Antipsychotic drugs in bipolar disorder

Transcription

1 International Journal of Neuropsychopharmacology (2003), 6, Copyright f 2003 CINP DOI: /S Antipsychotic drugs in bipolar disorder SPECIAL SECTION Aygun Ertugrul 1,2 and Herbert Y. Meltzer 1 1 Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA 2 Hacettepe University School of Medicine, Ankara, Turkey Abstract Antipsychotic drugs are useful in the treatment of acute mania and as maintenance treatment. While both typical and atypical antipsychotic drugs are able to diminish manic symptoms, agitation and aggression in acute mania, the atypical antipsychotic drugs enjoy a number of advantages, including significantly less extrapyramidal symptoms, diminished risk of tardive dyskinesia, lack of increase in serum prolactin levels (with the exception of risperidone), improvement in cognition, and possible decrease in suicidality. Most of the atypical antipsychotic drugs have been found to be effective as an add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients. Long-acting typical neuroleptic drugs may be useful in the treatment of non-compliant bipolar patients. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental. Side-effects of note with the atypical antipsychotic drugs are weight gain (most prominently with olanzapine and clozapine), sedation, and agranulocytosis (clozapine). Atypical antipsychotic drugs are recommended for use in bipolar disorder for acute treatment, maintenance treatment, and for treatment-resistant patients. Received 28 July 2002; Reviewed 13 November 2002; Revised 29 January 2003; Accepted 9 February 2003 Key words: Antipsychotic drugs, bipolar disorder, mania. Introduction Bipolar disorder is a complex syndrome which includes disorders of reality testing (psychosis), mood (mania and depression), motor behaviour (hyper- and hypoactivity), impulse control (aggression and suicidality) and cognitive impairment. While outcome in bipolar disorder is generally better than in schizophrenia, numerous studies have demonstrated a poor psychopathological and functional outcome in bipolar disorder (Harrow et al., 1990; MacQueen et al., 2001). Thus, despite the unquestionable benefit which was derived from the development of lithium and then anticonvulsant drugs as mood stabilizers, there remains a number of aspects of the treatment of bipolar disorder which require additional treatment. Chief among these are rapid control of mania which is sometimes life threatening, control of mania in those patients who fail to respond adequately to mood stabilizers alone, prevention of suicidality during the acute and chronic phases, prevention of relapse in Address for correspondence: Dr H. Y. Meltzer, Psychiatric Hospital at Vanderbilt, rd Avenue South, Nashville, TN 37212, USA. Tel.: (615) Fax: (615) Herbert.Meltzer@vanderbilt.edu rapid-cycling patients, and improvement in persistent cognitive impairment which probably contributes to a poor functional outcome in bipolar disorder as it does in schizophrenia. Antipsychotic drugs have been used in treatment of bipolar patients since the discovery of chlorpromazine in the early 1950s. Thereafter, it and the other classes of typical antipsychotic drugs were used to control manic excitement, hyperactivity, and aggression, and for prophylactic purposes in bipolar patients who did not respond to lithium. The use of typical antipsychotic drugs in bipolar disorder as a component of prophylactic treatment was limited by the sedation and extrapyramidal side-effects they produce, particularly tardive dyskinesia. Several studies have suggested tardive dyskinesia was more frequent or severe, or both, in patients with bipolar disorder, compared to schizophrenia. Despite recommendations from some authorities (e.g. Goldberg, 2000) that antipsychotic drugs be used only as adjunctive agents to treat euphoric mania, unless psychosis is clearly present or management of behavioural agitation is needed and that the drugs should be tapered, in the continuation and maintenance phase of treatment (Mendlewicz et al., 1999) various surveys show that

2 278 A. Ertugrul and H. Y. Meltzer the majority of patients with mania are discharged from hospital still taking antipsychotic medication and remain on it for at least 6 months (Keck et al., 1996; McElroy and Strakowski, 1996). These data could indicate that antipsychotic drugs are meeting a real need in bipolar disorder or that clinicians are resorting to their use too frequently and recommending continued use in patients who would do satisfactorily with a mood stabilizer as monotherapy. The use of clozapine, the first atypical antipsychotic drug, as a treatment for bipolar disorder, occurred shortly after its introduction for the treatment of schizophrenia in the 1960s. After the discovery of its association with agranulocytosis, its use for this indication largely disappeared. However, after its reintroduction in the USA and elsewhere in 1988 (Kane et al., 1988), its usefulness in treatment-resistant bipolar disorder was soon discovered. This, in turn, led to the study of the use of the subsequent atypical antipsychotic drugs, e.g. quetiapine, risperidone, olanzapine and ziprasidone, in the treatment of bipolar disorder, as a substitute for typical neuroleptic drugs. This paper will briefly summarize the major knowledge about the use of typical and atypical antipsychotic drugs in bipolar disorder. Typical antipsychotic drugs Acute mania Typical antipsychotics are effective in up to 70% of patients with acute mania, particularly those with psychomotor agitation and psychosis (Vestergaard, 1992). Several reports document the efficacy of chlorpromazine and haloperidol in the treatment of acute mania as monotherapy (Prien et al., 1972; Shopsin et al., 1975) or in combination with mood stabilizers (Garfinkel et al., 1980; Muller-Oerlinghausen et al., 2000). The dosages used are similar to those effective in schizophrenia. These studies indicate that the rate of control of mania with typical antipsychotics compared to mood stabilizers alone is comparable. The combination of the two classes of agents does provide for more rapid control of excitement, agitation, and psychosis than either mood stabilizer (Garfinkel et al., 1980) or typical neuroleptic alone (Muller-Oerlinghausen et al., 2000). Garfinkel et al. (1980) reported that the combination of lithium and haloperidol was superior to lithium alone in improving global clinical ratings in a randomized parallel-group study. In a randomized, double-blind, study, Muller- Oerlinghausen et al. (2000) showed that the combination of typical antipsychotic and valproate was superior to the combination of typical antipsychotic and placebo in alleviating the symptoms. Small et al. (1996) analysed the results of sequential therapeutic trials in hospitalized manic patients conducted over a 16-yr period, and reported that lithium combined with low doses of typical neuroleptics, or risperidone, was more effective than monotherapy with mood stabilizers. Maintenance treatment Antipsychotic drugs are effective as adjuncts to mood stabilizers in the maintenance treatment of bipolar disorder, especially for patients with more chronic and relapsing forms of bipolar disorder (Sernyak et al., 1994). There is no compelling data to support the use of neuroleptics alone as the maintenance treatment of bipolar disorder (Tohen and Zarate, 1998). Depot formulations of antipsychotics may be preferred for patients who are non-compliant. Lowe and Batchelor (1990) have reported haloperidol decanoate stabilizes mood swings in patients with rapid-cycling bipolar disorder but atypical antipsychotic drugs are more likely to be effective in this regard. As there are currently no long-acting formulations of atypical antipsychotic drugs, non-compliance is one of the indications for continued use of typical neuroleptics in bipolar disorder. As mentioned above, patients with bipolar disorder may have increased vulnerability to extrapyramidal side-effects and tardive dyskinesia (Mukherjee et al., 1986). This is one of the main reasons to prefer the use of an atypical antipsychotic drug for maintenance treatment of bipolar disorder. There is also some evidence that the combination of lithium and haloperidol may produce organic brain syndromes (Cohen and Cohen, 1974). Atypical antipsychotics Atypical antipsychotic drugs, by definition, are drugs which produce significantly less extrapyramidal sideeffects at clinically effective doses. They also have a lower risk for tardive dyskinesia. As will be discussed, atypical antipsychotic drugs appear to have moodstabilizing, anti-manic, and antidepressant actions. With the exception of risperidone, they do not increase serum prolactin levels, but they do improve cognitive function (Meltzer and McGurk, 1999). Clozapine has also been found to decrease suicidality in schizophrenia (Meltzer and Okayli, 1995; Walker et al., 1997), raising the intriguing possibility that it may also decrease suicidality in bipolar disorder. The atypical antipsychotic drugs have a number of side-effects

3 Antipsychotic drugs in bipolar disorder 279 Table 1. Atypical antipsychotics in treatment of acute mania Study Design Drug, n Duration Outcome Barbini et al. (1997) Calabrese et al. (1996) Green et al. (2000) Tohen et al. (1999) Tohen et al. (2000) Berk et al. (1999) Segal et al. (1998) Yatham et al. (2000) Sachs and Ghaemi (2000) Tohen et al. (1996) McElroy and Keck (2000) Randomized comparison (add-on to Li) (monotherapy) (monotherapy) Randomized, double-blind, Randomized, double-blind, Cloz, 15 Chlor, 15 3 wk Cloz=Chlor in decreasing manic symptoms as assessed by YMRS; onset of response more rapid with Cloz Cloz, wk 72 and 32% of patients had 50% or more improvement in YMRS and BPRS, respectively. Bipolars and non-rapid cyclers showed better response than schizoaffectives and rapid-cyclers Cloz, wk 77% had at least 20% improvement in YMRS, CGI, BPRS Olanz, 70 Pbo, 69 Olanz, 55 Pbo, 60 Randomized open label Olanz, 15 Li, 15 Randomized, double-blind, Ris, 15 controlled Hal, 15 (monotherapy) Li, 15 Randomized, doubleblind, (add-on to VPA or Li) Randomized parallelgroup, (add-on to VPA or Li) Randomized, doubleblind, Ris, 75 Pbo, 75 Ris, 52 Hal, 53 Pbo, 51 3 wk Olanz was superior to placebo in decreasing manic symptoms (49 vs. 24% had 50% or greater decrease in YMRS) 4 wk Olanz was superior to placebo in decreasing manic symptoms (65 vs. 43% had 50% or greater decrease in YMRS) 4 wk Olanz=Li in decreasing manic and psychotic symptoms as assessed by YMRS and BPRS 28 d Ris had equivalent efficacy with Li and Hal in acute mania as assessed by BPRS, YMRS, CGI and GAS 3 wk Ris was superior to placebo in controlling acute mania (59 vs. 42% had 50% or greater decrease in YMRS) 3 wk Ris-treated showed greater improvement than placebo-treated patients on YMRS and they had similar improvement with Hal Ris, wk 75% improvement in manic symptoms as assessed by YMRS Zipras, wk 50% of ziprasidone vs. 36% of patients receiving Pbo, 64 placebo had 50% or greater reduction in YMRS scores Abbreviations: BPRS, Brief Psychiatric Rating Scale; CGI, Clinical Global Impression; Cloz, clozapine; Chlor, chlorpromazine; GAS, Global Assessment of Functioning; Hal, haloperidol; Li, lithium; Olanz, olanzapine; Pbo, placebo; Ris, risperidone; VPA, valproic acid; YMRS, Young Mania Rating Scale; Zipras, ziprasidone. which influence their tolerability for patients with bipolar disorder. The evidence for the use of these drugs in bipolar disorder will now be discussed. Clozapine Acute mania The initial studies with clozapine in mania were in treatment-refractory bipolar disorder, reflecting its restricted use in treatment-refractory schizophrenia. Clozapine was found to be effective even in rapidcycling patients who did not respond to combined treatment with mood stabilizers and typical neuroleptic drugs (Calabrese et al., 1996; Suppes et al., 1992). Although there has been no double-blind, comparatorcontrolled studies of clozapine in the treatment of nonrefractory, acute bipolar mania, several open reports suggest clozapine has acute and long-term anti-manic, as well as, antipsychotic properties in bipolar disorder (Frye et al., 1998). In a randomized comparative trial, clozapine and chlorpromazine had equal efficacy in decreasing the manic symptoms after being added to lithium in acute manic patients, and the onset of response was reported to be more rapid for clozapine, despite a low clozapine dose (Barbini et al., 1997; Table 1). The dosage needed for acute mania is comparable to that in schizophrenia, mg/d.

4 280 A. Ertugrul and H. Y. Meltzer Table 2. Atypical antipsychotics in maintenance treatment of bipolar disorder Study Design n Duration Outcome Suppes et al. (1999) Zarate et al. (1995) Ciapperelli et al. (2000) McElroy et al. (1998) Sanger et al. (2001) Vieta et al. (2001) Ghaemi and Sachs (1997) Vieta et al. (1998) Randomized comparison Retrospective (add-on or monotherapy) Naturalistic (add-on or monotherapy) Cloz, 19, no Cloz, months Cloz-added group had significantly lower scores in mania, psychosis and tardive dyskinesia ratings Cloz, months Significant decrease in hospitalization rate and in CGI-I scores after Cloz was started; 65% continued on monotherapy without affective episode and rehospitalization Cloz, months 83% of bipolars had at least 50% improvement in BPRS; bipolars and schizoaffective patients improved significantly more than patients with schizophrenia; Cloz reduced suicidality Olanz, d 57% displayed much or very much overall improvement as assessed by CGI-BP Olanz, wk 41% of patients remained on monotherapy, the rest also received lithium or fluoxetine. In both groups manic or depressive symptoms improved significantly as assessed by YMRS and HAMD-21 Olanz, wk Significant decrease in manic, depressive, global symptoms as assessed by CGI-BP Ris, 12 6 months One third of patients had scores of improvement in GAS Ris, 10 6 months Frequency of affective episodes within 6 months after baseline was significantly lower than within 6 months before baseline (2.0 vs. 5.5); improvement in both manic and depressive symptoms as assessed by YMRS and HAMD Abbreviations: CGI-I, Clinial Global Impression Improvement; CGI-BP, Clinical Global Impression Bipolar Disorder; Cloz, clozapine; GAS, Global Assessment Scale; HAMD, Hamiltom Rating Scale for Depression; HAMD-21, Hamilton Rating Scale for Depression 21 item; Olanz, olanzapine; Ris, risperidone. Maintenance treatment Clozapine has also been shown to be effective as maintenance treatment for bipolar disorder as an add-on to mood stabilizers (Ciapparelli et al., 2000; Suppes et al., 1999) or monotherapy (Zarate et al., 1995a; Table 2). Suppes et al. (1999) reported equivalent mood stabilization for clozapine in psychotic and non-psychotic treatment-refractory bipolar patients, supporting an independent mood-stabilizing property. It has also been reported that clozapine alone, reduced the number of affective episodes and rehospitalizations in patients with severe refractory bipolar illness (Zarate et al., 1995a). Clozapine was also found to be effective in reducing suicidality in bipolar patients, in a 24-month follow-up study (Ciapparelli et al., 2000; Table 2). Because the completed suicide rate in bipolar disorder is approx. 15%, further controlled trials to determine if clozapine is superior to other treatments for reducing suicidality are needed. Lithium carbonate has also been reported to reduce suicidality in bipolar disorder (Coppen et al., 1991). According to a meta-analysis (Zarate et al., 1995b), patients in manic or psychotic phases of schizoaffective or bipolar disorder were significantly more likely to respond to clozapine than patients with schizophrenia or depressive syndromes (unipolar, bipolar, schizoaffective depression). Clozapine has also been found to improve functioning in patients with affective disorders refractory to standard therapies. Banov et al. (1994) reported that the social functioning of bipolar- and schizoaffective-disorder patients treated with clozapine improved at a mean of 16 months follow-up compared to before starting clozapine

5 Antipsychotic drugs in bipolar disorder 281 treatment. This advantage of clozapine may be related to its ability to improve cognition. Studies of the effect of clozapine and other atypical antipsychotic drugs in bipolar disorder are needed. The literature cited above supports clozapine s effectiveness as a mood stabilizer in both the acute and maintenance phase of bipolar disorder, including the treatment-refractory cases. Although it is not a firstline treatment due to the risk of agranulocytosis, it should be considered for patients not responsive to combined treatment with other atypical antipsychotic drugs or mood stabilizers. Clozapine produces significant weight gain and sedation which may affect tolerability in bipolar patients. Risperidone Risperidone is an atypical antipsychotic at doses in the 2 6 mg/d range. It produces increases in serum prolactin levels at all dose levels; higher doses can produce extrapyramidal symptoms comparable to typical neuroleptic drugs. Acute mania In a randomized, controlled, double-blind study risperidone monotherapy was found to have efficacy equivalent to lithium and haloperidol in the management of acute mania (Segal et al., 1998; Table 1). Open trials of risperidone monotherapy in bipolar mania have reported both positive (Goodnick, 1995; Singh and Catalan, 1994) and negative results (Sajatovic et al., 1996). Risperidone has also been shown to be effective as an add-on therapy in bipolar disorder. In a randomized double-blind study, Yatham (2000) reported that risperidone was superior to placebo in 150 patients for whom risperidone or placebo was added for 3 wk to lithium or valproic acid. Open studies support these findings (Guille et al., 2000; Tohen et al., 1996). A recent review of clinical experience suggests efficacy in treating the depressive phase of bipolar disorder (Keck et al., 1995). In contrast with the evidence for a therapeutic effect of risperidone in bipolar disorder, there are numerous case reports describing hypomanic symptoms subsequent to initation of treatment with risperidone, mainly in patients with schizophrenia or schizoaffective disorder (Aubry et al., 2000). While some reports present evidence that this is a genuine drug effect, the majority could be coincidental and a reflection of the overlap between bipolar disorder and schizophrenia spectrum disorders. Maintenance treatment Several open-label studies report the efficacy of risperidone as an add-on treatment in the maintenance phase of bipolar disorder (Ghaemi and Sachs, 1997; Vieta et al., 1998). Addition of risperidone was reported to decrease severity and frequency of manic, depressive and mixed episodes in patients with rapidcycling bipolar disorder who were refractory to lithium carbonate, carbamazepine and valproate (Vieta et al., 1998). Risperidone was found to be useful not only in severe psychotic mania or depression, but also in hypomanic and non-psychotic bipolar patients. In summary, risperidone is effective in the acute and maintenance phases of bipolar disorder when used with mood stabilizers. There are no studies to suggest whether its combination with an anticonvulsant or lithium is more effective. Dosage should be kept as low as possible in order to avoid extrapyramidal symptoms. Monotherapy with risperidone for acute or maintenance treatment is not supported by available studies. Olanzapine Acute mania Two trials have established the efficacy of olanzapine monotherapy in acute manic or mixed episodes in bipolar disorder (Tohen et al., 1999; Tohen et al., 2000; Table 1). In both of these studies, olanzapine demonstrated greater efficacy than placebo in the treatment of acute manic or mixed episodes and was generally well tolerated. Extrapyramidal symptoms were minimal. Olanzapine was also compared to lithium in an open-label study and was found to have equal efficacy in decreasing manic symptoms at 4 wk (Berk et al., 1999; Table 1). Case series and open reports provide additional evidence that olanzapine is effective in acute mania as an adjunctive treatment to mood stabilizers (Weisler et al., 1997; Zarate et al., 1998). In a recent study (Tohen et al., 2002) the efficacy of olanzapine and olanzapine in combination with fluoxetine was compared to placebo in the treatment of bipolar depression and both olanzapine and the olanzapine/fluoxetine combination significantly improved depressive symptoms in patients with bipolar depression and the magnitude of the effect was found to be significantly greater with the olanzapine/ fluoxetine combination. As with risperidone there are several case reports about mania and hypomania induced by olanzapine in patients with schizophrenia who had not previously experienced mania. Symptoms diminish after stopping

6 282 A. Ertugrul and H. Y. Meltzer olanzapine and treatment with mood stabilizers or other antipsychotic drugs (Aubry et al., 2000). Maintenance treatment An open-label, continuation phase study of olanzapine, either as monotherapy or in combination with lithium or fluoxetine, demonstrated significant improvement in manic and depressive symptoms with olanzapine (Sanger et al., 2001). Olanzapine was also reported to be useful as an add-on therapy in the maintenance treatment of treatment-refractory bipolar patients including those with manic, mixed or depressive episodes (McElroy et al., 1998; Vieta et al., 2001; Table 2). Adjunctive treatment of mood stabilizers with risperidone, olanzapine, and clozapine were found to produce comparable results in patients with bipolar disorder (Guille et al., 2000). Olanzapine produced significantly greater weight gain than risperidone. In summary, there is substantial evidence that olanzapine is effective as an adjunct treatment in acute mania. As with risperidone, more follow-up studies with olanzapine monotherapy are required to prove its efficacy as a maintenance treatment of bipolar disorder. Other atypical antipsychotics There are no published controlled trials of quetiapine in the treatment of acute mania. Zarate et al. (2000) reported that patients with a diagnosis of bipolar disorder manic, mixed or depressed, or schizoaffective dis order, bipolar type displayed higher response rates to quetiapine compared to patients with schizophrenia. There are case reports about addition of quetiapine to current medicine for treatment-resistant bipolar disorder (Dunayevich and Stratowski, 2000; Ghaemi and Katzow, 2000). There is also a case report of induction of hypomania with quetiapine in schizoaffective disorder (Benazzi, 2001). Another antipsychotic, ziprasidone was found to be effective in mania in a randomized, double-blind, study. A total of 195 patients with DSM-IV bipolar manic or mixed episodes were given ziprasidone ( mg/d) or placebo for 3 wk and 50% of the 131 patients receiving ziprasidone displayed a 50% or greater reduction in mania rating scores, compared to 36% of the 64 patients receiving placebo (McElroy and Keck, 2000). Ziprasidone was found to be superior to placebo in acute mania (Versiani et al., 2001). Significant improvement in manic symptoms was noted within 2 d of starting ziprasidone. Both quetiapine and ziprasidone have been found to be effective in the treatment of cognitive dysfunction in schizophrenia and schizoaffective disorder. Whether they are effective in this regard in bipolar disorder remains to be determined. Neither drug increases serum prolactin levels. Ziprasidone caused weight gain in the least number of patients compared to the other atypical antipsychotic drugs. There is concern over its ability to cause QTc prolongation, but as yet no hard evidence that this leads to clinically significant adverse consequences. Quetiapine has a moderate tendency to cause weight gain. Aripiprazole is the most recent addition to atypical antipsychotic medications, following the release of clozapine, risperidone, olanzapine, quetiapine and ziprasidone. There are no published studies about its use in bipolar disorder. It appears to be a promising treatment alternative given the early data about its low rates of reported side-effects (Goodnick and Jerry, 2002). Conclusions Antipsychotic drugs have an important role in both the acute and maintenance treatment of bipolar disorder. Effect sizes must be considered in the interpretation of the studies reviewed here. They are generally in the moderate range, (Tohen et al., 1999, 2000; Vieta et al., 2001). There is already sufficient evidence of at least equivalent efficacy and greater tolerability of atypical antipsychotics compared to the typical antipsychotic drugs to warrant their use in lieu of typical antipsychotic drugs. The ability of the atypical antipsychotic drugs to improve cognition and to reduce the risk of suicide are important advantages to keep in mind when considering choice of antipsychotic medication. With the possible exception of clozapine, there is no evidence that the atypical antipsychotic drugs differ in efficacy in bipolar disorder either for acute mania or as maintenance treatment. Their use as adjunctive treatment rather than monotherapy may be recommended at the present time. Studies which compare the various atypical antipsychotic drugs alone and with various mood stabilizers are needed to develop evidence-based treatment recommendations. References Aubry JM, Simon AE, Bertschy G (2000). Possible induction of mania and hypomania by olanzapine or risperidone: a critical review of reported cases. Journal of Clinical Psychiatry 61,

7 Antipsychotic drugs in bipolar disorder 283 Banov MD, Zarate CA, Tohen M, Scialabba D, Wines JD, Kolbrener M, Kim JW, Cole JO (1994). Clozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up. Journal of Clinical Psychiatry 55, Barbini B, Scherillo P, Crespi G, Colombo C, Smeraldi E (1997). Response to clozapine in acute mania is more rapid than that of chlorpromazine. International Journal of Clinical Psychopharmacology 12, Benazzi F (2001). Quetiapine-associated hypomania in a woman with schizoaffective disorder. Canadian Journal of Psychiatry 46, Berk M, Ichim L, Brook S (1999). Olanzapine compared to lithium in mania: a double-blind randomised controlled trial. International Journal of Clinical Psychopharmacology 14, Calabrese JR, Kimmel SE, Woyshville MJ, Rapport DJ, Faust CJ, Thompson PA, Meltzer HY (1996). Clozapine for treatment refractory mania. American Journal of Psychiatry 153, Ciapparelli A, Dell Osso L, Pini S, Chiavacci MC, Fenzi M, Cassano GB (2000). Clozapine for treatment-refractory schizophrenia, schizoaffective disorder, and psychotic bipolar disorder: a 24 month naturalistic study. Journal of Clinical Psychiatry 61, Cohen WJ, Cohen NH (1974). Lithium carbonate, haloperidol and irreversible brain damage. Journal of the American Medical Association 230, Cookson J (2001). Use of antipsychotic drugs and lithium in mania. British Journal of Psychiatry 178 (Suppl. 41), Coppen A, Standish-Barry H, Bailey J, Houston G, Silcocks P, Hermon C (1991). Does lithium reduce the mortality of recurrent mood disorders? Journal of Affective Disorders 23, 1 7. Dunayevich E, Strakowski SM (2000). Quetiapine in treatment resistant mania: a case report. American Journal of Psychiatry 157, 134. Frye MA, Ketter TA, Altshuler LL, Denicoff K, Dunn RT, Kimbrell TA, Cora-Locatelli G, Post RM (1998). Clozapine in bipolar disorder: treatment implications for other atypical antipsychotics. Journal of Affective Disorders 48, Garfinkel PE, Stancer HC, Persaud E (1980). A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania. Journal of Affective Disorders 2, Ghaemi SN, Katzow JJ (2000). The use of quetiapine for treatment-resistant bipolar disorder: series. Annals of Clinical Psychiatry 11, Ghaemi SN, Sachs GS (1997). Long-term risperidone treatment in bipolar disorder: 6-month follow-up. International Journal of Clinical Psychopharmacology 17, Goldberg JF (2000). Treatment guidelines: current and future management of bipolar disorder. Journal of Clinical Psychiatry 61 (Suppl. 13), Goodnick PJ (1995). Risperidone treatment of refractory acute mania. Journal of Clinical Psychiatry 56, Goodnick PJ, Jerry LM (2002). Aripiprazole: profile on efficacy and safety. Expert Opinion of Pharmacotherapy 3, Green AI, Tohen M, Patel JK, Banov M, DuRand C, Berman I, Chang H, Zarate C, Posener J, Lee H, Dawson Ree, Richards C, Cole JO, Schatzberg AF (2000). Clozapine in the treatment of treatment refractory psychotic mania. American Journal of Psychiatry 157, Guille C, Sachs GS, Ghaemi N (2000). A naturalistic comparison of clozapine, risperidone, and olanzapine in the treatment of bipolar disorder. Journal of Clinical Psychiatry 61, Harrow M, Goldberg JF, Grossman LS, Meltzer HY (1990). Outcome in manic disorders. A naturalistic follow-up study. Archives of General Psychiatry 47, Kane JM, Honigfeld G, Singer J, Meltzer H (1988). Clozapine in treatment-resistant schizophrenics. Psychopharmacology Bulletin 24, Keck PE, McElroy SL, Strakowski SM, Balistreri TM, Kizer DI, West SA (1996). Factors associated with maintenance antipsychotic treatment of patients with bipolar disorder. Journal of Clinical Psychiatry 57, Keck Jr. PE, Wilson DR, Stratowski SM, McElroy SL, Kizer DL, Balistreri TM, Holtman HM, DePriest M (1995). Clinical predictors of acute risperidone response in schizophrenia, schizoaffective disorder and psychotic mood disorders. Journal of Clinical Psychiatry 56, Lowe MR, Batchelor DH (1990). Depot neuroleptics in the management of manic depressive psychosis. Human Psychopharmacology 5, MacQueen GM, Young LT, Joffe RT (2001). A review of psychosocial outcome in patients with bipolar disorder. Acta Psychiatrica Scandinavica 103, McElroy SL, Frye M, Denicoff K, Altshuler L, Nolen W, Kupka R, Suppes T, Keck Jr. PE, Leverich GS, Kmetz GF, Post RM (1998). Olanzapine in treatment resistant bipolar disorder. Journal of Affective Disorder 49, McElroy SL, Keck Jr. PE (2000). Pharmacologic agents for the treatment of acute bipolar mania. Biological Psychiatry 48, McElroy SL, Strakowski SM (1996). Mania, psychosis and antipsychotics. Journal of Clinical Psychiatry 57 (Suppl. 3), Meltzer HY, McGurk SR (1999). The effects of clozapine, risperidone and olanzapine on cognitive function in schizophrenia. Schizophrenia Bulletin 25, Meltzer HY, Okayli G (1995). Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact on risk-benefit assessment. American Journal of Psychiatry 152, Mendlewicz J, Souery D, Rivelli SK (1999). Short and long-term treatment of bipolar patients: beyond the guidelines. Journal of Affective Disorders 55, Mukherjee S, Rosen AM, Caracci G, Shukla S (1986). Persistent tardive dyskinesia in bipolar patients. Archives of General Psychiatry 43, Muller-Oerlinghausen B, Retzow A, Henn FA (2000). Valproate as an adjunct to neuroleptic medication for the

8 284 A. Ertugrul and H. Y. Meltzer treatment of acute episodes of mania: a prospective, randomised, double-blind,, multicentre study (European Valproate Mania Study Group). Journal of Clinical Psychopharmacology 20, Prien RF, Caffey EM, Klett CJ (1972). Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Archives of General Psychiatry 26, Sajatovic M, DiGiovanni SK, Bastani B, Hattab H, Ramirez LF (1996). Risperidone therapy in treatment refractory acute bipolar and schizoaffective mania. Psychopharmacology Bulletin 32, Segal J, Berk M, Brook S (1998). Risperidone compared with both lithium and haloperidol in mania: a double-blind randomised controlled trial. Clinical Neuropharmacology 21, Sernyak MJ, Griffin RA, Johnson RM, Pearsall HR, Wexler BE, Woods SW (1994). Neuroleptic exposure following inpatient treatment of acute mania with lithium and neuroleptic. American Journal of Psychiatry 151, Shopsin B, Gershon S, Thompson H, Collins P (1975). Psychoactive drugs in mania: a controlled comparison of lithium carbonate, carbamazepine, and haloperidol. Archives of General Psychiatry 32, Singh AN, Catalan J (1994). Risperidone in HIV related main psychosis. Lancet 344, Small JG, Klapper MH, Milstein V, Marhande JD, Small IF (1996). Comparison of therapeutic modalities for mania. Psychopharmacology Bulletin 32, Suppes T, McElroy SL, Gilbert J, Dessain EC, Cole JO (1992). Clozapine in the treatment of dysphoric mania. Biological Psychiatry 32, Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush AJ (1999). Clinical outcome in a randomised 1-year trial of clozapine versus treatment as usual for patients with treatment-resistant illness and history of mania. American Journal of Psychiatry 156, Tohen M, Jacops TG, Grundy SL, McElroy SL, Banov MC, Janicak PG, Sanger T, Risser R, Zhang F, Toma V, Francis J, Tollefson GD, Breier A (Olanzapine HGGW Study Group) (2000). Efficacy of olanzapine in acute bipolar mania. Archives of General Psychiatry 57, Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, Petty F, Centorrino F, Wang R, Grundy SL, Greaney MG, Jacops TG, David SR, Toma V, and the Olanzapine HGEH Study Group (1999). Olanzapine versus placebo in the treatment of acute mania. American Journal of Psychiatry 156, Tohen M, Vieta E, Ketter T, Centorrino F, Calabrese J, Sachs G, Bowden C, Risser R, Baker RW, Evans AR, Dube S, Tollefson G, Breier A (2002). Olanzapine and olanzapine-flouxetine combination (OFC) in the treatment of bipolar depression. Poster presented at American Psychiatric Association Annual Meeting, Philadelphia. Tohen M, Zarate CA (1998). Antipsychotic agents and bipolar disorder. Journal of Clinical Psychiatry 59, Tohen M, Zarate CA, Centorrino F, Hegarty JI, Froeschl M, Zarate SB (1996). Risperidone in treatment of mania. Journal of Clinical Psychiatry 57, Versiani M, Keck Jr. P, Potkin S, West S, Giller E, for the Ziprasidone in Mania Study Group (2001). Ziprasidone in the acute treatment of mania: a double-blind,, randomized trial. Presented at the American Psychiatric Assocation Annual Meeting, New Orleans. Vestergaard P (1992). Treatment and prevention of mania: a scandinavian perspective. Neuropsychopharmacology 7, Vieta E, Gasto C, Colom F, Martinez A, Otero A, Vallejo J (1998). Treatment of refractory rapid cycling bipolar disorder with risperidone. Journal of Clinical Psychopharmacology 18, Vieta E, Reinares M, Corbella B, Benabarre A, Gilaberte I, Colom F, Martinez-Aran A, Gasto C, Tohen M (2001). Olanzapine as long-term adjuctive therapy in treatment-resistant bipolar disorder. Journal of Clinical Psychopharmacology 21, Walker AM, Lanza LL, Arellano F, Rothman KJ (1997). Mortality in current and former users of clozapine. Epidemiology 8, Weisler RH, Ahearn EP, Davidson JR, Wallace CD (1997). Adjunctive use of olanzapine in mood disorders: five case reports. Annals of Clinical Psychiatry 9, Yatham LN (2000). Safety and efficacy of risperidone as combination therapy for the manic phase of bipolar disorder: preliminary findings on a randomized, double-blind study (RIS-INT-46). International Journal of Neuropsychopharmacology 3 (Suppl. 1), 142. Zarate CA, Narendran R, Tohen M, Greaney JJ, Berman A, Pike S, Madrid A (1998). Clinical predictors of acute response with olanzapine in psychotic mood disorders. Journal of Clinical Psychiatry 59, Zarate Jr. CA, Rothhschild A, Fletcher KE, Madrid A, Zapatel J (2000). Clinical predictors of acute response with quetiapine in psychotic mood disorders. Journal of Clinical Psychiatry 61, Zarate CA, Tohen M, Baldessarini RJ (1995b). Clozapine in severe mood disorders. Journal of Clinical Psychiatry 56, Zarate CA, Tohen M, Banov MD, Weiss MK, Cole JO (1995a). Is clozapine a mood stabilizer? Journal of Clinical Psychiatry 56,