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EVIDENCE-BASED PHARMACOTHERAPY OF DYSPHORIC MANIA Eduard Vieta, Isabella Pacchiarotti, Margarita Garcia-Amador, Raul F. Sanchez, Jose M. Goikolea

Summary The treatment of dysphoric mania and bipolar mixed states is complex and supported by a scant number of controlled studies. There is some evidence that it may be more responsive to anticonvulsants than to = lithium. Valproate, and to a lesser extent carbamazepine, may be used either in monotherapy or as adjuncts to lithium. Use of other anticonvulsants, such as gabapentin, lamotrigine, leviteracetam, oxcarbazepine, tiagabine or topiramate, is not supported by controlled data as yet. The use of antidepressants is largely discouraged, as they may worsen this condition. Atypical antipsychotics, on the other hand, may be effective either in monotherapy or in combination with valproate or lithium. As dysphoric mania is associated to higher risk of switching to depression, and antipsychotics are not very good for the prevention of depression, antipsychotic monotherapy is not advised. Only the trials with olanzapine in combination with valproate or lithium enrolled a substantial number of patients to allow for statistical subanalyses on this population, with positive results. Aripiprazole and ziprasidone have shown efficacy in pooled analysis from a few trials. To a lesser extent, risperidone, quetiapine and clozapine have also been studied in randomized clinical trials but the number of patients enrolled was quite small. Both evidence and clinical experience point at combination therapy of an atypical antipsychotic and an anticonvulsant, preferably valproate, or lithium as first-line therapy for severe mixed states. Mild cases could be treated with valproate monotherapy. A good alternative is electroconvulsive therapy. More research is needed in this area, and particularly in mixed states other than dysphoric mania. Key Words: Dysphoric Mania – Bipolar Mixed States – Treatment – Valproate – Lithium Declaration of interest: Dr. Vieta has received research grants, acted as consultant, or present at meetings with the support of the following companies: Astra-Zeneca, Bial, Bristol-Myers-Squibb, Eli-Lilly, Glaxo-Smith-Kline, Janssen-Cilag, Lundbeck, Merck-Sharp-Dohme, Novartis, Otsuka, Pfizer, Sanofi, Servier, UCB. The author is grateful to the support of the Stanley Medical Research Institute (Bethesda, Md, USA) and the Instituto Carlos III, Spain. Eduard Vieta, Isabella Pacchiarotti, Margarita Garcia-Amador, Raul F. Sanchez, Jose M. Goikolea Bipolar Disorders Program, Institute of Clinical Neuroscience, Hospital Clinic, University of Barcelona, Barcelona, Spain. Corresponding Author Eduard Vieta [email protected]

Introduction The concept of dysphoric mania emerges as a specific subtype of bipolar mixed states. The existence of mixed states is, in some way, a contradiction with the concept of bipolarity (Court 1968, Whybrow and Mendels 1969). Indeed, if there were only two opposite poles, mixed states should not exist. The American Psychiatric Association classification of mental disorders does not address this contradiction, allowing for mixed bipolar states that actually involve the full manic and depressive syndrome. Kraepelin (1921) was the first to emphasize the clinical relevance of mixed states. He described 6 subtypes of mixed states: depression with racing thoughts, excited depression, depressive-anxious mania, improductive mania, inhibited mania, and manic stupor, all them as a result of different combinations of

mood, cognitive, and psychomotor symptoms. Unfortunately, these useful descriptions were hardly used by clinicians and mixed states remained a source of misdiagnosis for many years. In recent years, there has been greater awareness about the importance of mixed states. Several authors have contributed to this fact, including Himmelhoch, Akiskal, Marneros, Koukopoulos, McElroy, Perugi, Bauer, Benazzi, Swann, and many others, for whom the DSM and the ICD definitions are very disappointing. Their contribution to psychopathology, together with the development of clinical trials enrolling mixed patients, and particularly patients suffering from dysphoric mania, have led to a further knowledge about how to diagnose and treat this clinical picture, which is indeed one of the most stressing and life-threatening psychiatric conditions. The prevalence of mixed states may range between

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Evidence-Based Pharmacotherapy of Dysphoric Mania

14% and 67%, depending on the definition (Akiskal et al. 1998, Benazzi et al. 2005). Akiskal described a number of symptoms as more characteristics of a mixed state during a manic episode (dysphoric mania), including depressed mood, irritability, mood lability, anhedonia, hopelessness and helplessness, suicidal ideations and attempts, guilt, and fatigue (Akiskal et al. 1998). Mixed states may be more frequent in women (Akiskal et al. 1998) and in patients with alcohol or neuropsychiatric comorbidity (Himmelhoch et al. 1976). Mixed patients have more past depressive episodes (Perugi et al. 2000), higher risk of suicide (Goldberg et al. 1998), and family history is more often depressive than manic (Dell’Osso et al. 1991). These authors, with Akiskal, have emphasized the relationship between mixed states and premorbid temperament. Mixed bipolar patients would be more likely to have depressive temperament than pure manics (Akiskal et al. 1998, Hantouche et al. 2001). For some reason, that may have to do with educational or cultural issues, or even with differences about antidepressant use across the oceans, drug trials conducted in North America are more likely to enrol mixed patients than trials conducted in Europe or Asia. Generally, mixed manic patients are more likely to score lower in mania rating scales and to provide informed consent to participate in drug trials, because they have more illness awareness during the episode (insight is more related to depressive symptoms than to manic symptoms). The first published trial on the treatment of mixed states was carried out as early as 1759. Indeed, one hundred years before the description of Falret and Baillarger, a Spanish physician, Piquer, described a case report on a patient who suffered from “a melancholicmanic affect” Piquer described his condition as “an illness in which at some point there was a predominant mood, and suddenly the opposite, but always as a result of insanity, not nature”. His patient was Ferdinand the VIth, king of Spain, and the treasure of the full description o his illness and treatment was recently rediscovered and published by Vieta and Barcia (1999). Of course, many things have changed since then, and a good number of evidence-based treatment options are available now for this condition.

has been obtained from trials that were not powered to seek for differences between treatment approaches in mixed bipolar patients. As mentioned, the first steps in the treatment of mixed states are making a correct diagnosis and screening for comorbidities, which are more frequent in these patients. Several studies suggest that mixed bipolar patients have higher prevalence rates of substance abuse (Himmelhoch et al. 1976), physical comorbidities (Himmelhoch and Garfinkel 1986) and suicidal behaviour (Dilsaver et al. 1994, Sato et al. 2004), which are all them very relevant aspects for treatment choice. Mixed states are difficult to treat, and recovery from an index mixed episode takes usually longer than recovery from a manic or depressive episode (Keller et al. 1986, Kupfer 2000). As general rules, there is some consensus about discontinuing antidepressants during mixed states, because they have been described to worsen them (Akiskal and Mallya 1987, Koukopoulos et al. 1992), and benzodiazepines may be used if there is prominent anxiety or insomnia, which is quite common (Winokur et al. 1969). However, Rihmer et al treated a mixed bipolar patient succesfully with adjunctive antidepressants (Rihmer et al. 1998). Very simple, but supportive psychotherapy may be useful to help the patient to understand what is happening. Formal psychotherapy, however, such as cognitive-behavioural therapy or psychoeducation, should only be delivered once the patient has achieved remission from acute symptoms (Vieta and Colom 2004). The American Psychiatric Association guidelines for the treatment of bipolar disorder recommend to treat severe mixed episodes with the combination of lithium or divalproate plus an antipsychotic, and among these atypicals are preferred (APA 2002). For milder episodes, monotherapy with lithium, divalproate or olanzapine may be enough (APA 2002). Other drugs, such as carbamazepine, oxcarbazepine, or clozapine, may be used in treatment resistant patients (APA 2002), and electroconvulsive therapy (ECT) is also an option. We will review the evidence base that supported these statements and more recent data that may shed more light into the treatment of this condition.

Pharmacotherapy of dysphoric mania

Lithium has been reported to be more effective in pure mania than in depressive mania (Secunda et al. 1987, Prien et al. 1988, Swann et al. 1997). Neither lithium nor the combination of lithium and imipramine were effective in the prevention of mixed episodes (Prien and Gelenberg 1989). However, lithium may still play a role in the treatment of mixed states, especially in combination with atypical antipsychotics.

The first and crucial step in the treatment of mixed states is to make a correct diagnosis. As mentioned, there are a number of mixed subtypes and it is reasonable to think that treatment may differ according to subtype. However, little evidence is available about how to treat mixed states other than dysphoric mania. Hence, the only controlled data available so far comes from subanalyses of randomised controlled trials in mania that enrolled a variable number of mixed patients fulfilling standardized criteria for mania and scoring over a certain threshold in a mania scale, with no specific requirements with regards to the intensity of depressive symptoms. Unfortunately, there is no trial dealing specifically with the treatment of mixed states. Therefore, most of the information provided in this chapter

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Lithium

Anticonvulsants In a divalproate comparative mania trial versus lithium and placebo, the presence of concomitant depressive symptoms was associated with response to divalproate but not to lithium (Swann et al. 1997). This finding has not been consistently replicated, but still

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divalproate may be a good choice for manic patients with dysphoric features. For example, Calabrese and Delucchi (1990) found that among rapid cyclers, those with mixed episodes were more likely to respond to divalproate, both acutely and prophylactically. Carbamazepine has also been suggested to be a good option in these patients (Post et al. 1987, Ballenger 1988), but controlled data are not available. The same happens with oxcarbazepine. Other anticonvulsants, such as lamotrigine, have failed to show acute antimanic properties (Bowden 2003) and, in fact, mixed states were a predictor of non-response in the long-term trials (Calabrese, personal communication). Topiramate has been reported to be helpful in open studies, but controlled studies in mania were negative, although most excluded explicitly mixed patients (Vieta et al. 2002b).

Antipsychotics The first-generation antipsychotics are clearly efficacious in the treatment of manic symptoms, but may be less efficacious than the second generation in the treatment of depressive symptoms during mania, according to some authors (Yatham 2003). This statement, however, has not been confirmed in controlled trials, but what those trials did suggest was that there was a higher switch rate to depression with haloperidol, as compared with olanzapine (Tohen et al. 2003). Most of the available data on the treatment of mixed states come from randomised controlled mania trials with atypical antipsychotics, and depending on the proportion of mixed patients in the trials, specific subanalyses may be performed. For instance, olanzapine has a large number of trials and some of them enrolled a substantial proportion of mixed manics, whereas the quetiapine mania trials excluded mixed patients and, therefore, little evidence is available about the efficacy of quetiapine in mixed states. We shall discuss the available evidence on these drugs individually. For clozapine, only open studies are available, suggesting that it may be effective for the treatment of mixed states (Suppes et al. 1992) Due to safety concerns and limited evidence, clozapine should not be used as a first-line treatment in this condition, even though clinical experience suggests that it may be quite effective. For treatment-refractory cases, however, it remains as a valuable option. Risperidone trials only enrolled a very limited number of mixed patients. Some trials excluded them (Hirschfeld et al. 2004), and others, perhaps because they were conducted in Asian or European countries, or perhaps because of higher severity, were only able to enrol few patients with this condition (Khanna et al. 2005). Only one trial, comparing risperidone plus lithium or divalproate versus lithium or divalproate alone and haloperidol plus lithium and divalproate, included slightly more than 20% mixed patients (2002), but there were no significant differences between the three groups at the endpoint. A large, observational study enrolling more than 500 bipolar patients, 31 of

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whom were mixed, reported risperidone plus mood-stabilizers to be effective in this condition (Vieta et al. 2001a), but this was not a controlled study. The average risperidone dose in mixed manic patients may be around 4 mg/day (Benabarre et al. 2001). At least 2 out of 8 olanzapine mania trials enrolled enough mixed patients to allow for statistical subanalyses of the data. The second placebo-controlled study (Tohen et al. 2000) enrolled 43% mixed patients. Improvement in the Young Mania Rating Scale (YMRS) was similar for pure and mixed patients treated with olanzapine (15 versus 14 points), but probably due to limited sample size differences between olanzapine and placebo did not reach statistical significance in mixed patients. However, looking at patients scoring 20 or more in the Hamilton Depression Rating Scale (HDRS), the olanzapine-treated patients improved significantly more than the patients who received placebo. Further analysis from the two placebo-controlled trials suggest that olanzapine may be useful for the treatment of mixed mania (Baldessarini et al. 2003). The second olanzapine study that enrolled a significant number of mixed manics (52%, more than 150 patients) compared olanzapine plus lithium or divalproate with lithium or divalproate alone (Tohen et al. 2002). This study did show a statistical advantage for olanzapine-treated patients versus placebo in patients taking mood-stabilizers. Open studies have also reported good results with olanzapine in mixed patients (Vieta et al. 2001b, Gonzalez-Pinto et al. 2002). Quetiapine has been quite extensively studied in mania, but most trials excluded mixed patients. Only a small controlled trial of adjunctive quetiapine in adolescents taking divalproate provided some information, such as significant improvements in both mania and depression rating scales (Delbello et al. 2002). Zarate et al. (2000) reported preliminary good results as well in a retrospective study. Finally, quetiapine might be useful for the long-term treatment of mixed states in rapid cyclers if the results of a small, observational study are replicated (Vieta et al. 2002a). Ziprasidone has been assessed in a few placebocontrolled mania trials. Pooled data from those suggest that it may be effective in the treatment of mixed mania, as 101 mixed patients on ziprasidone monotherapy improved significantly more than 50 on placebo (Potkin et al. 2004). The aripiprazole monotherapy trials enrolled a good number of mixed patients, allowing for statistical subanalyses of pooled data. Pooling the 3 datasets, there was indeed a significant advantage of aripiprazole over placebo in the treatment of mixed mania (Jody et al. 2004). There are no data available as yet for combination therapy with this drug. There are no published studies with amisulpride in the treatment of mania or mixed states. A recent uncontrolled study with only 20 patients, including 3 mixed manics, reported significant improvements in both mania and depression rating scales (Vieta et al. 2005), but this is indeed very little evidence about how this drug works in this population.

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Evidence-Based Pharmacotherapy of Dysphoric Mania

Electroconvulsive therapy (ECT) ECT has been reported to be an effective treatment for various mixed states, including mixed mania, mixed depression, and agitated depression (Dilsaver et al. 1993, Evans and Nemeroff 1983, Ciapparelle et al. 2001, Kupfer 2000). Baseline ratings of depression during mania were the strongest predictor of response to ECT, rather than lithium, in a randomized, controlled trial (Small et al. 1988).

Other There are anecdotal reports on other drugs that might be effective in some patients, but little evidence is available so far beyond the therapies mentioned above. There is no evidence that psychotherapy may help these patients during acute states, although it is important to provide information, support, and prevent suicide. Psychoeducation has actually proven effective for the prevention of mixed relapse in a prospective randomised trial (Colom et al. 2003). Beyond clinical trials, experience also tells us that combination therapy is more likely to be successful than monotherapy. In the near future, we hope that different combinations of the compounds that have been mentioned in this review, and other that may come, will be assessed in randomised trials specifically addressed to dysphoric manics and other mixed bipolar patients.

Conclusions Bipolar mixed states remain a nosological dilemma, a diagnostic challenge, and a neglected area of therapeutic research. Only dysphoric mania has been reasonably addressed in clinical trials, but very little is known about the treatment of other mixed states. There is some indirect evidence that dysphoric mania may be more responsive to anticonvulsants than to lithium. Divalproate, and to a lesser extent carbamazepine, may be used either in monotherapy or as adjuncts to lithium. Use of other anticonvulsants, such as gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, or zonisamide is not supported by controlled data as yet. The use of antidepressants is largely discouraged, as they may worsen this condition. Atypical antipsychotics, on the other hand, may be effective and safe either in monotherapy or in combination with lithium or valproate. Only the trials with olanzapine, aripiprazole, and ziprasidone enrolled a substantial number of dysphoric patients to allow for statistical subanalyses on this population. Risperidone, quetiapine and clozapine have also been studied in randomized clinical trials but the number of patients enrolled was quite small. Both evidence and clinical experience point at combination therapy of an atypical antipsychotic and an anticonvulsant or lithium as first-line therapy for mixed states. A good alternative is electroconvulsive therapy. Psychotherapy, and particularly psychoeducation, may be helpful as an adjunct to medication or ECT to deal with the anxiety and suicidality that is often associated with mixed states, and may prevent mixed relapses. Hopefully further research will focus

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on this neglected area of psychiatry, which is associated with poor outcome and high mortality rates.

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