Evidence-Based Reviews

Treatment-resistant schizophrenia: What role for mood stabilizers?

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

References

1. Citrome L, Jaffe A, Levine J. Datapoints - mood stabilizers: utilization trends in patients diagnosed with schizophrenia 1994-2001. Psychiatr Serv 2002;53(10):1212.-

2. Citrome L. Antipsychotic polypharmacy versus augmentation with anticonvulsants: the U.S.perspective (presentation). Paris: Collegium Internationale Neuro-Psychopharmacologicum(CINP), June 2004 [abstract in Int J Neuropsychopharmacol 2004;7(suppl 1):S69].

3. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia revisited: a systematic review and meta-analysis of randomized clinical trials. J Clin Psychiatry 2004;65(2):177-86.

4. Neppe VM. Carbamazepine as adjunctive treatment in nonepileptic chronic inpatients with EEG temporal lobe abnormalities. J Clin Psychiatry 1983;44:326-31.

5. Dose M, Apelt S, Emrich HM. Carbamazepine as an adjunct of antipsychotic therapy. Psychiatry Res 1987;22:303-10.

6. Okuma T, Yamashita I, Takahashi R, et al. A double-blind study of adjunctive carbamazepine versus placebo on excited states of schizophrenic and schizoaffective disorders. Acta Psychiatr Scand 1989;80:250-9.

7. Nachshoni T, Levin Y, Levy A, et al. A double-blind trial of carbamazepine in negative symptom schizophrenia. Biol Psychiatry 1994;35(1):22-26.

8. Simhandl C, Meszaros K, Denk E, et al. Adjunctive carbamazepine or lithium carbonate in therapy-resistant chronic schizophrenia. Can J Psychiatry 1996;41(5):317.-

9. Leucht S, McGrath J, White P, et al. Carbamazepine augmentation for schizophrenia: how good is the evidence? J Clin Psychiatry 2002;63(3):218-24.

10. Citrome L. Schizophrenia and valproate. Psychopharmacol Bull 2003;37(suppl 2):74-88.

11. Basan A, Kissling W, Leucht S. Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials. Schizophr Res 2004;70(1):33-7.

12. Ko GN, Korpi ER, Freed WJ, et al. Effect of valproic acid on behavior and plasma amino acid concentrations in chronic schizophrenia patients. Biol Psychiatry 1985;20:209-15.

13. Dose M, Hellweg R, Yassouridis A, et al. Combined treatment of schizophrenic psychoses with haloperidol and valproate. Pharmacopsychiatry 1998;31(4):122-5.

14. Fisk GG, York SM. The effect of sodium valproate on tardive dyskinesia—revisited. Br J Psychiatry 1987;150:542-6.

15. Wassef AA, Dott SG, Harris A, et al. Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol 2000;20(3):357-361.

16. Casey DE, Daniel DG, Wassef AA, et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacol 2003;28(1):182-92.

17. Citrome L, Casey DE, Daniel DG, et al. Effects of adjunctive valproate on hostility in patients with schizophrenia receiving olanzapine or risperidone: a double-blind multi-center study. Psychiatr Serv 2004;55(3):290-4.

18. Cramer JA, Sernyak M. Results of a naturalistic study of treatment options: switching atypical antipsychotic drugs or augmenting with valproate. Clin Ther 2004;26(6):905-14.

19. Tiihonen J, Hallikainen T, Ryynanen OP, et al. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled trial. Biol Psychiatry 2003;54(11):1241-8.

20. Kremer I, Vass A, Gurelik I, et al. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol Psychiatry 2004;56(6):441-6.

21. Drapalski AL, Rosse RB, Peebles RR, et al. Topiramate improves deficit symptoms in a patient with schizophrenia when added to a stable regimen of antipsychotic medication. Clin Neuropharmacol 2001;24:290-4.

22. Millson RC, Owen JA, Lorberg GW, Tackaberry L. Topiramate for refractory schizophrenia. Am J Psychiatry 2002;159(4):675.-

23. Chouinard G, Beauclair L, Belanger MC. Gabapentin: long term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders. Can J Psychiatry 1998;43:305.-

24. Megna JL, Devitt PJ, Sauro MD, Dewan MJ. Gabapentin’s effect on agitation in severely and persistently mentally ill patients. Ann Pharmacother 2002;35:12-16.

25. Jablonowski K, Margolese HC, Chouinard G. Gabapentin-induced paradoxical exacerbation of psychosis in a patient with schizophrenia. Can J Psychiatry 2002;47(10):975-6.

26. Baird P. The interactive metabolism effect of oxcarbazepine coadministered with tricyclic antidepressant therapy for OCD symptoms. J Clin Psychopharmacol 2003;23(4):419.-

27. Centorrino F, Albert MJ, Berry JM, et al. Oxcarbazepine: clinical experience with hospitalized psychiatric patients. Bipolar Disord 2003;5(5):370-4.

28. Leweke FM, Gerth CW, Koethe D, et al. Oxcarbazepine as an adjunct for schizophrenia. Am J Psychiatry 2004;161(6):1130-1.

29. Stahl SM. Psychopharmacology of anticonvulsants: do all anticonvulsants have the same mechanism of action? J Clin Psychiatry 2004;65(2):149-50.

30. Ketter TA, Wong PW. The emerging differential roles of GABAergic and antiglutaminergic agents in bipolar disorders. J Clin Psychiatry 2003;64(suppl 3):15-20.

31. Wassef A, Baker J, Kochan LD. GABA and schizophrenia: a review of basic science and clinical studies. J Clin Psychopharmacol 2003;23(6):601-40.

Initial double-blind, RCTs of adjunctive valproate in patients with schizophrenia were limited in size and failed to show benefit with adjunctive valproate^12-15 (Table 2). A more recent study¹⁶ showed that adjunctive valproate affects acute psychotic symptoms rather than mood. This study, however, did not answer whether adjunctive valproate would help patients with persistent symptoms of schizophrenia.

Table 2

Double-blind studies of adjunctive carbamazepine in schizophrenia

Author (yr)	n	Duration (days)	Design	Diagnosis	Outcome
Neppe (1983)	11	42	Crossover	Mixed, 8 with schizophrenia	“Overall clinical rating” improved
Dose et al (1987)	22	28	HAL + CBZ vs HAL + placebo	Schizophrenia or schizoaffective disorder	No difference on BPRS
Okuma et al (1989)	162	28	NL + CBZ vs NL + placebo	Schizophrenia or schizoaffective disorder	No difference on BPRS; possible improvement in suspiciousness, uncooperativeness, and excitement
Nachshoni et al (1994)	28	49	NL + CBZ vs NL + placebo	“Residual schizophrenia with negative symptoms”	No difference on BPRS or SANS
Simhandl et al (1996)	42	42	NL + CBZ vs NL + lithium vs NL + placebo	Schizophrenia(treatment- nonresponsive)	No difference on BPRS; CGI improved from baseline in groups receiving CBZ and lithium
n = number of subjects
BPRS = Brief Psychiatric Rating Scale
CGI = Clinical Global Impression scale
CBZ = carbamazepine
HAL = haloperidol
NL = neuroleptic (first-generation antipsychotic)
SANS = Scale for the Assessment of Negative Symptoms

In this large (n = 249), multicenter, randomized, double-blind trial, hospitalized patients with an acute exacerbation of schizophrenia received olanzapine or risperidone plus divalproex or placebo for 28 days. Patients with schizoaffective disorder and treatment-resistant schizophrenia were excluded.

By day 6, dosages reached 6 mg/d for risperidone and 15 mg/d for olanzapine. Divalproex was started at 15 mg/kg and titrated to a maximum of 30 mg/kg by day 14. Mean divalproex dosage was approximately 2300 mg/d (mean plasma level approximately 100 mg/mL).

Positive and Negative Syndrome Scale (PANSS) total scores improved significantly in patients receiving adjunctive divalproex compared with those receiving antipsychotic monotherapy, and significant differences occurred as early as day 3. The major effect was seen on schizophrenia’s positive symptoms. A post-hoc analysis¹⁷ also showed greater reductions in hostility (as measured by the hostility item in the PANSS Positive Subscale) in patients receiving adjunctive divalproex compared with antipsychotic monotherapy. This effect was independent of the effect on positive symptoms or sedation.

A large, multi-site, 84-day acute schizophrenia RCT similar to the 28-day trial—but using extended-release divalproex—is being conducted. An extended-release preparation may be particularly helpful in encouraging medication adherence for patients taking complicated medication regimens.

Table 3

Double-blind studies of adjunctive valproate in schizophrenia

Author (yr)	n	Duration (days)	Design	Diagnosis	Outcome
Ko et al (1985)	6	28	Crossover	Neurolepticresistant patients with chronic schizophrenia, not exacerbation	No valproate effect noted
Fisk and York (1987)	62	42	Antipsychotic + valproate vs antipsychotic + placebo	Chronic psychosis and tardive dyskinesia	No differences in mental state and behavior, as measured by“ Krawiecka scale”*
Dose et al (1998)	42	28	HAL + valproate vs HAL + placebo	Acute, nonmanic schizophrenic or schizoaffective psychosis	No difference on BPRS; possible effect on “hostile belligerence”
Wassef et al (2000)	12	21	HAL + valproate vs HAL + placebo	Acute exacerbation of chronic schizophrenia	CGI and SANS scores improved significantly, but BPRS scores did not
Casey et al (2003)	249	28	RIS + valproate vs OLZ + valproate vs RIS + placebo vs OLZ + placebo	Acute exacerbation of schizophrenia	PANSS scores improved
* Krawiecka M, Goldberg D, Vaughan M. A standardized psychiatric assessment scale for rating chronic psychotic patients. Acta Psychiatr Scand 1977;55(4):299-308.
n = number of subjects
BPRS = Brief Psychiatric Rating Scale
CGI = Clinical Global Impression scale
HAL = haloperidol
OLZ = olanzapine
PANSS = Positive and Negative Syndrome Scale
RIS = risperidone
SANS = Scale for the Assessment of Negative Symptoms

In a recent large (n = 10,262), retrospective, pharmacoepidemiologic analysis,¹⁸ valproate augmentation led to longer persistence of treatment than did the strategy of switching antipsychotics. Average valproate dosages were small, however (<425 mg/d), as were antipsychotic dosages (risperidone <1.7 mg/d, quetiapine <120 mg/d, and olanzapine <7.5 mg/d). Patients’ diagnostic categories were not available. One interpretation of this study is that valproate augmentation would be more successful than switching antipsychotics, assuming that treatment persistence can be viewed as a positive outcome.

Table 4

Double-blind studies of adjunctive lamotrigine in schizophrenia

Author (yr)	n	Duration (days)	Design	Diagnosis	Outcome
Tiihonen et al (2003)	34	84	Crossover; clozapine with or without lamotrigine	Clozapine-resistant male inpatients with chronic schizophrenia, not exacerbation	BPRS, PANSS positive, and PANSS general psychopathology symptom scores improved Negative symptoms did not improve
Kremer et al (2004)	38	70	Antipsychotic* + lamotrigine vs antipsychotic* + placebo	Treatment- resistant inpatients with schizophrenia	Completers’ PANSS positive, general psychopathology and total symptom scores improved No difference in negative symptoms or total BPRS scores No difference with intent-to-treat analyses
n = number of patients
* First- or second-generation antipsychotic
BPRS = Brief Psychiatric Rating Scale
PANSS = Positive and Negative Syndrome Scale

Lamotrigine is the only other anticonvulsant for which published, double-blind, randomized evidence of use in patients with schizophrenia is available (Table 4).^19,20 Adjunctive lamotrigine may be effective in managing treatment-resistant schizophrenia, as was shown in a small (n = 34), double-blind, placebo-controlled, crossover trial.¹⁹ Hospitalized patients whose symptoms were inadequately controlled with clozapine monotherapy received lamotrigine, 200 mg/d, for up to 12 weeks. Adjunctive lamotrigine improved positive but not negative symptoms.