Expert: Ivan Goldberg, M.D. - 12/1/2007

Question
QUESTION: Dear Dr. Goldberg,
I have a sister,37, who is currently suffering from bipolar.She is on Risperidone 2mg, & taking 50mg lamictal at her discretion.In addition,she takes Midazolam 15mg at night (Lorazepam is not available here in Kenya although Klonopin can be gotten, as also Ziprasidone & Abilify is not available here.)  Although her boyfriend says he does not want her, she insists on calling him & saying she is married to him. She calls him on cell-phone & refuses to give up, despite all attempts by him to say NO. What should I do in addition to giving counselling, what drug should I increase or add ? Remember your answer to this question will be forwarded to Kenyan pdocs who also lecture in Main Universities here, like I did to your last response, which then they will concur with you.

Thanks for your help. Really to be in a Third World Country is really trying.

S.Lakhani


ANSWER: I think if the doctors asked me what to do I would suggest that they increase the risperidone to a maximally tolerated dose. If your sister is kept on that dose for three weeks and still does not improve I'd next suggest that the same thing be done with perphenazine and, if possible, the dose be kept at 64 mg per day.

I don't know if electroconvulsive therapy is available but if perphenazine therapy is not effective the next thing I'd suggest would withe be treatment with clozapine or electroconvulsive therapy.

Best regards . . .
Ivan
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---------- FOLLOW-UP ----------

QUESTION: ECT is available, i will try my best to up the risperidone, but this usually occurs around the time when she is pre-menstual usually. I do understand your need for ECT, but last time a combination of CPZ, lithium, carbamazepine(NB not approved for Bipolar) & artane was administered to her, we saw there was no need for ECT. I also have managed to get a 3o day stock standby of Aripiprazole & Ziprasidone (from reputable Indian co's like Sun, cipla, intas,) in case of anything.
I really hate to have put my sister on clozapine, that is for treatment resistant schizophrenia. But let me see what to do if worse comes to worse.
Thanks for your help.
S.Lakhani

Answer
Hi . . .

Clozapine is frequently very useful in the management of people with Bipolar Disorder.

Below are a few abstracts.

Best regards . . .
Ivan

1: Bull Menninger Clin. 2001 Winter;65(1):26-40.

Treatment-resistant bipolar disorder.

Gitlin MJ.

Department of Psychiatry, UCLA School of Medicine, USA.

Over the last few years, the number of potential pharmacotherapies for bipolar
disorder has greatly expanded. Yet the database for virtually all these newer
treatments consists of case reports and case series. Among these newer
treatments, recently released anticonvulsants are most promising. Lamotrigine has
already shown efficacy for treating bipolar depression, while gabapentin's
efficacy has yet to be documented in a controlled study. Alone among its
medication class, topiramate, another anticonvulsant, is associated with weight
loss. Novel antipsychotics are effective in treating acute mania. With the
exception of clozapine, their efficacy as true mood stabilizers is still unknown.
Utilizing combinations of mood stabilizers is common and appropriate but demands
knowledge of potential pharmacokinetic interactions. Other approaches for
treatment resistant bipolar disorder include high-dose thyroid hormones, calcium
channel blockers, electroconvulsive therapy, and omega-3 fatty acids. Finally,
the efficacy of adjunctive psychosocial strategies is a topic of active
investigation.

Publication Types:
   Review

PMID: 11280956 [PubMed - indexed for MEDLINE]

2: Psychopharmacology (Berl). 2003 Apr;166(4):315-32. Epub 2003 Feb 27.

Atypical antipsychotics and mood stabilization in bipolar disorder.

Brambilla P, Barale F, Soares JC.

Department of Psychiatry, University of Texas Health Science Center at San
Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.

The available literature on the use of atypical antipsychotics for the treatment
of bipolar disorder was reviewed. All uncontrolled and controlled reports were
identified through a comprehensive Medline search. Based on the available
evidence, olanzapine was found to be the most appropriate atypical antipsychotic
agent utilized for the treatment of manic bipolar patients, although there is
also preliminary data suggesting the efficacy of risperidone and clozapine. The
preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar
disorder are still very limited. Double-blind controlled studies with atypical
antipsychotics in the long-term treatment of bipolar disorder are still largely
not available, but will be critical to determine the effectiveness of these
agents in the maintenance treatment of bipolar disorder. There are recent
uncontrolled suggestions that olanzapine may have beneficial effects in depressed
bipolar patients, which deserve further investigation in controlled studies. In
conclusion, atypical antipsychotics, due to lower potential for neurotoxicity and
preliminary evidence suggesting better efficacy than typical antipsychotics, are
increasingly having a more prominent role in the pharmacological management of
bipolar patients. Nonetheless, until there is systematic data from long-term
controlled follow-up studies on the comparative efficacy of these agents with
mood stabilizers, atypical antipsychotics should be cautiously utilized, and
preferably in combination with a mood stabilizer for the maintenance phase of
treatment.

Publication Types:
   Research Support, Non-U.S. Gov't
   Research Support, U.S. Gov't, P.H.S.
   Review

PMID: 12607072 [PubMed - indexed for MEDLINE]

3: J Clin Psychiatry. 2003 Apr;64(4):451-8.

Clozapine in treatment-resistant patients with schizophrenia, schizoaffective
disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study.

Ciapparelli A, Dell'Osso L, Bandettini di Poggio A, Carmassi C, Cecconi D, Fenzi
M, Chiavacci MC, Bottai M, Ramacciotti CE, Cassano GB.

Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology,
University of Pisa, Italy. ciapparelli.a@tin.it

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and
safety of clozapine in patients with treatment-resistant schizophrenia,
schizoaffective disorder, or bipolar disorder with psychotic features. METHOD:
101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34);
schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with
psychotic features (N = 37) were naturalistically treated with clozapine at
flexible doses over a 48-month period. Data were collected from 1994 to 2000. The
Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of
Illness scale total predicted scores over time were estimated with random-effects
regression models. Time to response to clozapine, defined as 50 reduction of
BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier
method. Survival curves were compared using the log-rank test. RESULTS: The BPRS
total predicted score halved its baseline value in 3 months for bipolar disorder
patients, in 6 months for schizoaffective disorder patients, and in 24 months for
schizophrenia patients. The proportion of subjects who satisfied the criterion
for response to clozapine after 48 months of follow-up was significantly (p <.01)
higher in the schizoaffective and bipolar disorder groups (90.0
nd 83.8,
respectively) than in the schizophrenia group (64.7). Baseline scores on the
Global Assessment of Functioning (GAF) showed low levels of psychosocial and
occupational functioning in all 3 groups. After 48 months of treatment, GAF
scores showed a functional improvement in all 3 groups, with significantly (p
<.01) greater improvement in the bipolar disorder group compared with the other
groups. CONCLUSION: The findings of this study confirm the efficacy and safety of
clozapine for treatment-resistant patients with a diagnosis of schizophrenia,
schizoaffective disorder, or bipolar disorder with psychotic features. Patients
with schizoaffective disorder and those with bipolar disorder show greater
clinical improvement than those with schizophrenia. Patients with bipolar
disorder have the shortest time to response and the highest psychosocial and
occupational functioning levels. Patients with schizoaffective disorder have the
lowest treatment discontinuation rate.

Publication Types:
   Clinical Trial
   Comparative Study

PMID: 12716249 [PubMed - indexed for MEDLINE]

4: J Child Adolesc Psychopharmacol. 2004 Spring;14(1):57-63.

The off-label use of clozapine in adolescents with bipolar disorder, intermittent
explosive disorder, or posttraumatic stress disorder.

Kant R, Chalansani R, Chengappa KN, Dieringer MF.

Head Injury Clinic, Pittsburgh, Pennsylvania, USA.

OBJECTIVE: There are limited data in the literature regarding clozapine use in
adolescents with diagnoses other than schizophrenia. This report describes the
use of clozapine in adolescents with diagnoses of bipolar disorder, intermittent
explosive disorder (IED), and posttraumatic stress disorder (PTSD). METHODS: A
chart review of 39 adolescents treated with clozapine at two residential
facilities was undertaken. Data extraction included demography, illness
variables, medication information, and clinical outcomes. Categorical outcomes
were analyzed using contingency statistics, and continuous variables were
analyzed using a paired t test. RESULTS: The cohort included 26 females and 13
males with a mean age of 14 years. Clozapine was titrated slowly, and the mean
daily dose was 102 mg. The diagnoses included bipolar disorder (n = 7), IED (n =
9), and PTSD (n = 19). There were significant reductions in polypharmacy once the
clozapine dosage was stabilized. Prior to clozapine treatment, nearly 70 of the
subjects were receiving either mood-stabilizing or antidepressant agents in
combination with the previous antipsychotic drug. Once the clozapine dosage was
stabilized, only 24 of the subjects required concomitant mood stabilizers (p <
0.001), and only 21 of the subjects required concomitant antidepressants (p <
0.001). Anxiolytic medication use was also significantly reduced during clozapine
treatment. Most patients were discharged to a less restrictive setting. Eight
subjects discontinued clozapine due to agranulocytosis (n = 1), neutropenia (n =
2), excessive weight gain (n = 2), or not requiring it long term (n = 1), and
data were unavailable in 2 subjects. Significant weight gain (5 or greater
change from baseline) was noted in 20 subjects. CONCLUSIONS: Clozapine, in
relatively modest doses, appears to have clinical benefits for adolescent with
bipolar disorder, IED, and PTSD. There is no labeled indication for clozapine use
in these disorders. Clozapine is also associated with serious side effects in
subsets of individuals. Therefore, a very careful evaluation of the
risk-to-benefit ratio in each individual subject being considered for clozapine
is highly recommended.

Publication Types:
   Comparative Study

PMID: 15142392 [PubMed - indexed for MEDLINE]

5: Mol Psychiatry. 2006 Mar;11(3):227-40.

Treatment-resistant bipolar disorder.

Gitlin M.

Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
mgitlin@mednet.ucla.edu

Despite the remarkable increase in medications validated as effective in bipolar
disorder, treatment is still plagued by inadequate response in acute manic or
depressive episodes or in long-term preventive maintenance treatment. Established
first-line treatments include lithium, valproate and second-generation
antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance
treatments. Recently validated treatments include extended release carbamazapine
for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance
treatments. For treatment-resistant mania and as maintenance treatments, a number
of newer anticonvulsants, and one older one, phenytoin, have shown some promise
as effective. However, not all anticonvulsants are effective and each agent needs
to be evaluated individually. Combining multiple agents is the most commonly used
clinical strategy for treatment resistant bipolar patients despite a relative
lack of data supporting its use, except for acute mania (for which lithium or
valproate plus an SGA is optimal treatment). Other approaches that may be
effective for treatment-resistant patients include high-dose thyroid
augmentation, clozapine, calcium channel blockers and electroconvulsive therapy
(ECT). Adjunctive psychotherapies show convincing efficacy using a variety of
different techniques, most of which include substantial attention to education
and enhancing coping strategies. Only recently, bipolar depression has become a
topic of serious inquiry with the dominant controversy focusing on the place of
antidepressants in the treatment of bipolar depression. Other than mood
stabilizers alone or the combination of mood stabilizers and antidepressants,
most of the approaches for treatment-resistant bipolar depression are relatively
similar to those used in unipolar depression, with the possible exception of a
more prominent place for SGAs, prescribed either alone or in combination with
antidepressants. Future work in the area needs to explore the treatments commonly
used by clinicians with inadequate research support, such as combination therapy
and the use of antidepressants as both acute and adjunctive maintenance
treatments for bipolar disorder.

Publication Types:
   Review

PMID: 16432528 [PubMed - indexed for MEDLINE]

6: CNS Drugs. 2006;20(7):591-9.

Economics of atypical antipsychotics in bipolar disorder: a review of the
literature.

Fleurence RL, Dixon JM, Revicki DA.

United BioSource Corporation, Health Care Analytics Group, Bethesda, Maryland
20814, USA. rachael.fleurence@unitedbiosource.com

Economic evaluations are increasingly being used by policy makers to evaluate the
relative costs and benefits of healthcare interventions. These analyses provide
economic and clinical evidence to decision makers seeking to make recommendations
on treatment alternatives for patients. This article describes the economic
evidence on the atypical antipsychotics currently approved for the treatment of
bipolar disorder. This area remains under-researched. A literature search
identified only six relevant studies of atypical antipsychotics in bipolar
disorder: two retrospective database analyses, three economic analyses alongside
clinical trials and one cost-effectiveness analysis. Based on the limited
available studies, there appears to be no significant difference in healthcare
resource use between olanzapine, quetiapine, risperidone and valproate semisodium
(divalproex sodium; an antiepileptic drug and a standard treatment for mania
associated with bipolar disorder). While a cost-effectiveness study for the UK
found haloperidol (a conventional antipsychotic) to be more cost effective than
atypical antipsychotics, these results must be considered with caution because of
the non-inclusion of adverse effects in the model. No economic data are available
for aripiprazole, clozapine or ziprasidone in bipolar disorder. Until more
economic evidence becomes available, the economic implications of atypical
antipsychotic treatment in patients with bipolar disorder are unlikely to
significantly impact on prescribing and treatment patterns. Future economic
studies evaluating atypical antipsychotics in bipolar disorder should address the
issue of long-term costs and effectiveness to reflect the chronic nature of the
disease, the variety of health states that patients may experience and the range
of treatments they may receive. A better understanding of the complex interplay
between effectiveness, safety, quality of life, adherence and resource use should
ultimately contribute to improving the treatment of bipolar disorder.

Publication Types:
   Review

PMID: 16800717 [PubMed - indexed for MEDLINE]