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Clozapine in the Treatment of Dysphoric Mania Trisha Suppes, Susan L. McElroy, Jeffrey Gilbert, Eric C. Dessain, and Jonathan O. Cole
Seven patients with bipolar disorder, characterized by dysphoric mania with psychotic features and chronic disability, refractory to standard treatments and anticonvulsants, all showed marked symptomatic and functional improvement when given the atypical antipsychotic clozapine. During follow-up over 3-5 years, most of the patients sustained substantial gains in psychosocial function; and of the six patients remaining on clozapine, no further hospitalizations were needed. This remarkable improvement in a severely ill group of patients suggests that clozapine may have utility in the treatment of bipolar disorder as well as schizophrenia. Introduction Dysphoric mania or mixed bipolar disorder was called depressive or anxious mania by Kraepelin [1921] who classified it as a mixed manic-depressive state. More recently it has been described as mania accompanied by prominent depressive symptoms (Akiskal 1983; Dell'Osso et al 1991; Goodwin and Jamison 1990; Himmelhoch and Garfinkel 1986', Himmelhoch et ai 1976; Keller et al 1986; Nunn 1979; Post et al 1989; Prien et al 1988; Secunda et al 1987; Swannet al 1986; Winokur et al 1969). Initially thought to be uncommon (Kraeplin 1921; Winokur et al 1969), recent estimates suggest that 30% or more bipolar patients hospitalized for acute mania simultaneously experience significant depression (Goodwin and Jamison 1990). Nevertheless, dysphoric mania remains a poorly studied condition. Some studies hypothesize that dysphoric and nondysphoric mania are similar conditions (Carlson and Goodwin 1973); others suggest that dysphoric mania is a distinct state and, compared with patients lacking such mixed symptom patterns, may be associated with poor treatment response and long-term outcome (Himmeihoch and Garfinkel 1986; Himmelhoch et al 1976; Keller et al 1986), high rates of recurrence (Post et al 1989; Prien et al 1988), and poor response to lithium (Goodwin and Jamison 1990; Himmelhoch and Garfinkel 1986; Prien et al 1988; Secunda et al 1985; Secunda et al 1987; Swann e~ al 1986). A recent survey of 85 patients receiving clozapine on an open-label basis at McLean IIospital from 1974 to 1989, included 14 patients with bipolar disorder and psychotic features by DSM-III-R criteria (APA 1987). Twelve of the 14 bipolar patients (86%)
From the Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA and McLean Hospital, Belmont, MA (TS, JG, ED, JC); and the Biological Psychiatry Program, Department of Psychiatry, University of ~incinnati College of Medicine, Cincinnati, OH (SM). Address reprint requests to Tdsha Sup~s, M.D., Ph.D., Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.~Dallas, 'IX 75235-9070. Received January 18. 1992; revised May 25, 1992. © 1992 Society of Biological Psychiatry
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were noted to display moderate or marked reductions in psychotic and affective symptoms in response to clozapine treatment (McElroy et al 1991). Five patients had persistent psychotic symptoms and mania without depressive features. Seven of the 12 patients had manic episodes characterized by prominent depressive symptoms. All seven, despite failing to respond adequately to treatment with various combinations of lithium, typical neuroleptics, carbamazepine, or valproate, in response to clozapine, displayed clinically significant reductions in affective and psychotic symptoms that persisted for 3-5 years of follow-up. This report describes these seven patients in detail.
Methods In a recent survey of 85 consecutive patients who participated in an open-labeled compassionate use protocol of clozapine conducted at McLean Hospital between 1975 and 1989, seven patients with bipolar disorder with manic episodes characterized by marked dysphoria and other depressive symptoms were identified (McEIroy et al 1991). This earlier survey, which described 14 bipolar patients in the cohort, did not differentiate subtyping of bipolar patients nor did it detail their histories and treatment response or longevity of response to clozapine. For the present case series, diagnosis and treatment histories before and after clozapine were determined by reviewing each patient's medical records, interviewing each patient's primary psychiatrist, and by direct examination of all patients by one of the investigators. Diagnoses recorded were made by the investigators by consensus and according to DSM-HI-R criteria (APA 1987).
Results Case ] Mr. A was a 29-year-old single man with an 8-year history of bipolar disorder with psychotic features. Family history was negative for psychiatric illness. Medical history was notable for a brain computed tomography (CT) scan displaying prominent temporal ventricular horns bilaterally with otherwise normal ventricles. Mr. A's illness began in college, after 2 years of extensive marijuana and LSD use. His manic episodes were characterized by dysphoric mood, irritability, hopelessness, helplessness, decreased sleep, grandiosity, hyperreligiousity, hypersexuality, suicidal ideation, assaultive behavior, visual and auditory hallucinations, referential ideation, and delusions. His symptoms and assaultive behavior persisted despite treatment with perphenazine, lithium carbonate, and carbamazepine. Addition of valproate resulted in partial mood stabilization leading to discharge to a half-way house, where he experienced significant manic and psychotic symptoms leading to readmission 1 year later for clozapine treatment. In 1987, clozapine started and was gradually increased to 400 mg/day, and Cespite discontinuation of lithium, valproate, and perphenazine over the next 6 months, he displayed resolution of manic symptoms and a significant decrease in psychotic symVoms. His abuse of illicit drugs ceased as well. He was maintained on clozapine 500 rag/day for more than 4 years during which he experienced euthymic mood and very mild i~,termittent psychotic symptoms which did not interfere with his functioning. Decreases in daily clozapine dose by 50 mg led to increased affective and psychotic symptoms, which resolved quickly at 500 mg/day. Because his psychosocial functioning was markedly
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improved, he was able to move to a halfway house, then to a supervised apartment, completed several college courses, developed new friends, and worked part-time. Case 2 Mr. B, a 26-year-old s~nglc professional man, had a 7-year history of bipolar disorder. He was born prematurely, had delayed vocalization, and remained socially isolated as a child. His identical twin brother was diagnosed with paranoid schizophrenia responsive to clozapine; three second-degree relatives had lithium-responsive bipolar disorder. Neurologic examination, electroencephalogram (EEG), and brain CT scan with contrast were all normal. He was first hospitalized in 1985, after assaulting a police officer, in an acute manic psychotic episode with dysphoric mood, anhedonia, grandiosity, decreased sleep, racing thoughts, visual hallucinations, assaultive behavior, ruminations, referential and paranoid ideation, and delusions of guilt and persecution. He responded poorly to lithium, haloperidol, perphenazine, carbamazepine, and, though valproate helped ameliorate manic symptoms, his depression worsened and doxepin was started. Due to his persistent intrusive violent fantasies and hallucinations, manic symptoms, and markedly impaired functioning, lithium, perphenazine, and doxepin were gradually discontinued and clozapine was given up to 900 rag/day. Although psychotic symptoms diminished and mood became more stable, a dysphoric manic episode occurred 6 months later. Vaiproate was added resulting in steady improvement ef manic and psychotic symptoms, and maximum benefit of clozapine was achieved at 800 mglday, with enuresis as the only prominent side effect which resolved with oxybutynin chloride. Mild depressive symptoms appeared 1 year later and responded to fluoxetine 20 mg every other day. About 6 months later, his granulocyte count dropped to less than 2000/ram2, and lithium was restarted resulting in a rise in white blood count (WBC) to greater than 4000/ram2. Mr. B did well over the next 2 years with only mild intermittent hypomania, though decreasing clozapine by 50-100 mg resulted in prompt exacerbations of manic and psychotic symptoms on at least two trials, Over time he made significant psychosocial gains living in a less structured halfway house, increasing his social interactions, and working 15 hours per week at a paying job. Case 3 Ms. C, a 30-year-old single woman, had a 15-year history of bipolar disorder, beginning with a manic psychotic episode occurring soon after being ill with aseptic meningitis. She recovered from the aseptic meningitis without obvious sequelae, including a normal EEG and CT scan. Family history included treatment for depression in a parent and a sibling; a maternal uncle with alcohol dependence; postpartum "insanity," two suicides, and a case of bipolar disorder in second-degree relatives; and several paternal great uncle,,; with histories of extreme violence. The patient was initially partially stabilized in Europe with ciozapine 75 mg and valproate (dose unknown). She then came to the United States where clozapine was anavailable and had a relapse. Subsequent manic episodes were dysphoric, with marked mood lability, depression, anhedonia, irritability, agitation; homicidal ideation with frequent assaultive behavior including injury of multiple caregivers; poor hygiene, paranoid delusions, and auditory hallucinations. Depressive episodes were characterized by low mood, anergy, amo-
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tivation, muteness, social withdrawal, and weight gain. She was hospitalized multiple times in the next 9 years; treatment with ECT (20 treatments) and multiple medications, including haloperidol, thioridazine, fluphenazine, thiothixene, diazepam, clonazepam, clorazepate, clonidine, lithium (discontinued due to nephrotic syndrome), valproate, and carbamazepine were of little benefit. When out of the hospital for brief periods she required 24-hr supervision due,to erratic and dangerous behavior. In 1988, due to persistent significant symptoms, Ms. C was restarted on clozapine up to 800 rag/day, and within 6 months she became ¢uthymic, violent behavior and auditory hallucinations ceased, and her delusions were reduced in severity. Although she continued to experience mild psychotic symptoms under stress, she sustained herself without emergence of behavioral deterioration or violence. Decreases of daily clozapine by 50 or 100 rag were associated with recurrence of dysphoric mania and psychosis. Over the next 4 years, the patient remained on clozapine and valproate (750 rag/day) and was euthymic, nonviolent, without overt delusions, and lived in a halfway house. Case 4 Ms. D, a 31-year-old single woman, had a 14-year history of severe bipolar disorder. Medical history was unremarkable except for lithium-induced goiter. Neurological evaluation included a normal brain CT scan and EEG studies. Family history was notable for bipolar disorder in a parent, a sibling, and two second-degree relatives; and for depression and alcoholism in another second-degre~ relative. The patient had three hospitalizations between 1977 and 1980 for depressive episodes characterized by catatonia, muteness, decreased oral intake, and inability to care ['or herself. Lithium was found to be helpful for mood stability, and chlorpromazine induced remission of psychotic symptoms and decreased assanltiveness. She was discharged on lithium, to a halfway house, and remained out of the hospital for 2 years. Between 1982 and late 1988 Ms. D had multiple hospitalizations for manic psychotic episodes characterized by irritability, depression, anhedonia, hopelessness, severe agitation, hypersexuality, paranoid and referential ideation, delusions of guilt, auditory hallucinations, decreased sleep, poor judgment and impulse control, and both self-destructive and assaultive behavior. Although some admissions were precipitated by medication noncompliance, she also had break-through episodes while receiving doses of lithium and carbamazepine within the therapeutic serum concentration. Of note, in 1985, while receiving thioridazine`, lithium carbonate, and carbamazepine, she experienced a period of ultrafast rapid cycling with depression in the morning and hypomania or mania later in the day. Any period out of the hospital required continuous family supervision due to persistence, of significant affectiv¢ and psychotic symptoms. Due to the increasing severity of her illness, in 1988, clozapine 400 mg was added to valproate 1000 me, and her manic and psychotic symptoms remitted in about 5 weeks. Over the next 3 years, valproate was discontinued and the patient was maintained on clozapine 450 me, with continued remission of symptoms and sustained ability to live independently, complete college courses, and support herself financially. Case 5 Ms. E, a 35-year-old divorced professional writer, had a 16-year history of bipolar disorder. Medical history was notable for high fevers at age 6 and near-drowning at age
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7. Neurological evaluation was unremarkable, including a normal EEG in 1985. Family history was notable for alcoholism in her father. After her first hospitalization in 1975 at age 19 for mania characterized by dysphoria, anhedonia, paranoia, grandiosity, delusions of guilt, referential ideation, auditory hallucinations, decreased sleep, increased energy, and agitation, the patient remained functional for the next 9 years while receiving lithium in combination with trifluoperazine or thiothixene. Despite continued treatment, she was rehospitalized for dysphoric mania at age 28. A 3-month trial of carbamazepine proved ineffective, and the patient was discharged on lithium carbonate and thiothixene. However, she complained of depression characterized by low mood, amotivation, difficulty concentrating, impairment of memory, disrupted sleep, poor appetite, anergy, and delusions. She was rehospitalized for 1 year for psychotic depression, receiving multiple medication trials of little benefit including phenelzine (associated with the development of rapid cycling), perphenazine (12 mg associated with tardive dyskinesia), carbamazepine, and clonazepam. At midhospitalization, levothyroxine sodium (0.1 rag/day) was added for a persistently low 1"4 with normal thyroid-stimulating hormone (TSH), and valproate 3000 rag/day (50 rag/! serum) was added resulting in remission of manic symptoms though depressive symptoms emerged and bupropion (150 mg BID) was started. She was discharged to a halfway house and put on multiple medications (see Table l), but was unable to work 0ue to persecutory delusions. Clozapine was initiated (200 rag) 4 months later when the patient was rehospitalized for a dysphoric manic episode. Despite gradual discontinuation of the majority of her medications, clozapine use was associated with rapid resolution of affective and psychotic symptoms. For the past 5 years, the patient has remained on clozapine 250 rag, plus levothyroxine sodium 0.15 mg and clonazepam 0.25 mg with sustained improvement in mood and psychotic symptoms, she has lived at home with her family, and maintained demanding full-time employment. Case 6
Mr. F was a 33-year-old white man with a 13-year-history of severe rapid-cycling bipolar disorder with multiple suicide attempts leading to 20 psychiatric hospitalizations. Manic episodes were characterized by dysphoria, irritability, angry outbursts, hopelessness, helplessness, severe suicidality with plan, increased energy, decreased sleep, weight loss, racing thoughts, referential ideation, and auditory hallucinations. Depressive episodes were characterized by depressed mood, anergy, amotivation, hopelessness, and suicidal plans. His affective and psychotic symptoms had not responded to lithium, standard antipsychotics, carbamazepine, clonidine, verapamil, clonazepam, and bilateral electroconvulsive therapy (ECT). Some of these treatments produced intolerable or dangerous side effects, including renal insufficiency with lithium, Stevens4ohnson syndrome with carbamazepine, and intractable akathisia with the antipsychotics. Valproate produced a significant response but caused persistent elevation of hepatic Uansaminases that led to drug discontinuation. Treatment with clozapine (350 rag/day) produced a remarkable remission of both affect~ve and psychotic symptoms, causing the most complete clearing of symptoms since the onset of his illness, and enabling significant improvement in psychosocial functioning. However, 8 months after initiation of clozapine, he developed agranulocytosis (granulocyte count to <700/ram 2) and the drug was stopped. Despite extensive psychopharmacological efforts, his affective and psychotic symptoms promptly recurred and persisted. He was hospitalized twice more and committed suicide.
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Case 7 Ms. G, a 46-year-old single college graduate, had a 24-year history of bipolar da~order with psychotic features poorly responsive to medication. Medical history was remarkable for mononucleosis with hepatitis in her early 20s, a nonfocal neurological examination, a normal brain CT scan with contrast, and an EEG with diffuse slowing interpreted as due to medication and normal on repeat EEG study. Family history was notable for imipramine-responsive major depression in her mother. The patient was first psychiatrically hospitalized at age 34 for dysphoric mania and psychosis while receiving im~pramine for major depression characterized by low mood, social withdrawal, obsessive ruminations, indecisiveness, low self-esteem, and suicidal ideation. Her manic episodes, which often were precipitated by treatment with antidepressants, were characterized by prominent dysphoria, anhedonia, irritability, anxiety, agitation, increased energy, racing thoughts, hypersexuality, referential ideation, persecutory delusions, and homicidality with assaultive behavior. For the next 8 years she experienced constant dysphoric mood swings, reckless hypersexuality, and chronic psychotic symptoms inadequately responsive to treatment with chlorpromazine, thioridazine or loxapine, lithium carbonate, carbamazepine, or valproate. In early 1987, clozapine was started and increased to 400 mg over 4 months as other medications were discontinued. She sustained gradual remission of mood swings, psychosis, and hypersexual behavior. During the next 5 years, on only clozapine 400 mg/day, Ms. G's affective and psychotic symptoms remained in remission, and she lived independently and maintained responsible full-time employment.
Discussion Among 85 consecutive patients treated with clozapine at McLean Hospital between 1975 and 1989, seven with treatment-resistant bipolar disorder with manic episodes associated with significant depressive symptoms were identified. All had a history of well-documented treatment resistance marked by recurrent episodes of illness and incomplete response of symptoms to standard neumleptics, lithium, antidepressants, and anticonvulsants, alone or in combination. Nevertheless, all patients displayed significant reductions in affective and psychotic symptoms when treated with clozapine alone or in combination with lithimn, an antidepressant, or valproate. Clozapine's effects we, e often evident within the first few weeks of ~atment, and were sustained throughout the followup period which ranged from 3 to 5 years, Indeed, the six patients who continued on clozapine required no further hospitalizvtions and displayed significant improvement in psychosocial functioning, evidenced by an ability to live in less structured settings, to sustain personal relationships, return to school, and to maintain employment. Further, although all patients had been treated with complicated polypharmacy prior to clozapine, three cases (1, 4, and 7) eventually were maintained on clozapine alone and two cases (3 and 5) on much simpler medication regimens (see Table 1). This case series describes a severely ill group of bipolar patients with an early age of onset, history of psychiatric illness in family members, and an unrelenting course of illness with decreased capacity to funcgon and fewer well periods between episodes, Additionally, a number of the cases had a history of neurological soft signs, impairment, or insult (cases 1, 2, 3, 5, and possibly 7). This high percentage of potential neuropsychiatric factors is consistent with the results of Himmelhoch and Garfinkle (1986) who
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found a highly significant association of a "neurological condition" with mixed mania in lithium-resistant patients. Their findings suggest that the presence of a mixed or dysphoric manic history is more likely to be seen in patients severely ill, treatment-resistant, and with complicated neurological histories. As well, almost 30% of their patient group of mixed manics had a history of drug or alcohol abuse, suggesting that secondary mania may present in a mixed form (possibly case 1). At this time it is difficult to speculate in detail on how these or unrelated factors provide causal explanation for this severe form of bipolar disorder. Although these patients' apparent response to clozapine could be happenstance, this seems unlikely for several reasons. No patient had a recent history of effective symptom resolution on any medication regimen prior to clozapine; no patient had been sustained on a single medication out of the hospital; improvement in all cases began soon after initiating clozapine treatment, and the six of seven patients who remained on clozapine showed sustained improvement. Given the chronicity, severity, and apparent treatment resistance of these illnesses, the likelihood of spontaneous remission or placebo response seems remote (Goodwin and Jamison 1990; Kraepelin 1921; McEIroy et al 1991; Nunn 1979; Winokur et al 1969). Moreover, the prompt recurrence of affective and psychotic symptoms in five patients after small reductions in clozapine dose (cases 1, ",, 3, and 4) or discontinuation (case 6), and the prompt decrease in %~se symptoms after increasing the dose supports the likelihood that patients were rcspo,ding to this drug. The majority of patients, five of seven, complained of side effects from clozapine, with morning sedation and weight gain the most commonly reported (see Table 1). The patients, however, tolerated these side effects without significant complaint or loss of compliance, stating that their symptoms were substantially improved with the medication, allowing them to function better. This side effect profile is consistent with recent reports (Baldessarini and Frankenburg 1991). The finding that clozapine may be effective in the treatment of bipolar patients with dysphoric mania is interesting in light of the multiple receptor actions of this drug which include affinities at noradrenergic (alpha and beta), as well as serotonergic (5-HT2), histaminic, and muscarinic acetylcholine receptors with weak interactions on dopaminergic (D~ and D2) receptors (Baldcssarini and Frankenburg 1991). The classic hypothesis that typical antipsychotic action was due to D2 receptor blockade and the low potency of clozapine at these receptors seemed inconsistent with this long-held view. The recent identification and cloning of additional putative dopamine receptors D3, D+, and Ds may help to clarify the actions of clozapine (Sokoloff et al 1990; Sunahara et al 1991; Van Tel et al 1991). In particular, the D4 receptor has a higher affinity for clozapine than other dopamine receptors and a preferential limbic distribution of its RNA (Van 1"ol et al 1991). This pattern of D4-RNA may reflect binding patterns of clozapine which contribute to clozapine's mood-stabilizing and antipsychotic properties including increased activity in frontal and temporal cerebral cortex and decreased activity in the extrapyramidal basal ganglia, However, the powerful antiadrenergic and antise~'otonergic actions of clozapine supports speculation that these neurotransmitters may play a role in psychosis and affective illness (Baldessarini et al 1992; Meltzer 1989). Further study is needed to elucidate the primary or multiple complex actions of clozapine central to symptom resolution in severe bipolar disorder. Clozapine appeared to exert bidirectional mood stabilization in five patients (cases 1, 3, 4, 5, and 7). These patients not only experienced rapid reduction in their dysphoric manic symptoms, but also did not develop subsequent manic-depressive episodes. Pre-
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liminary evidence suggests that clozapine may have an antidepressant or mood-elevating effect independent of its other actions (Roubicek and Major 1977). In conclusion, although clozapine has been widely studied and recommended for use in schizophrenia, there are few studies of its efficacy in bipolar disorders (Calabrese et al 1991). The marked improvement of both psychiatric symptoms and psychosocial functioning following initiation of clozapine in this severely ill group of patients suggests it may be an effective treatment for bipolar disorder when other more standard treatments have failed. Moreover, the degree of benefit may even exceed that commonly found in treatment-resistant schizophrenia (Baldessariai and Frankenburg 1991). This case series suggests that clozapine may be especially useful in bipolar patients with mixed, dyspboric manic-depression, a form of bipolar disorder that may be associated with a poor outcome and less favorable response to lithium (see Introduction). More study is needed to determine if this medication is generally useful in the treatment of bipolar disorder patients, and to elucidate its mechanisms of action in affective illness. Systematic study of clozapine in patients with treatment-resistant bipolar disorders, including those with dysphoric or depressive mania and other severe forms that are difficult to treat (rapid cycling, psychotic, or chronic), is recommended. The authors wish m thank the,NeumscienceFellowshipof McLeanand MassachusettsGeneralHospitalfor fundingprovidedto T.S., and for editorialassistancefromDr. RossBaldessarini,and graphicsassistancefrom MeridithKolbrener.
References Akiskal HS (1~83): The bipolar spectrum: New concepts in classification and diagnosis. In L Grimpoon (ed), Psychiatry Update, vol II. Washington, DC: American Psychiatric Press, pp 271-292. American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Baldessarini RJ, FrankenburgFit (1991): Clozapine, a novel antipsychotieagent. NEJM 324:746754. Baldessarini RJ, Huston-LyonsD, Campbell A, Marsh ER, Cohen BM (1992): Do central antiadrenergic actions contribute to the atypical propertiesof clozapine? Br J Psycttiatry (in press). Calabrese JR, Meltzer HY, Markovitz PJ (1991): Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 11:396-397. Carlson GA, Goodwin FK (1973): The stages of mania, a longitudinalanalysisof the manic episode. Arch Gen Psychiatry 28:221-228. Dell'Osso L, Placidi GF, Nassi R, Freer P, Casano GB, Akiskal HS (1991): The manic-depressive mixed state: Familial, temperamental and psychopathological characteristics in 108 female patients. Fur Arch Psychiatry Clin Neurosci 240:234-239. Goodwin FK, Jamison KR (1990): Manic.DepressiveIllness. New York: Oxford University Press, Inc. HimmelhochJM, GarfinkelME (1986): Souwes of lithium resistance in mixed mania. Psychopharm Bull 22:613--620. Himmelhoch JM, Mulla D, Neil IF, Detre PD, Kupfer DJ (1976): Incidence and significe~ceof mixed affective stales in a bipolar population. Arch Gen Psychiatry 33:1062-1066. Keller MB, Lavori PW, CoryellW, et al (1986): Differentialoutcomeof pule manic, mixeA/cycling, and pure depressive episodes in patients with bipolar illness. JAMA 2~55:3138-3142. Kraepelin E (1921): Manic.Depressive In,sanity and Paranoia. Robertson GM (ed), Barclay RM (translator). Edinburgh, Scotland, E & S Livingstone.
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McElroy SL, Dessain EC, Pope HG Jr et al (1991): Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 52:411-414. Meltzer HY (1989): Clinical studies on the mechanism of action of clozapine: The dopamineserotonin hypothesis of schizophrenia. Psychopharmacology 99:S18-$27. Nunn CM (1979): Mixed affective states and the natural history of manic-depressive psychosis. Br J Psychiatry 134:153-160. Post RM, Rubinow DR, Uhde TW, et al (1989): Dysphoric mania: Clinical and biological correlates. Arch Gen Psychiatry 46:353-358. Prien RF, Himmelhoch JM, Kupfer DJ (1989): Treatment of mixed mania. J Affective Disord 15:915. Roubicek J, Major I (1977): EEG profile and behavioral changes after a single dose of clozapine in normals and schizophrenics. Biol Psychiatry 12:613--633. Secunda SK, Katz MM, Swarm A, et al (1985): Mania: Diagnosis, state measurement and prediction of treatment response. J Affective Disord 8:113-121. Secunda SK, Swarm A, Katz MM, Koslow SH, Croughan J, Chang $ (1987): Diagnosis and treatment of mixed mania. Am J Psychiatry 144:96-98. Sokoloff P, Giros B, Martres MP, Bouthenet ML. Schwartz JC (1990): Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 347:146151. Sunahara RK, Guan HC, O'Dowd BF, et al (1991): Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than DI. Nature 350:614-619. Swarm AC, Secunda SK, Katz MM, et al (1986): Lithium treatment of mania: Clinical characteristic, specificity of symptom change, and outcome. Psychiatry Res 18:127-141. Van Tol HHM, Bunzow JR, Guan HC, et al (1991): Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610-6i4. Winokur G, Clayton PJ, Ruch T (1969): Manic Depressive Illness. St. Louis: The.• C.V. Mosby Company.
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Clozapine in the Treatment of Dysphoric Mania Trisha Suppes, Susan L. McElroy, Jeffrey Gilbert, Eric C. Dessain, and Jonathan O. Cole
Seven patients with bipolar disorder, characterized by dysphoric mania with psychotic features and chronic disability, refractory to standard treatments and anticonvulsants, all showed marked symptomatic and functional improvement when given the atypical antipsychotic clozapine. During follow-up over 3-5 years, most of the patients sustained substantial gains in psychosocial function; and of the six patients remaining on clozapine, no further hospitalizations were needed. This remarkable improvement in a severely ill group of patients suggests that clozapine may have utility in the treatment of bipolar disorder as well as schizophrenia. Introduction Dysphoric mania or mixed bipolar disorder was called depressive or anxious mania by Kraepelin [1921] who classified it as a mixed manic-depressive state. More recently it has been described as mania accompanied by prominent depressive symptoms (Akiskal 1983; Dell'Osso et al 1991; Goodwin and Jamison 1990; Himmelhoch and Garfinkel 1986', Himmelhoch et ai 1976; Keller et al 1986; Nunn 1979; Post et al 1989; Prien et al 1988; Secunda et al 1987; Swannet al 1986; Winokur et al 1969). Initially thought to be uncommon (Kraeplin 1921; Winokur et al 1969), recent estimates suggest that 30% or more bipolar patients hospitalized for acute mania simultaneously experience significant depression (Goodwin and Jamison 1990). Nevertheless, dysphoric mania remains a poorly studied condition. Some studies hypothesize that dysphoric and nondysphoric mania are similar conditions (Carlson and Goodwin 1973); others suggest that dysphoric mania is a distinct state and, compared with patients lacking such mixed symptom patterns, may be associated with poor treatment response and long-term outcome (Himmeihoch and Garfinkel 1986; Himmelhoch et al 1976; Keller et al 1986), high rates of recurrence (Post et al 1989; Prien et al 1988), and poor response to lithium (Goodwin and Jamison 1990; Himmelhoch and Garfinkel 1986; Prien et al 1988; Secunda et al 1985; Secunda et al 1987; Swann e~ al 1986). A recent survey of 85 patients receiving clozapine on an open-label basis at McLean IIospital from 1974 to 1989, included 14 patients with bipolar disorder and psychotic features by DSM-III-R criteria (APA 1987). Twelve of the 14 bipolar patients (86%)
From the Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA and McLean Hospital, Belmont, MA (TS, JG, ED, JC); and the Biological Psychiatry Program, Department of Psychiatry, University of ~incinnati College of Medicine, Cincinnati, OH (SM). Address reprint requests to Tdsha Sup~s, M.D., Ph.D., Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd.~Dallas, 'IX 75235-9070. Received January 18. 1992; revised May 25, 1992. © 1992 Society of Biological Psychiatry
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were noted to display moderate or marked reductions in psychotic and affective symptoms in response to clozapine treatment (McElroy et al 1991). Five patients had persistent psychotic symptoms and mania without depressive features. Seven of the 12 patients had manic episodes characterized by prominent depressive symptoms. All seven, despite failing to respond adequately to treatment with various combinations of lithium, typical neuroleptics, carbamazepine, or valproate, in response to clozapine, displayed clinically significant reductions in affective and psychotic symptoms that persisted for 3-5 years of follow-up. This report describes these seven patients in detail.
Methods In a recent survey of 85 consecutive patients who participated in an open-labeled compassionate use protocol of clozapine conducted at McLean Hospital between 1975 and 1989, seven patients with bipolar disorder with manic episodes characterized by marked dysphoria and other depressive symptoms were identified (McEIroy et al 1991). This earlier survey, which described 14 bipolar patients in the cohort, did not differentiate subtyping of bipolar patients nor did it detail their histories and treatment response or longevity of response to clozapine. For the present case series, diagnosis and treatment histories before and after clozapine were determined by reviewing each patient's medical records, interviewing each patient's primary psychiatrist, and by direct examination of all patients by one of the investigators. Diagnoses recorded were made by the investigators by consensus and according to DSM-HI-R criteria (APA 1987).
Results Case ] Mr. A was a 29-year-old single man with an 8-year history of bipolar disorder with psychotic features. Family history was negative for psychiatric illness. Medical history was notable for a brain computed tomography (CT) scan displaying prominent temporal ventricular horns bilaterally with otherwise normal ventricles. Mr. A's illness began in college, after 2 years of extensive marijuana and LSD use. His manic episodes were characterized by dysphoric mood, irritability, hopelessness, helplessness, decreased sleep, grandiosity, hyperreligiousity, hypersexuality, suicidal ideation, assaultive behavior, visual and auditory hallucinations, referential ideation, and delusions. His symptoms and assaultive behavior persisted despite treatment with perphenazine, lithium carbonate, and carbamazepine. Addition of valproate resulted in partial mood stabilization leading to discharge to a half-way house, where he experienced significant manic and psychotic symptoms leading to readmission 1 year later for clozapine treatment. In 1987, clozapine started and was gradually increased to 400 mg/day, and Cespite discontinuation of lithium, valproate, and perphenazine over the next 6 months, he displayed resolution of manic symptoms and a significant decrease in psychotic symVoms. His abuse of illicit drugs ceased as well. He was maintained on clozapine 500 rag/day for more than 4 years during which he experienced euthymic mood and very mild i~,termittent psychotic symptoms which did not interfere with his functioning. Decreases in daily clozapine dose by 50 mg led to increased affective and psychotic symptoms, which resolved quickly at 500 mg/day. Because his psychosocial functioning was markedly
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improved, he was able to move to a halfway house, then to a supervised apartment, completed several college courses, developed new friends, and worked part-time. Case 2 Mr. B, a 26-year-old s~nglc professional man, had a 7-year history of bipolar disorder. He was born prematurely, had delayed vocalization, and remained socially isolated as a child. His identical twin brother was diagnosed with paranoid schizophrenia responsive to clozapine; three second-degree relatives had lithium-responsive bipolar disorder. Neurologic examination, electroencephalogram (EEG), and brain CT scan with contrast were all normal. He was first hospitalized in 1985, after assaulting a police officer, in an acute manic psychotic episode with dysphoric mood, anhedonia, grandiosity, decreased sleep, racing thoughts, visual hallucinations, assaultive behavior, ruminations, referential and paranoid ideation, and delusions of guilt and persecution. He responded poorly to lithium, haloperidol, perphenazine, carbamazepine, and, though valproate helped ameliorate manic symptoms, his depression worsened and doxepin was started. Due to his persistent intrusive violent fantasies and hallucinations, manic symptoms, and markedly impaired functioning, lithium, perphenazine, and doxepin were gradually discontinued and clozapine was given up to 900 rag/day. Although psychotic symptoms diminished and mood became more stable, a dysphoric manic episode occurred 6 months later. Vaiproate was added resulting in steady improvement ef manic and psychotic symptoms, and maximum benefit of clozapine was achieved at 800 mglday, with enuresis as the only prominent side effect which resolved with oxybutynin chloride. Mild depressive symptoms appeared 1 year later and responded to fluoxetine 20 mg every other day. About 6 months later, his granulocyte count dropped to less than 2000/ram2, and lithium was restarted resulting in a rise in white blood count (WBC) to greater than 4000/ram2. Mr. B did well over the next 2 years with only mild intermittent hypomania, though decreasing clozapine by 50-100 mg resulted in prompt exacerbations of manic and psychotic symptoms on at least two trials, Over time he made significant psychosocial gains living in a less structured halfway house, increasing his social interactions, and working 15 hours per week at a paying job. Case 3 Ms. C, a 30-year-old single woman, had a 15-year history of bipolar disorder, beginning with a manic psychotic episode occurring soon after being ill with aseptic meningitis. She recovered from the aseptic meningitis without obvious sequelae, including a normal EEG and CT scan. Family history included treatment for depression in a parent and a sibling; a maternal uncle with alcohol dependence; postpartum "insanity," two suicides, and a case of bipolar disorder in second-degree relatives; and several paternal great uncle,,; with histories of extreme violence. The patient was initially partially stabilized in Europe with ciozapine 75 mg and valproate (dose unknown). She then came to the United States where clozapine was anavailable and had a relapse. Subsequent manic episodes were dysphoric, with marked mood lability, depression, anhedonia, irritability, agitation; homicidal ideation with frequent assaultive behavior including injury of multiple caregivers; poor hygiene, paranoid delusions, and auditory hallucinations. Depressive episodes were characterized by low mood, anergy, amo-
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tivation, muteness, social withdrawal, and weight gain. She was hospitalized multiple times in the next 9 years; treatment with ECT (20 treatments) and multiple medications, including haloperidol, thioridazine, fluphenazine, thiothixene, diazepam, clonazepam, clorazepate, clonidine, lithium (discontinued due to nephrotic syndrome), valproate, and carbamazepine were of little benefit. When out of the hospital for brief periods she required 24-hr supervision due,to erratic and dangerous behavior. In 1988, due to persistent significant symptoms, Ms. C was restarted on clozapine up to 800 rag/day, and within 6 months she became ¢uthymic, violent behavior and auditory hallucinations ceased, and her delusions were reduced in severity. Although she continued to experience mild psychotic symptoms under stress, she sustained herself without emergence of behavioral deterioration or violence. Decreases of daily clozapine by 50 or 100 rag were associated with recurrence of dysphoric mania and psychosis. Over the next 4 years, the patient remained on clozapine and valproate (750 rag/day) and was euthymic, nonviolent, without overt delusions, and lived in a halfway house. Case 4 Ms. D, a 31-year-old single woman, had a 14-year history of severe bipolar disorder. Medical history was unremarkable except for lithium-induced goiter. Neurological evaluation included a normal brain CT scan and EEG studies. Family history was notable for bipolar disorder in a parent, a sibling, and two second-degree relatives; and for depression and alcoholism in another second-degre~ relative. The patient had three hospitalizations between 1977 and 1980 for depressive episodes characterized by catatonia, muteness, decreased oral intake, and inability to care ['or herself. Lithium was found to be helpful for mood stability, and chlorpromazine induced remission of psychotic symptoms and decreased assanltiveness. She was discharged on lithium, to a halfway house, and remained out of the hospital for 2 years. Between 1982 and late 1988 Ms. D had multiple hospitalizations for manic psychotic episodes characterized by irritability, depression, anhedonia, hopelessness, severe agitation, hypersexuality, paranoid and referential ideation, delusions of guilt, auditory hallucinations, decreased sleep, poor judgment and impulse control, and both self-destructive and assaultive behavior. Although some admissions were precipitated by medication noncompliance, she also had break-through episodes while receiving doses of lithium and carbamazepine within the therapeutic serum concentration. Of note, in 1985, while receiving thioridazine`, lithium carbonate, and carbamazepine, she experienced a period of ultrafast rapid cycling with depression in the morning and hypomania or mania later in the day. Any period out of the hospital required continuous family supervision due to persistence, of significant affectiv¢ and psychotic symptoms. Due to the increasing severity of her illness, in 1988, clozapine 400 mg was added to valproate 1000 me, and her manic and psychotic symptoms remitted in about 5 weeks. Over the next 3 years, valproate was discontinued and the patient was maintained on clozapine 450 me, with continued remission of symptoms and sustained ability to live independently, complete college courses, and support herself financially. Case 5 Ms. E, a 35-year-old divorced professional writer, had a 16-year history of bipolar disorder. Medical history was notable for high fevers at age 6 and near-drowning at age
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7. Neurological evaluation was unremarkable, including a normal EEG in 1985. Family history was notable for alcoholism in her father. After her first hospitalization in 1975 at age 19 for mania characterized by dysphoria, anhedonia, paranoia, grandiosity, delusions of guilt, referential ideation, auditory hallucinations, decreased sleep, increased energy, and agitation, the patient remained functional for the next 9 years while receiving lithium in combination with trifluoperazine or thiothixene. Despite continued treatment, she was rehospitalized for dysphoric mania at age 28. A 3-month trial of carbamazepine proved ineffective, and the patient was discharged on lithium carbonate and thiothixene. However, she complained of depression characterized by low mood, amotivation, difficulty concentrating, impairment of memory, disrupted sleep, poor appetite, anergy, and delusions. She was rehospitalized for 1 year for psychotic depression, receiving multiple medication trials of little benefit including phenelzine (associated with the development of rapid cycling), perphenazine (12 mg associated with tardive dyskinesia), carbamazepine, and clonazepam. At midhospitalization, levothyroxine sodium (0.1 rag/day) was added for a persistently low 1"4 with normal thyroid-stimulating hormone (TSH), and valproate 3000 rag/day (50 rag/! serum) was added resulting in remission of manic symptoms though depressive symptoms emerged and bupropion (150 mg BID) was started. She was discharged to a halfway house and put on multiple medications (see Table l), but was unable to work 0ue to persecutory delusions. Clozapine was initiated (200 rag) 4 months later when the patient was rehospitalized for a dysphoric manic episode. Despite gradual discontinuation of the majority of her medications, clozapine use was associated with rapid resolution of affective and psychotic symptoms. For the past 5 years, the patient has remained on clozapine 250 rag, plus levothyroxine sodium 0.15 mg and clonazepam 0.25 mg with sustained improvement in mood and psychotic symptoms, she has lived at home with her family, and maintained demanding full-time employment. Case 6
Mr. F was a 33-year-old white man with a 13-year-history of severe rapid-cycling bipolar disorder with multiple suicide attempts leading to 20 psychiatric hospitalizations. Manic episodes were characterized by dysphoria, irritability, angry outbursts, hopelessness, helplessness, severe suicidality with plan, increased energy, decreased sleep, weight loss, racing thoughts, referential ideation, and auditory hallucinations. Depressive episodes were characterized by depressed mood, anergy, amotivation, hopelessness, and suicidal plans. His affective and psychotic symptoms had not responded to lithium, standard antipsychotics, carbamazepine, clonidine, verapamil, clonazepam, and bilateral electroconvulsive therapy (ECT). Some of these treatments produced intolerable or dangerous side effects, including renal insufficiency with lithium, Stevens4ohnson syndrome with carbamazepine, and intractable akathisia with the antipsychotics. Valproate produced a significant response but caused persistent elevation of hepatic Uansaminases that led to drug discontinuation. Treatment with clozapine (350 rag/day) produced a remarkable remission of both affect~ve and psychotic symptoms, causing the most complete clearing of symptoms since the onset of his illness, and enabling significant improvement in psychosocial functioning. However, 8 months after initiation of clozapine, he developed agranulocytosis (granulocyte count to <700/ram 2) and the drug was stopped. Despite extensive psychopharmacological efforts, his affective and psychotic symptoms promptly recurred and persisted. He was hospitalized twice more and committed suicide.
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Case 7 Ms. G, a 46-year-old single college graduate, had a 24-year history of bipolar da~order with psychotic features poorly responsive to medication. Medical history was remarkable for mononucleosis with hepatitis in her early 20s, a nonfocal neurological examination, a normal brain CT scan with contrast, and an EEG with diffuse slowing interpreted as due to medication and normal on repeat EEG study. Family history was notable for imipramine-responsive major depression in her mother. The patient was first psychiatrically hospitalized at age 34 for dysphoric mania and psychosis while receiving im~pramine for major depression characterized by low mood, social withdrawal, obsessive ruminations, indecisiveness, low self-esteem, and suicidal ideation. Her manic episodes, which often were precipitated by treatment with antidepressants, were characterized by prominent dysphoria, anhedonia, irritability, anxiety, agitation, increased energy, racing thoughts, hypersexuality, referential ideation, persecutory delusions, and homicidality with assaultive behavior. For the next 8 years she experienced constant dysphoric mood swings, reckless hypersexuality, and chronic psychotic symptoms inadequately responsive to treatment with chlorpromazine, thioridazine or loxapine, lithium carbonate, carbamazepine, or valproate. In early 1987, clozapine was started and increased to 400 mg over 4 months as other medications were discontinued. She sustained gradual remission of mood swings, psychosis, and hypersexual behavior. During the next 5 years, on only clozapine 400 mg/day, Ms. G's affective and psychotic symptoms remained in remission, and she lived independently and maintained responsible full-time employment.
Discussion Among 85 consecutive patients treated with clozapine at McLean Hospital between 1975 and 1989, seven with treatment-resistant bipolar disorder with manic episodes associated with significant depressive symptoms were identified. All had a history of well-documented treatment resistance marked by recurrent episodes of illness and incomplete response of symptoms to standard neumleptics, lithium, antidepressants, and anticonvulsants, alone or in combination. Nevertheless, all patients displayed significant reductions in affective and psychotic symptoms when treated with clozapine alone or in combination with lithimn, an antidepressant, or valproate. Clozapine's effects we, e often evident within the first few weeks of ~atment, and were sustained throughout the followup period which ranged from 3 to 5 years, Indeed, the six patients who continued on clozapine required no further hospitalizvtions and displayed significant improvement in psychosocial functioning, evidenced by an ability to live in less structured settings, to sustain personal relationships, return to school, and to maintain employment. Further, although all patients had been treated with complicated polypharmacy prior to clozapine, three cases (1, 4, and 7) eventually were maintained on clozapine alone and two cases (3 and 5) on much simpler medication regimens (see Table 1). This case series describes a severely ill group of bipolar patients with an early age of onset, history of psychiatric illness in family members, and an unrelenting course of illness with decreased capacity to funcgon and fewer well periods between episodes, Additionally, a number of the cases had a history of neurological soft signs, impairment, or insult (cases 1, 2, 3, 5, and possibly 7). This high percentage of potential neuropsychiatric factors is consistent with the results of Himmelhoch and Garfinkle (1986) who
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found a highly significant association of a "neurological condition" with mixed mania in lithium-resistant patients. Their findings suggest that the presence of a mixed or dysphoric manic history is more likely to be seen in patients severely ill, treatment-resistant, and with complicated neurological histories. As well, almost 30% of their patient group of mixed manics had a history of drug or alcohol abuse, suggesting that secondary mania may present in a mixed form (possibly case 1). At this time it is difficult to speculate in detail on how these or unrelated factors provide causal explanation for this severe form of bipolar disorder. Although these patients' apparent response to clozapine could be happenstance, this seems unlikely for several reasons. No patient had a recent history of effective symptom resolution on any medication regimen prior to clozapine; no patient had been sustained on a single medication out of the hospital; improvement in all cases began soon after initiating clozapine treatment, and the six of seven patients who remained on clozapine showed sustained improvement. Given the chronicity, severity, and apparent treatment resistance of these illnesses, the likelihood of spontaneous remission or placebo response seems remote (Goodwin and Jamison 1990; Kraepelin 1921; McEIroy et al 1991; Nunn 1979; Winokur et al 1969). Moreover, the prompt recurrence of affective and psychotic symptoms in five patients after small reductions in clozapine dose (cases 1, ",, 3, and 4) or discontinuation (case 6), and the prompt decrease in %~se symptoms after increasing the dose supports the likelihood that patients were rcspo,ding to this drug. The majority of patients, five of seven, complained of side effects from clozapine, with morning sedation and weight gain the most commonly reported (see Table 1). The patients, however, tolerated these side effects without significant complaint or loss of compliance, stating that their symptoms were substantially improved with the medication, allowing them to function better. This side effect profile is consistent with recent reports (Baldessarini and Frankenburg 1991). The finding that clozapine may be effective in the treatment of bipolar patients with dysphoric mania is interesting in light of the multiple receptor actions of this drug which include affinities at noradrenergic (alpha and beta), as well as serotonergic (5-HT2), histaminic, and muscarinic acetylcholine receptors with weak interactions on dopaminergic (D~ and D2) receptors (Baldcssarini and Frankenburg 1991). The classic hypothesis that typical antipsychotic action was due to D2 receptor blockade and the low potency of clozapine at these receptors seemed inconsistent with this long-held view. The recent identification and cloning of additional putative dopamine receptors D3, D+, and Ds may help to clarify the actions of clozapine (Sokoloff et al 1990; Sunahara et al 1991; Van Tel et al 1991). In particular, the D4 receptor has a higher affinity for clozapine than other dopamine receptors and a preferential limbic distribution of its RNA (Van 1"ol et al 1991). This pattern of D4-RNA may reflect binding patterns of clozapine which contribute to clozapine's mood-stabilizing and antipsychotic properties including increased activity in frontal and temporal cerebral cortex and decreased activity in the extrapyramidal basal ganglia, However, the powerful antiadrenergic and antise~'otonergic actions of clozapine supports speculation that these neurotransmitters may play a role in psychosis and affective illness (Baldessarini et al 1992; Meltzer 1989). Further study is needed to elucidate the primary or multiple complex actions of clozapine central to symptom resolution in severe bipolar disorder. Clozapine appeared to exert bidirectional mood stabilization in five patients (cases 1, 3, 4, 5, and 7). These patients not only experienced rapid reduction in their dysphoric manic symptoms, but also did not develop subsequent manic-depressive episodes. Pre-
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liminary evidence suggests that clozapine may have an antidepressant or mood-elevating effect independent of its other actions (Roubicek and Major 1977). In conclusion, although clozapine has been widely studied and recommended for use in schizophrenia, there are few studies of its efficacy in bipolar disorders (Calabrese et al 1991). The marked improvement of both psychiatric symptoms and psychosocial functioning following initiation of clozapine in this severely ill group of patients suggests it may be an effective treatment for bipolar disorder when other more standard treatments have failed. Moreover, the degree of benefit may even exceed that commonly found in treatment-resistant schizophrenia (Baldessariai and Frankenburg 1991). This case series suggests that clozapine may be especially useful in bipolar patients with mixed, dyspboric manic-depression, a form of bipolar disorder that may be associated with a poor outcome and less favorable response to lithium (see Introduction). More study is needed to determine if this medication is generally useful in the treatment of bipolar disorder patients, and to elucidate its mechanisms of action in affective illness. Systematic study of clozapine in patients with treatment-resistant bipolar disorders, including those with dysphoric or depressive mania and other severe forms that are difficult to treat (rapid cycling, psychotic, or chronic), is recommended. The authors wish m thank the,NeumscienceFellowshipof McLeanand MassachusettsGeneralHospitalfor fundingprovidedto T.S., and for editorialassistancefromDr. RossBaldessarini,and graphicsassistancefrom MeridithKolbrener.
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