Neuropsychobiology 2002;45(suppl 1):37–42
`
`Clozapine as Add-On Medication in the
`Maintenance Treatment of Bipolar and
`Schizoaffective Disorders
`
`A Case Series
`
`B. Hummel S. Dittmann A. Forsthoff N. Matzner B. Amann H. Grunze
`
`Department of Psychiatry, LMU University Hospital, Munich, Germany
`
`Key Words
`Bipolar disorder W Schizoaffective disorder W Clozapine
`
`Introduction
`
`Abstract
`Atypical neuroleptics are increasingly used in the treat-
`ment of bipolar and schizoaffective disorders. Currently,
`numerous controlled short-term studies are available for
`clozapine, olanzapine, risperidone or quetiapine, but
`long-term data are still missing. Three patients (2 with
`bipolar disorder, 1 with schizoaffective disorder) are de-
`scribed who showed a marked reduction of affective
`symptomatology after clozapine had been added to
`mood stabilizer pretreatment. The patients were seen
`once a month before and after the introduction of cloza-
`pine for at least 6 months. Treatment response was eval-
`uated using different rating scales (IDS, YMRS; GAF; CGI-
`BP) and the NIMH Life Chart Methodology. All patients
`showed a marked improvement after the add-on treat-
`ment with clozapine had been initiated. Clozapine was
`tolerated well with only transient and moderate weight
`gain and fatigue as only side effects. This case series
`underlines the safety and efficacy of clozapine as add-on
`medication in the treatment of bipolar and schizoaffec-
`tive disorders.
`
`Copyright © 2002 S. Karger AG, Basel
`
`The management of bipolar and schizoaffective disor-
`ders is a challenging task for clinicians. Although several
`mood stabilizers, e.g., lithium, valproic acid or carbama-
`zepine, are available, there is still a number of patients
`unresponsive to either a monotherapy or even a combina-
`tion treatment [1]. Lithium nonresponse is estimated at
`33% in patients with ‘classical’ bipolar disorder [2] and
`thought to be even higher in patients with mixed episodes
`or rapid cycling [3, 4]. Additionally, manic patients are
`still treated with typical antipsychotics in the acute phase
`and even as maintenance treatment, despite the high risk
`of tardive dyskinesia [5, 6]. A longitudinal study could
`also demonstrate that the long-term use of neuroleptic
`agents was associated with a cycle acceleration and thus a
`worsening of the long-term course of the illness [7]. In
`another double-blind study in which lithium monothera-
`py was compared to the combination treatment of lithium
`and flupentixol for 2 years, patients randomized to com-
`bination treatment suffered from more depressive epi-
`sodes while the frequency of manic episodes was not sig-
`nificantly different [8]. Atypical antipsychotics such as
`clozapine, olanzapine, risperidone or quetiapine are con-
`sidered as relatively safe alternatives used as add-on med-
`
`ABC
`Fax + 41 61 306 12 34
`E-Mail karger@karger.ch
`www.karger.com
`
`© 2002 S. Karger AG, Basel
`0302–282X/02/0455–0037$18.50/0
`
`Accessible online at:
`www.karger.com/journals/nps
`
`Sandra Dittmann
`Psychiatric Hospital of the University of Munich
`Nussbaumstrasse 7, D–80336 Munich (Germany)
`Tel. +49 89 5160 5781, Fax +49 89 5160 5330
`E-Mail sandra.dittmann@psy.med.uni-muenchen.de
`
`Exhibit 2135
`Slayback v. Sumitomo
`IPR2020-01053
`
`1
`
`

`

`ication in the maintenance treatment of bipolar and schi-
`zoaffective disorders [9]. Hints at efficacy of clozapine in
`schizoaffective [10–12] and bipolar disorders [13–15]
`were reported by several authors. However, controlled
`trials of clozapine in maintenance treatment are still miss-
`ing. This might be not only due to the fact that clozapine
`has the side effect of agranulocytosis, but also to a lack of
`commercial interest in this relatively old drug.
`Here we report on 3 well-characterized and followed-
`up patients in whom clozapine as add-on medication led
`to complete remission of symptoms.
`
`Case Reports
`
`Case 1
`Mr. B. is a 34-year-old patient with bipolar I disorder and a rap-
`id cycling course. His first depressive episode occurred at the age of
`13, the first mania at the age of 15. Shortly after he developed a
`rapid cycling course with mood switches every 14 days and without
`any symptom-free interval. Combination treatment of lithium and
`carbamazepine led to a complete remission of symptoms for 15
`years. Then the ultrarapid cycling reoccurred, and additionally he
`developed comorbid kleptomania, panic attacks, binge-eating disor-
`der and marihuana abuse. Attempts to stabilize his mood with e.g.
`valproate, lamotrigine or different antidepressants failed. He was
`on a combination treatment with lithium, valproate, lamotrigine
`and paroxetine without any change of his rapid cycling course when
`he first visited our outpatient clinic. Both his depressive and manic
`episodes ranged from moderate to severe. Especially in his de-
`pressed phases, he had strong suicidal ideations. We decided to tap-
`er lithium, lamotrigine and paroxetine gradually and to start treat-
`ment with clozapine. After the titration phase, the daily dose of clo-
`zapine was 250 mg. In the following 6 months, his manias subsided
`completely, and the depressive episodes became fewer and milder.
`With the later addition of ˆ-3 fatty acids it was possible to manage
`also his depressive episodes. The combination treatment of val-
`proate, clozapine and ˆ-3 fatty acids was shown to be safe and
`effective. The only side effects were weight gain, fatigue and mild
`diarrhea, which all subsided after some weeks of treatment. Con-
`trolling his eating habits, the patient now even lost 14 kg of weight
`and had no manias for 1 year and no severe depressions for several
`months (fig. 1). Comorbid symptoms and suicidal ideations are no
`longer present.
`
`Case 2
`Mr. R. is a 34-year-old patient with bipolar I disorder. His first
`depressive episode with psychotic symptoms occurred at the age of
`19. During the course of his illness, he had many very severe dys-
`phoric manias, sometimes with mood-incongruent psychotic features
`that always led to hospitalization and which were mostly treated with
`the combination of lithium and carbamazepine as maintenance
`treatment and haloperidol in the acute phase. During the 3 years
`before he visited our outpatient clinic, he also received haloperidol as
`a maintenance treatment. This led to an increase in the rate and
`severity of the depressive episodes. We first put Mr. R. on the combi-
`nation of lamotrigine and clozapine, but a severe manic episode in
`
`which two hospitalizations were necessary led to the substitution of
`lamotrigine with valproate. The daily dosage of clozapine is now
`200 mg and that of valproate 1,500 mg. Mr. R. has been taking cloza-
`pine in combination with valproate for 1 year now, and no recurrence
`has been noted so far (fig. 2). Side effects are not present. Even with
`the combination treatment of valproate and clozapine, Mr. R has lost
`10 kg of weight since he stopped taking lithium, carbamazepine and
`haloperidol as maintenance treatment. He is also able to exercise,
`which he said he had not been able to do for years due to severe
`fatigue.
`
`Case 3
`Ms. F. is a 23-year-old woman suffering from schizoaffective dis-
`order. Besides her mood episodes, incongruent psychotic features
`like paranoid delusions and ideas of reference were the prominent
`symptoms, independently from mood deflections. Her first mania
`occurred at the age of 20. At that time delusions were also prominent
`symptoms. The treatment with risperidone 4 mg/day led to a fast
`remission. After discontinuing the medication, she experienced
`another exacerbation of mania which again led to hospitalization.
`The treatment with valproate 1,500 mg/day led to a fast stabilization,
`but still mild mood swings occurred. Shortly after her release, Ms. F.
`had to be hospitalized again due to another manic episode. Besides
`manic symptoms, psychotic symptoms were again prominent fea-
`tures. In addition to valproate, haloperidol was necessary to treat the
`psychotic symptoms. After the acute symptomatology had faded, we
`tried to replace haloperidol with risperidone to continue with the
`combination of valpraote and risperidone as maintenance treatment.
`However, another exacerbation of the manic and psychotic symp-
`toms occurred. A trial with olanzapine was also unsuccessful, due to
`severe side effects (fatigue, depressive symptoms, difficulties to con-
`centrate). We finally switched to a combination treatment of val-
`proate 1,300 mg/day and clozapine 100 mg/day. During the titration
`phase, Ms. F. suffered from fatigue; no other side effects occurred.
`For the last 9 months, Ms. F. has had no more mood symptoms and
`has tolerated the drugs without side effects (fig. 3).
`
`Discussion
`
`The 3 cases described here show that clozapine is a safe
`and effective add-on medication in bipolar and schizoaf-
`fective disorder. All patients tolerated it well. No blood
`count changes have occurred yet. This case series is in line
`with other reports and trials which describe clozapine as
`an effective treatment for bipolar and schizoaffective
`patients [9, 16]. In the 2 patients in whom also incon-
`gruent psychotic features occurred, clozapine was an
`effective antipsychotic as well. Keeping the risk of tardive
`dyskinesia in mind and knowing that even nowadays
`many bipolar patients still receive long-term treatment
`with typical antipsychotics, clozapine seems to be an
`alternative of choice. There is also the risk of inducing
`depressive episodes by putting patients on typical antipsy-
`chotics. Given that clozapine might not have strong anti-
`depressant properties, it seems not to induce depression.
`
`38
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`Neuropsychobiology 2002;45(suppl 1):37–42
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`Amann/Grunze
`
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`Fig. 1. NIMH Life Chart Method clinician ratings (prospective) of patient 1.
`
`39
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`Clozapine in Bipolar Disorder
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`Neuropsychobiology 2002;45(suppl 1):37–42
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`

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`Fig. 2. NIMH Life Chart Method clinician ratings (prospective) of patient 2.
`
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`Amann/Grunze
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`Fig. 3. NIMH Life Chart Method clinician ratings (prospective) of patient 3.
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`41
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`Clozapine in Bipolar Disorder
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`Neuropsychobiology 2002;45(suppl 1):37–42
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`In the cases described here, the only side effects which
`occurred were fatigue and weight gain during the titration
`phase. Later on, tolerability was no longer a problem.
`Interestingly, 2 patients who suffered from severe weight
`gain before they got clozapine and during the titration
`phase even lost more than 10 kg during the continuation
`
`treatment with the combination of clozapine and val-
`proate. In summary, this case series is another hint at the
`effectiveness and safety of clozapine in the treatment of
`bipolar and schizoaffective disorders, but still more con-
`trolled studies are necessary to further investigate the use
`of clozapine and other atypical antipsychotics.
`
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