bipolar depression, and even some unipolar depressions. Even when it does not prevent recurrence, it often reduces the severity of an attack.

Lithium was the first psychotropic drug to be tested on the basis of theory. But, for more than ten years, it was virtually boycotted, not because Cade’s theory was wrong, which it was, but because at the time when Cade tried it in mania medical doctors were using it as a salt substitute in congestive heart failure with disastrous results. In the 1960s, Schou, Baastrup, and other Scandinavians who replicated Cade’s work were alert to lithium’s narrow mar- gin of safety and used laboratory tests to closely monitor lithium blood levels, a method still used. Lithium is a remarkable drug with considerable toxicity.

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Anyone evaluating its clinical effect on a patient in long-term prophylaxis must appreciate that toxicity and its often subtle presentation for many weeks before the full-blown picture is clearly seen. In acute treatment, blood levels are drawn at short intervals, but in prophylaxis, the intervals are long, and a patient’s lithium level can rise to toxic levels on steady doses for many reasons. Thus, whenever a patient in lithium prophylaxis experiences a change in men- tal or physical state, it is always wise to assume that it is due to lithium toxicity. Lithium should be stopped, and a lithium level should be taken. Tests for level are inexpensive, and most laboratories can get the results back in a matter of hours. The therapist should always assume lithium toxicity until a lithium level test shows otherwise. Even then, some unlucky patients can experience toxic effects at levels within the therapeutic range.

Conduct of Drug Treatment: Major Depression, Single Episode

Trial Period. There is no highly predictable, cookbook treatment for depression. The way in which the therapist conducts the trial period of a patient’s first depression is crucial, for two important reasons: First, this may be the patient’s first depression, but it may not be the last, and should it recur, it is helpful for the patient to be so well educated in the psychological and physi- cal symptoms that he or she will come for treatment long before the recurrence gets so severe that suicide becomes a serious risk. Second, patients expect treatment of depression to be like treatment for strep throat or headache - quick and inexpensive, with no return. Unless the therapist explains why it is otherwise, the patient. will be disappointed and discouraged and may drop out of treatment. The therapist must tell the patient that the drug will have little therapeutic effect for seven to ten days, that the drug may not have its full effect for as many as four to six weeks, that he or she will experience some side effects, and that the therapist is available to answer any questions, especially about side effects.

Huston (1975) suggests making a list of‘ depressive symptoms that a patient has at the start of treatment and checking on them at each return. Many of these depressive symptoms are similar to the side effects of anti- depressants. Unless the therapist has a remarkable memory, he or she runs the risk of later believing that the depressive symptoms are side effects. Such symptoms as dry mouth, constipation, difficulty urinating, blurred vision, and episodes of tachycardia can occur. A printed list of depressive symptoms that can be mistaken for side effects can save time and worry.

The effects of drug treatment on depressed patients vary from patient to patient. The therapist learns how a patient responds to treatment only by undertaking a trial. Most patients will respond well and without any major problem, but it is always prudent to assume that the patient is an exception. There are five major unknowns at the start of treatment: Which group of drugs is most likely to benefit the patient? Which drug within that group

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should be prescribed? What is the starting dose? How rapidly should the dose be raised? What is the optimal dose?

Which Group of Drugs? The tricyclics are the drugs of choice for single- episode major depression. Considering their effectiveness and Iong history of safety, the first-episode patient must be allowed a chance to respond to them. Only the presence of an absolute contraindication or a worrisome relative contraindication should make the therapist consider using another group at this point. Many practitioners consider pregnancy an absolute contraindica- tion to any kind of drug treatment.

Second-line treatment is unsettled. Many clinicians consider second- generation tricyclics as second-line, electroconvulsive therapy as third-line, and MAOIs as last, while others change the order. Many factors are involved, including state laws. For some physically ill depressives who take many medi- cations, a stimulant such as dextroamphetamine (Dexedrine) or methylpheni- date (Ritalin) is used because it is impossible to predict the interactions of these many medications with antidepressants. There is no reason to use lithium for this disorder unless all other treatments are contraindicated. Neuroleptics are adjuncts in the treatment of the psychotic subtypes, with mood-congruent features and with mood-incongruent features, and they can sometimes help the melancholia subtype when delusions require quick suppression, but the neuroleptic must be discontinued when the patient‘s mood returns to neutral or, failing that, at the end of a four- to six-week fair trial.

The use of antianxiety agents depends on one’s interpretation of the inclusiveness of this new DSM-I11 category. The new category was meant to include some patients diagnosed by DSM-I1 as neurotic depressives. If patients with mixed anxiety and depression formerly classified as neurotic depression are classified as primarily depressed, depressives without melancholia may be treated with antianxiety agents alone. However, some therapists argue that, until a highly sensitive and specific diagnostic test for depression is available, all depressed patients should have a chance to respond to antidepressants, lest some who would respond should be missed.

Which Drug? If the therapist believes that it is possible to differentiate the various neurotransmitter disorder depressions clinically, he or she will pre- scribe the corresponding antidepressant. If the therapist does not believe that this is possible as yet, he or she will rely on the classical dichotomy in picking a drug: sedating antidepressants for agitated depression, nonsedating anti- depressants for retarded depressions. A choice made by this method depends on the therapist’s estimate of the patient’s need for sedation and of the patient’s ability to tolerate the expected side effects. Another factor is the relative cost. The difference between the new antidepressants and generics can be fivefold. If the therapist knows that the patient cannot tolerate further anticholinergic drugs or that the patient should not be exposed to them and the therapist wishes to prescribe an antidepressant, then he or she should consider trazodone or an MAOI.

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Other Questions. The therapist’s other questions- What is the starting dose? How rapidly should the dose be raised? and What is the optimal dose? - are related by a common problem, the wide variation in blood level from the same dose. Looked at in this way, patients taking standard doses fall into three groups: those who fail to reach a therapeutic blood level, those whose blood levels end in the therapeutic range, and those whose blood levels rise far above normal. Patients in the first and third groups are often treatment failures.

Using imipramine or amitriptyline as examples, the maximum out- patient dose recommended by the PDR is 150 milligrams a day. At that limit, 60 percent of all patients can be expected to respond, while 40 percent will fail. Inpatient doses are much less stringently limited, and hospital studies have shown that as many as 80 percent of all patients, excluding those with certain delusions, will respond to a 250-milligram dose over a six-week trial period.

The maximum outpatient dose recommended by the PDR is not the optimal dose. The optimal dose is particular to the individual patient; it is the maximum dose that the patient can take without important side effects. Treat- ing by the optimal dose concept can meet the problem of individual variation in metabolizing antidepressants and the consequent highly variable blood levels, Normal metabolizers will have blood levels within the therapeutic range and a good clinical response, and there will be few important side effects at standard doses. Most patients fall into this group. Rapid metabolizers will have low blood levels, and slow metabolizers will have high levels at standard doses, and neither group will show a good response. Overall, rapid metabo- lizers experience many side effects, some quite severe. Under the optimal dose concept, the dose for rapid metabolizers can be raised above the PDR limits until the patient responds, if there are no side effects. The slow metabolizers pose a problem. Many patients is this group quit treatment early in the trial period.

Every patient wants relief from suffering as soon as possible. The stan- dard tricyclics treatment program provides this for most patients. The patient is started at 25 to 75 milligrams of imipramine or arnitriptyline-usually at bedtime, because it is easier for the patient to remember to take the drug then, because maximum side effects occur during the night, and because the drug often helps the sleep disturbance, which makes hypnotic drugs unnecessary. Every second or third day, the dose is raised by 25 or 50 milligrams until it reaches 150 milligrams a day or until the symptoms respond. With elderly patients, it is advisable to start at 10 milligrams a day and to restrict the dose increases to 10 milligrams. After seven to ten days of treatment, many patients will sleep better, and many will show improved energy and appetite. Mood is usually unchanged. In another week or so, the blood level reaches a steady state, and two to four weeks later, most patients will experience adrug-induced remission. Except for some side effects, they feel well. Considering how human beings have had to suffer through depressions without effective treat- ment for thousands of years, the standard program just described is a marvel- ous achievement - but not for all patients.

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The standard program is set up to detect rapid metabolizers. If the rapid metabolizer is asked what he or she notices from the medicine at a point between weeks four to six, when most other patients are responding, the patient will say that he or she notices little or nothing-no beneficial effects, no side effects. This is a signal that the dose should be raised. However, the standard program confuses efforts to detect slow metabolizers. Within a few days of the first dose, the slow metabolizer’s blood level is already high. He or she goes through the therapeutic window. He or she feels more dysphoric- tense, sedated, or both at the same time. The patient develops many side effects, blames them on the medicine, stops taking it, blames the therapist for pre- scribing the medicine, and stops therapy. It takes between seven and ten days for each dose increase to being to have an effect. For this reason, we might do well to consider the 150 milligram outpatient limit set by the PDR as a safe limit to prevent overdosing slow metabolizers.

The best way of detecting slow metabolizers is to draw a tricyclics blood level whenever a patient develops side effects of inordinate number or severity during the trial period. Another way is to have the patient come in once or twice a week for the first month or two. However, few patients can afford it, and the therapist who is treating any volume of patients does not have the time. A better alternative is to educate the patient and the patient’s family in the kind of therapeutic relationship needed for treatment of depression - a relationship in which the patient assumes increasing responsibility for the con- duct of treatment as he or she learns more about the illness and its treatment. At the first appointment, the therapist can do one of two things: instruct the patient and the patient’s family to have the patient call once or twice a week until the next appointment to report on his or her condition and treatment response, or instruct them to call if anything out of the ordinary happens or if the patient feels worse. These instructions must be clear and emphatic so that even an indecisive and self-derogatory depressive will understand his or her duty to notify the therapist. This is the most economical way of detecting the slow metabolizers. It will also pick up patients whose depression is worsening in spite of treatment. A drug blood level can help to differentiate those in the two groups. Teaching the patient to take therapeutic responsibility will also make treatment easier during the continuing treatment phase and any future recurrences.

Dealing with the three different groups of metabolizers by the measures just described improves response and reduces the need to switch drugs or drug groups or to add the various adjunctive measures described by Gerner (1983). However, some patients will not respond to any drug or to any combination of drugs. The therapist can reduce their suffering by sticking to a fair trial plan that includes no more than two or three trials of different drugs with no trial lasting more than four weeks. At that point, if the response is still not ade- quate, hospitalization for more thorough evaluation is appropriate..

Continuing Treatment. Once the single-episode patient has responded

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to treatment during the trial period, the therapist should continue to prescribe the optimal dose. The dose should not be reduced unless the therapist believes that the dose increases overshot the mark. Antidepressants do not terminate the episode. The therapist finds the drug and the dose needed to suppress the episode. Treatment should continue until the depression spontaneously remits. Some unlucky patients never remit. A few single-episode depressives become chronic, and continuing treatment never stops. Other patients get no more than an incomplete response from the optimal dose. Treatment serves only to take the edge off their depression. Even so, many such patients may not accept any other treatment.

A few patients go into spontaneous remission within one or two days. This is a rare and dramatic event. The patient figuratively jumps through the therapeutic window, and a massive eruption of dysphoria, tension, lability, and side effects, especially sedation, follows. Through it all, the patient may wonder why he or she is not depressed, although he or she feels awful, Fortu- nately, most patients remit gradually. When this happens, some will say that they think the medicine is starting to make them sick again. If they are on a bedtime dose schedule, they report starting to feel bad in the morning but better in the evening. If they are on a split daytime dose schedule, they report feeling bad in the evening but good in the norming. These patients are report- ing that they are going out the therapeutic window for a few hours, then corn- ing back in again. Some- but far from all - patients will notice that they feel best just before they take the first dose of the day.

Some patients do splendidly, but their time in treatment mounts up. The therapist who remembers that depression is a self-limited disorder with episodes lasting from three to twelve months may begin to worry, but the patient, who by now associates feeling better with taking medicine, is reluctant to rock the boat and resists the therapist’s suggestions. Any reduction program will require the therapist to exert authority. However, in any decision to do so, the therapist must share some authority with the patient to prevent relapse if the decision is premature. The dexamethasone suppression test can often but- tress the therapist’s argument, at least for patients who are nonsuppressors when they are depressed. Many become normal suppressors when the depres- sion spontaneously remits during treatment (Greden and others, 1980).

Precipitous reduction in tricyclic dosage produces withdrawal symp- toms: insomnia, nightmares, and gastrointestinal disturbances, Unless there is an overriding need to discontinue the drug suddenly, gradual reduction in increments of 25 milligrams every two weeks improves patient’s acceptance and compliance and provides better data on which to base future decisions. It is advisable to have the patient make the judgment about his or her mood between ten and fourteen days after the dosage reduction. If the patient’s mood has lowered, the patient can be asked to decide whether to resume the p&vious.dosage. If the patient’s mood remains stable, he or she can be asked to decide whether to reduce the dose again at day fourteen. The therapist will

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need to see the patient at least every four weeks to monitor the reduction pro- cess. If the patient has a brief relapse during the process and decides to raise the dose to the previous level, the dose should be held for some time before reduction is resumed. The antidepressant can eventually be discontinued in all patients save the few whose depression becomes chronic.

Now and then, a patient goes into spontaneous remission during the trial period, never feeling better and never responding adequately to treat- ment. Raising the drug dose does not help. It may even make the patient feel worse. Both this patient and the incomplete responder clinically seem much alike. A dexamethasone suppression test may be helpful here. If not, dosage reduction, closely watched, will differentiate between the two.

Prophylactic Treatment. There is no need for prophylaxis after spon- taneous remission of single-episode major depression as a result of drug treat- ment. For patients in whom the first episode was so severe or dangerous that electroconvulsive therapy was the primary treatment, six to twelve months of prophylactic tricyclics is the general rule. At the end of the prophylactic period, dose reduction should proceed by increments of 25 milligrams a day, as just described.

Conduct of Drug Treatment: Major Depression, Recurrent

Conduct of drug treatment of recurrent major depression is the same as that of single-episode major depression, but it is complicated by three addi- tional considerations: First, how were previous episodes treated? Second, should lithium be added to the treatment program? Third, is a prophylactic phase after the continuing treatment phase likely?

Trial Period. At the start of the trial period, patients with recurrent depression can be separated into two groups: those whom the therapist has already treated and those whom someone else has treated. For returning patients, the therapist must review his or her records to learn what worked and what did not work in previous treatment programs. The therapist must obtain an interval medical history, and any examinations and consultations sug- gested by that information must be performed, in case intercurrent illnesses and their treatment require modification of a treatment plan that was success- ful in the past. Finally, no matter how beneficial the previous treatment plan was, the therapist must compare it with current standards, so that it is up to date.

In the case of a recurrent depressive patient whom the therapist has never seen before, the data gathering and decision making is much more diffi- cult. The therapist must learn why the patient has come; the therapist cannot assume that it is because of his or her outstanding reputation as a healer. The therapist wants to learn about three other things as well: What does the patient recall about previous treatment? What does the patient believe was the out- come of previous treatment, and does this correspond with the actual outcome?

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Was the patient satisfied or dissatisfied with previous treatment, and what factors led to the patient’s opinion?

In addition to the information that the patient supplies, the therapist will need corroborating information. This information is the more necessary as the case becomes more complicated and chronic. The therapist can tap a number of sources: the referring source, next of kin, those who conducted the previous treatment, and, if the patient has been hospitalized, the record room librarian. The therapist must often start treatment with a historical data base that he or she knows is not complete. In these cases, the therapist will have to start a drug treatment trial using inferences about the meaning of past treat- ment events. Because the therapist knows that these inferences can be wrong, he or she will not want to adopt a treatment program that he or she cannot easily change when additions to this data base indicate that change is in order. The therapist must clearly identify the therapy as a trial, which he or she will evaluate at regular intervals to determine whether it must be continued, modi- fied, or stopped.

Use of lithium may have to be considered in the treatment of recurrent depressives. With every recurrence, the likelihood that the patient is a bipolar depressive who has yet to have a manic attack increases (Fieve and others, 1976). If the recurrences are frequent, if the recurrence is a retarded depression (the type most likely seen in bipolars), if there is a family history of bipolar illness, or if there is a personal history of cyclothymia, a trial of lithium is warranted.

Continuing Treatment. Conduct of continuing treatment of recurrent major depression is the same as treatment of single-episode depression, except in cases where lithium has been added to the treatment program and it seems to make the difference in treatment response. In such cases, the therapist can plan to discontinue antidepressants before starting to reduce the dosage of lithium carbonate.

Prophylactic Treatment. Each recurrence means giving greater weight to the threat of suicide in a depressive episode, to the additive effects of social and economic disruption in the patient’s life, and to the possibility that stress on the cardiovascular system caused by symptomatic depression reduces the patient’s life expectancy, These factors increase the chance that the therapist, the patient, or both will want prophylaxis as the recurrences mount up.

Antidepressants are indicated in the prophylaxis of unipolar recurrent depression. Lithium seems equally effective, but patients usually prefer an antidepressant, because they feel slowed down while taking lithium. Neverthe- less, if lithium was the factor that turned the tide in earlier treatment phases, it should be continued with or without antidepressants.

As the years go by, certain events may require the therapist to alter the doses of prophylactic drugs or even the drugs themselves. Five common events force such changes: intercurrent illness, aging, pregnancy, the development of more effective treatments, and changes in the patient’s financial status. Many illnesses, either in themselves or due to the medical or surgical measures needed

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to treat them, necessitate changes in the prophylactic program. This is espe- cially true for MAOIs. Patients cannot be expected to tell the therapist promptly or accurately about such illnesses, so the therapist must make it a point to inquire. Many clinical problems can emerge when the patient has several chronic illnesses needing concurrent long-term treatment. The best way of handling such situations is to head off trouble by getting a release of informa- tion from the patient and by talking with the patient’s doctor.

As patients age, they often need smaller doses of medicine to obtain either therapeutic or prophylactic effects, or they become unable to tolerate the side effects. These developments often go hand in hand. There are no accurate data on when they happen, but it seems to be at about age seventy-five.

Pregnancy can completely disrupt effective prophylaxis. Twenty-five years of use have shown that antidepressants are safe in pregnancy, but many pregnant women will want to discontinue them anyway. After stopping the drugs, the therapist will have to keep a close watch for relapse. If the pregnant patient wants to continue prophylaxis, the therapist will need her informed consent. Lithium carbonate is quite another matter, because it has been shown to produce considerable risk of serious cardiovascular malformations in the baby (Weinstein, 1980). It must be stopped immediately when pregnancy is diagnosed. The period of greatest risk for the baby is the first trimester, and most women do not know that they are pregnant until well into that period. The therapist should consider using lithium with women of childbearing years only after obtaining their informed consent at a time when they are not preg- nant. They should be told to alert the therapist before they plan a pregnancy or as soon as they believe that they are pregnant. When lithium is the prophy- lactic drug, carbamazepine (Tegretol) seems a safe substitute for those who should continue prophylaxis and who agree to it.

The pressure to improve outcome is always present, and the glowing statements that accompany new drugs and new treatments are always compel- ling. In established prophylactic programs, i t is prudent to wait for the firmest kind of evidence before making a substitution. Forbearance is not the easiest course in this era of modern communications. A forthright discussion of risks and benefits is called for.

Finally, any change in the patient’s financial status may force an altera- tion in the treatment program. It is not often that a patient suddenly gets so much money that the therapist can prescribe an expensive medication that he or she had avoided because the patient could not afford it. More often, it is the opposite. The patient’s income is reduced, and the costs of treatment must also be reduced.

Conduct of Drug Treatment: Bipolar Disorder, Depressed

T&Z Period. The conduct of treatment of this disorder is the same as that for the treatment of depressive illnesses discussed earlier, except that lithium or an established substitute is always part of the program. Bipolar

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depression is never diagnosed until after the patient has experienced one or more manic attacks. Many such patients are already in lithium prophylaxis. Frequently, the relapse occurs after the patient stops lithium or after the dose is reduced. Bipolar depression is usually of the retarded type, and an anti- depressant with lower levels of sedation is preferred. Because antidepressants can produce rapid switches into mania, it is important to keep the dose at the lowest effective level.

Continuing Treatment. Conduct of the continuing treatment of bipolar depression is the same as that for unipolar depression, except in regard to anti- depressants. Lithium levels should stay in the range needed to stabilize the patient’s mood.

Prophylactic Treatment. Noncompliance with lithium prophylaxis in bipolar patients who have only manias is very common, whether the attacks are euphoric or angry. Several episodes of depressior, seem to motivate many bipolars to stay in prophylaxis and maintain an adequate blood level. Every return visit should include a test for lithium level, even if the patient reports taking a dose only a few hours before. An unexpected memory lapse is some- times an indication that the patient has become noncompliant. Because lith- ium prophylaxis often continues for many years and because there is serious concern about the chronic effect of lithium on the kidney, an annual check of renal function by an appropriate test is a wise precaution. If the test shows a significant change in renal function, the therapist should consult with a spe- cialist in internal medicine. Finally, the therapist should always assume lithium toxicity whenever there is a change in the patient’s physical or mental state. The assumption can be tested by stopping the lithium and obtaining a lithium level.

Conduct of Drug Treatment: Bipolar Disorder, Manic

First ECT, then antipsychotics, controlled the death rate of manic patients after 1940, which allowed us to forget that mania is a life-threatening illness with a significant mortality rate. Neither of these two treatment methods can prevent relapses and the disruption that relapses bring to the lives of those so afflicted. Significant reduction in the number and severity of relapses is the glory of lithium.

Trial Period. Lithium alone can terminate a manic attack. Few events in the treatment of mental illness can match the impact of such sudden, com- plete remission. Manias are now treated aggresively. Such treatment is no easy task, given lithium’s narrow margin of safety. Ten days of lithium at a dose sufficient to produce a blood level of 1.4 milliequivalents per liter pro- duces a sudden break in many manias. Mood falls to normal levels, while lithium mysteriously rises to toxic levels unless the dose is lowered to mainte- nance, where levels range between 0.6 and 1 milliequivalent per liter. Iflithium is stopped when the break occurs, many patients relapse. Lithium takes a while longer to stabilize mood.

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Before the break, lithium has little effect on behavior, so antipsychotics are also prescribed to reduce overactivity, maintain nutrition and fluid intake, and promote sleep. Haloperidol (Haldol) is very effective, and it is widely used, although it sometimes occasions severe side effects in patients taking lithium. The maximum interval between doses is six hours.

Most manic patients are angry and hostile, and some have delusions, which is one of the reasons why so many manic patients were diagnosed in the past as paranoid schizophrenics. Antipsychotic drug refusal is common, so these drugs are administered intramuscularly after the legal niceties have been taken care of. For phenothiazines, the intramuscular dose is only about half the oral dose, but haloperidol is poorly absorbed from intramuscular sites, so the dose must be three or four times the oral dose.

Although they bicker and bargain about antipsychotics, many manics still appreciate the importance of getting a good night’s sleep and want more than the two or three hours that they are getting. Chlorpormazine (Thorazine) is very useful in such cases, and it can help to keep down the total dose of halo- peridol. A realistic goal for antipsychotic treatment while awaiting the lithium break is five hours of sleep a night and sufficient control to allow the patient to eat three meals a day, maintain fluid balance, and use the bathroom. With that amount of control, a hospital team can manage the rest of the manic’s behavior.

Some manics do not break with lithium. ECT is the most effective alternate treatment in these cases. Clinical research is proceeding on substitute drugs, including carbamazepine (Tegretol) and clonidine (Catapres). Mild manics are not often hospitalized, but the cumulative effect of their illness can disrupt their lives as much as the severe form. Outpatient lithium treatment is effective at levels far below 1.4 milliequivalents per liter. Clinical research is now evaluating the effect of lithium on persons who have unstable mood dis- orders that could respond to lithium, such as cyclothymia. Although this research is not yet complete, the prospect seems so promising that many patients have been offered lithium trials in nonexperimental settings. Some- thing similar happened in the late 1960s, when the FDA tested lithium in mania pending approval.

Continuing Treatment. After a lithium break, the lithium dose must be lowered to avoid toxicity. Most manics who break on lithium have no further need for antipsychotics. To avoid unpleasant withdrawal symptoms, the dose of antipsychotic is gradually reduced over a period of three or four days, then discontinued. Some manics have an incomplete break. These patients may need both lithium and an antipsychotic for a while. Lithium appears to have a cumulative effect and to produce a slow and gradual remission in many patients who do not experience the classical break. Continuing treatment ends when the patient’s mood remains neutral while taking only lithium in amounts suffi- cient to produce a prophylactic blood level between 0.6 and 1 milliequivalent per liter.

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Pro@hytylactic Treatment. First-episode manics should have lithium pro- phylaxis. At each recurrence the duration of prophylaxis should increase until prophylaxis finally becomes lifelong. For a first-episode manic, the duration of prophylaxis is no less than one year. All other figures are arbitrary. The impor- tant determinant is the disruption caused by the illness in the life of the patient and the other people in the patient’s life.

During follow-up, the interval between return visits can gradually increase to three months. Lithium blood levels should be drawn at each visit, and renal function tests should be done every year. Noncompliance is com- mon in manics, particularly among those who never experience depression, and it seems to relate to personality maturation or “creativity.” The therapist must be prepared to comply with the state’s legal statutes and court rulings when he or she disagrees with the patient about the need for treatment.

Conduct of Drug Treatment: Bipolar Disorder, Mixed

There is no general agreement about treatment of bipolar disorder, mixed except that it is uncertain and difficult. Because of the risk of suicide, treatment should always start in hospital. Lithium does not seem to be as effec- tive as it is in mania. If cycles are frequent and severe, electroconvulsive therapy is indicated.

References

Berkowitz, R. L., Coustan, D. R., and Mochizuki, T. K. Handbook for Prescribing Medi- cations During Pregnancy. Boston: Little, Brown, 1981.

Fieve, R. R., Kurnbarici, T., and Dunner, D. L. “Lithium Prophylaxis of Depression in Bipolar I, Bipolar 11, and Unipolar Patients.” A m ’ c a n Journal dPvchiatry , 1976,

Gerner, R. G. “Systematic Treatment Approach to Depression and Treatment-Resistant Depression.” Psychiatric Annals, 1983, 13, 40-49.

Gilman, A. G., Goodman, L. S., and Gilman, A. (Eds.). Goodman and GilmanS The Pharmacological Basis of Therapeutics. (6th ed.) New York: Macmillan, 1980.

Greden, J. F., Albala, A. A., and Haskett, R. F. “Normalization of Dexamethasone Suppression Test: A Laboratory Index of Recovery from Endogenous Depression.” Biological Psychiatty, 1980, 15, 449-458.

133, 925-929.

Hansten, P. D. Drug Interactions. (4th ed.) Philadelphia: Lea & Febiger, 1979. Huston, P. E. “Psychotic Depressive Reaction.” In A. M. Freedman, H. I. Kaplan,

and B. J. Sadock (Eds.), Comprehensive Textbook ofpsychiatry ZI. (2nd ed.) Baltimore, Md.: Williams and Wilkins, 1975.

Jefferson, J. W., Greist, J. H., and Ackerman, D. L. Lithium EnqcZopeddaJor Clinical Practice. Washington, D.C.: American Psychiatric Press, 1983.

Johnson, F. N. (Ed.). Handbook .f Lithium Therapy. Baltimore, Md.: University Park Press, 1980.

Kuhn, R. “The Imipramine Study.” In F. J. Ayd and B. Blackwell (Eds.), Discoveries in Biological Psychiatry. Philadelphia: Lippincott, 1970.

McCabe, M. S. “ECT in the Treatment of Mania: A Controlled Study.” American Jour- nal of Psychiatry, 1976, 133, 688-691.

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“Mediphor Drug Interaction Facts.” Facts and Comparison Division. St. Louis: J . B. Lippincott, 1983.

Perry, P. J., Alexander, B., and Liskow, B. I. Psychotropic Drug Handbook. (3rd ed.) Cincinnati: Harvey Whitney Books, 1981.

Weinstein, M . R. “Lithium Treatment of Women During Pregnancy and in the Post- delivery Period.” In F. N. Johnson (Ed.), Handbook of Lithium Therapy. Baltimore, Md.: University Park Press, 1980.

Richard Finn, M . D., is associate professor, Department of Pvchiaty, The University of Iowa, Iowa City.