Evidence-Based Reviews

Treatment-resistant schizophrenia: What role for mood stabilizers?

Current Psychiatry. 2004 December;3(12):23-40

References

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Similar results were seen in treatment-resistant inpatients with schizophrenia (n = 38) in a 10-week, double-blind, parallel group trial by Kremer et al.²⁰ Adjunctive lamotrigine improved PANSS positive, general psychopathology, and total symptom scores in the 31 patients who completed the trial. No differences were seen, however, in negative symptoms, total BPRS scores, or in the intent-to-treat analysis. These results have spurred the launch of a large, multi-site, RCT of adjunctive lamotrigine in patients with schizophrenia who have responded inadequately to antipsychotics alone.

Topiramate, one of the few psychotropics associated with weight loss, has attracted interest as an adjunct to second-generation antipsychotics to address weight gain. Although case reports have shown benefit,²¹ one showed deterioration in both positive and negative symptoms when topiramate was added to second-generation antipsychotics.²²

Table 5

Double-blind study of adjunctive topiramate in schizophrenia

Author (yr)	n	Duration (days)	Design	Diagnosis	Outcome
Tiihonen (2004)*	26	84	Crossover; SGA plus topiramate or placebo	Treatment- resistant male inpatients with chronic schizophrenia	PANSS general scores improved No difference in total PANSS, PANSS positive, or PANSS negative scores
* 2004 Collegium Internationale Neuro-Psychopharmacologicum (CINP) presentation, and personal communication (6/22/04)
n = number of patients
PANSS = Positive and Negative Syndrome Scale
SGA = Second-generation antipsychotic (patients were taking clozapine, olanzapine, or quetiapine)

An unpublished, randomized, crossover trial compared second-generation antipsychotics plus topiramate or placebo in 26 male inpatients with chronic schizophrenia. With adjunctive topiramate, the authors found a statistically significant improvement in the PANSS general psychopathology subscale but not in PANSS total, positive subscale, or negative subscale scores (Table 5) (Tiihonen J, personal communication 6/22/04).

Other agents. Very little information—all uncontrolled—supports adjunctive use of gabapentin or oxcarbazepine for patients with schizophrenia.^23-28 Of concern are reports of patients suffering worsening of psychosis with gabapentin²⁵ or of dysphoria and irritability with oxcarbazepine (attributed to a pharmacokinetic interaction).²⁶

Conclusion. More trials are needed to examine the use of adjunctive mood stabilizers in patients with schizophrenia—particularly in those with chronic symptoms. Although mood stabilizers are widely used in this population, important questions remain unanswered, including:

characteristics of patients likely to require adjunctive treatment
how long treatment should continue.

MECHANISMS OF ACTION

Unlike antipsychotics, mood stabilizers do not exert their therapeutic effects by acting directly on dopamine (D2) receptors. Differences in mechanism of action among the anticonvulsants may help explain why some—such as valproate and lamotrigine—have been useful for bipolar disorder or schizophrenia and others—such as gabapentin—have not.²⁹

One possibility is that anticonvulsants that affect voltage-gated sodium channels—such as valproate, lamotrigine, carbamazepine and oxcarbazepine—may be most useful for patients with bipolar disorder or schizophrenia. On the other hand, agents that affect voltage-gated calcium channels—such as gabapentin—may be efficacious as anticonvulsants but not as efficacious for bipolar disorder or schizophrenia.

Ketter et al³⁰ proposed an anticonvulsant classification system based on predominant psychotropic profiles:

the “GABA-ergic” group predominantly potentiates the inhibitory neurotransmitter GABA, resulting in sedation, fatigue, cognitive slowing, and weight gain, as well as possible anxiolytic and antimanic effects
the “anti-glutamate” group predominantly attenuates glutamate excitatory neurotransmission and is associated with activation, weight loss, and possibly anxiogenic and antidepressant effects.

In the GABA-ergic group are anticonvulsants such as barbiturates, benzodiazepines, valproate, gabapentin, tiagabine, and vigabatrin. The antiglutamate group includes agents such as felbamate and lamotrigine. A “mixed” category includes anticonvulsants with GABA-ergic and anti-glutaminergic actions such as topiramate, which has sedating and weight-loss properties.

Because GABA appears to modulate dopamine neurotransmission,³¹ this may explain valproate’s role as an adjunctive agent for schizophrenia. Similarly, mechanisms related to Nmethyl-D-aspartate (NMDA) and non-NMDA glutamate receptor function may explain lamotrigine’s usefulness in this setting.^19,20

SUMMARY

Clinicians resort to combination therapies when monotherapies fail to adequately control symptoms or maintain response. Co-prescribing of anticonvulsants with antipsychotics for inpatients with schizophrenia is common practice in New York State and most likely elsewhere. In general, antipsychotics’ and mood stabilizers’ different—and perhaps complementary—mechanisms of action explain the synergism between them. Mechanisms of action also may explain why some anticonvulsants help in schizophrenia (or bipolar disorder) whereas others do not.

Evidence for using adjunctive anticonvulsants is variable. The strongest data support using valproate (and perhaps lamotrigine), followed by carbamazepine and then topiramate. Gabapentin and oxcarbazepine have only anecdotal evidence, some of it negative. Well-designed, randomized clinical trials with the appropriate populations are needed.

Related resources

Stahl SM. Essential psychopharmacology of antipsychotics and mood stabilizers. New York: Cambridge University Press, 2002.
Harvard Medical School Department of Psychiatry’s psychopharmacology algorithm project. Osser DN, Patterson RD. Consultant for the pharmacotherapy of schizophrenia. Available at http://mhc.com/Algorithms/. Accessed Nov. 5, 2004.

Drug brand names

Carbamazepine • Tegretol
Clozapine • Clozaril
Gabapentin • Neurontin
Haloperidol • Haldol
Lamotrigine • Lamictal
Lithium • Lithobid, Eskalith
Olanzapine • Zyprexa
Oxcarbazepine • Trileptal
Quetiapine • Seroquel
Risperidone • Risperdal
Topiramate • Topamax
Valproate (valproic acid, divalproex sodium) • Depakene, Depakote