Evidence-Based Reviews

When Clozapine is not enough: Augment with lamotrigine?

Current Psychiatry. 2009 January;8(1):41-46

John A. Gray, MD, PhD

Samuel C. Risch, MD

Stabilizing glutamate transmission may benefit some patients with treatment-resistant schizophrenia

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References

1. Gray JA, Roth BL. The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007;12(10):904-922.

2. Agid Y, Buzsaki G, Diamond DM, et al. How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov. 2007;6(3):189-201.

3. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem. 2004;11(3):313-327.

4. Miller AL, McEvoy SP, Jeste DV, et al. Treatment of chronic schizophrenia. In: Lieberman JA, Stroup TS, Perkins DO, eds. Textbook of schizophrenia. Arlington, VA: American Psychiatric Publishing; 2006:365-381.

5. Miller AL. Combination treatments for schizophrenia. CNS Spectr. 2004;9(9 suppl 9):19-23.

6. Premkumar TS, Pick J. Lamotrigine for schizophrenia. Cochrane Database Syst Rev. 2006;(4):CD005962.-

7. Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK lamotrigine/carbamazepine monotherapy trial group. Lancet. 1995;345(8948):476-479.

8. Buckley P, Miller A, Olsen J, et al. When symptoms persist: clozapine augmentation strategies. Schizophr Bull. 2001;27(4):615-628.

9. Chan YC, Miller KM, Shaheen N, et al. Worsening of psychotic symptoms in schizophrenia with addition of lamotrigine: a case report. Schizophr Res. 2005;78(2-3):343-345.

10. Konstantakopoulos G, Oulis P, Koulouris GC, et al. Lamotrigine-associated exacerbation of positive symptoms in paranoid schizophrenia. Schizophr Res. 2008;98(1-3):325-326.

11. Messenheimer J, Mullens EL, Giorgi L, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Saf. 1998;18(4):281-296.

12. Smith D, Baker G, Davies G, et al. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia. 1993;34(2):312-322.

13. Post RM, Ketter TA, Denicoff K, et al. The place of anticonvulsant therapy in bipolar illness. Psychopharmacology (Berl). 1996;128(2):115-129.

14. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 study group. J Clin Psychiatry. 1999;60(2):79-88.

15. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 study group. J Clin Psychiatry. 2000;61(11):841-850.

16. Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003;60(4):392-400.

17. Large CH, Webster EL, Goff DC. The potential role of lamotrigine in schizophrenia. Psychopharmacology (Berl). 2005;181(3):415-436.

18. Goff DC, Coyle JT. The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am J Psychiatry. 2001;158(9):1367-1377.

19. Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004;9(11):984-997.

20. Chohan MO, Iqbal K. From tau to toxicity: emerging roles of NMDA receptor in Alzheimer’s disease. J Alzheimers Dis. 2006;10(1):81-87.

21. Konradi C, Heckers S. Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther. 2003;97(2):153-179.

22. Leach MJ, Baxter MG, Critchley MA. Neurochemical and behavioral aspects of lamotrigine. Epilepsia. 1991;32(suppl 2):S4-S8.

23. Anand A, Charney DS, Oren DA, et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: support for hyperglutamatergic effects of n-methyl-D-aspartate receptor antagonists. Arch Gen Psychiatry. 2000;57(3):270-276.

24. Deakin JF, Lees J, McKie S, et al. Glutamate and the neural basis of the subjective effects of ketamine: a pharmaco-magnetic resonance imaging study. Arch Gen Psychiatry. 2008;65(2):154-164.

25. Large CH. Do NMDA receptor antagonist models of schizophrenia predict the clinical efficacy of antipsychotic drugs? J Psychopharmacol. 2007;21(3):283-301.

26. Dursun SM, Deakin JF. Augmenting antipsychotic treatment with lamotrigine or topiramate in patients with treatment-resistant schizophrenia: a naturalistic case-series outcome study. J Psychopharmacol. 2001;15(4):297-301.

27. Dursun SM, McIntosh D, Milliken H. Clozapine plus lamotrigine in treatment-resistant schizophrenia. Arch Gen Psychiatry. 1999;56(10):950.-

28. Saba G, Dumortier G, Kalalou K, et al. Lamotrigine-clozapine combination in refractory schizophrenia: three cases. J Neuropsychiatry Clin Neurosci. 2002;14(1):86.-

29. Tiihonen J, Hallikainen T, Ryynanen OP, et al. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Biol Psychiatry. 2003;54(11):1241-1248.

30. Kremer I, Vass A, Gorelik I, et al. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Biol Psychiatry. 2004;56(6):441-446.

31. Akhondzadeh S, Mackinejad K, Ahmadi-Abhari SA, et al. Does the addition of lamotrigine to risperidone improve psychotic symptoms and cognitive impairments in chronic schizophrenia? Therapy. 2005;2(3):399-406.

32. Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol. 2007;27(6):582-589.

33. Zoccali R, Muscatello MR, Bruno A, et al. The effect of lamotrigine augmentation of clozapine in a sample of treatment-resistant schizophrenic patients: a double-blind, placebo-controlled study. Schizophr Res. 2007;93(1-3):109-116.

34. Lieberman JA, Perkins DO, Jarskog LF. Neuroprotection: a therapeutic strategy to prevent deterioration associated with schizophrenia. CNS Spectr. 2007;12(3 suppl 4):1-13.

Current antipsychotics are reasonably effective in treating positive symptoms, but they do less to improve the negative and cognitive symptoms¹ that contribute to patients’ long-term poor functional capacity and quality of life.² So what do psychiatrists do in clinical practice to mitigate antipsychotics’ limitations? We augment.

Schizophrenia patients routinely are treated with polypharmacy—often with antidepressants or anticonvulsants—in attempts to improve negative symptoms, aggression, and impulsivity.³ Most adjuncts, however—including divalproex, antidepressants, and lithium—have shown very small, inconsistent, or no effects.^4,5 The only agent with a recent meta-analysis supporting its use as augmentation in treatment-resistant schizophrenia is lamotrigine,⁶ an anticonvulsant approved for use in epilepsy.⁷

This article examines the evidence supporting off-label use of lamotrigine as an augmenting agent in schizophrenia and explains the rationale, based on lamotrigine’s probable mechanism of action as a stabilizer of glutamate neurotransmission.

Is lamotrigine worth trying?

Some 20% of schizophrenia patients are considered treatment-resistant, with persistent positive symptoms despite having undergone ≥2 adequate antipsychotic trials.⁸ Evidence suggests clozapine then should be tried,⁴ but approximately one-half of treatment-resistant patients do not respond to clozapine. Treatment guidelines are limited for these 10% of schizophrenia patients with an inadequate response to available therapies, including clozapine.⁴

Clinical Point

Evidence does not support routine use of lamotrigine in patients taking antipsychotics other than clozapine

In a meta-analysis of 5 controlled trials in patients with treatment-resistant schizophrenia, adjunctive lamotrigine was shown to significantly reduce Positive and Negative Syndrome Scale (PANSS) total scores, positive symptom subscores, and negative symptom subscores.⁶ In these trials, lamotrigine was added to various antipsychotics, including clozapine. Based on the results—as outlined below—we suggest:

In treatment-resistant patients with residual symptoms while taking clozapine, lamotrigine given in dosages ≥200 mg/d could be a first-line adjunct (Figure 1).
Lamotrigine augmentation also might help patients whose positive symptoms are adequately controlled but who have persistent negative and/or cognitive symptoms.
Evidence does not support routine use of lamotrigine in patients taking antipsychotics other than clozapine.

Managing side effects. Lamotrigine is generally well tolerated; in the meta-analysis, nausea was the only side effect more common with lamotrigine (9%) than with placebo (3.9%).⁶ Close follow-up is required, however, as a few case reports have noted worsening positive symptoms when lamotrigine was added to antipsychotics.^9,10

Lamotrigine produces a skin rash in approximately 10% of patients; the rash usually is benign but may be severe, including the potentially fatal Stevens-Johnson syndrome.¹¹ In the meta-analysis, rash was no more likely in patients receiving placebo (3%) than those receiving lamotrigine (2.2%), and no serious rashes were reported.⁶ Even so, lamotrigine needs to be titrated upwards very slowly over weeks, and patients must be able to monitor for rash.

Figure 1 An evidence-based approach to treatment-resistant schizophrenia

Treatment-resistant schizophrenia is defined as residual positive symptoms after ≥2 adequate antipsychotic trials. Evidence supports trying clozapine as the next step.⁴ When patients show an inadequate response to clozapine, a meta-analysis of 5 controlled trials⁶ indicates that lamotrigine may be a useful first-line adjunct.

Why consider lamotrigine?

During clinical trials of lamotrigine for epilepsy, patients showed improved mood¹² as is seen with other anticonvulsants such as valproate and carbamazepine.¹³ A series of randomized trials then demonstrated lamotrigine’s effectiveness in treating patients with bipolar I disorder, especially during depressive episodes,^14,15 and the FDA approved lamotrigine for maintenance treatment of bipolar I disorder.¹⁶ In those early studies, lamotrigine also improved bipolar patients’ quality of life and cognitive function in addition to showing mood-stabilizing properties.¹²

The glutamate hypothesis. Lamotrigine is an inhibitor of voltage-gated sodium channels and has been shown to inhibit the excessive synaptic release of glutamate.¹⁷ Glutamate is the primary excitatory neurotransmitter for at least 60% of neurons in the brain, including all cortical pyramidal neurons. A large body of evidence implicates dysfunctional glutamate signaling in the pathophysiology of schizophrenia.¹⁸

For example, phencyclidine (PCP) and ketamine—antagonists of one subtype of glutamate receptor, the N-methyl-D-aspartate (NMDA) receptor—are well known to produce positive psychotic symptoms, negative symptoms, and cognitive dysfunction.¹⁹ This led to a long-held hypothesis that schizophrenia is caused by too little glutamate. However, ketamine and PCP also increase the release of glutamate at synapses that then can act on glutamate receptors other than the NMDA receptor, which suggests that too much glutamate also may be involved in schizophrenia.

Too little or too much glutamate? These competing hypotheses could both be at least partially true, suggesting an “inverted-U” pattern of glutamate signaling (Figure 2). Because glutamate is involved in most cortical functions, too little glutamate can cause cognitive and processing deficits such as those seen in schizophrenia. On the other hand, too much glutamate can be toxic to neurons and may be a factor in neurodegeneration, such as in Alzheimer’s disease.²⁰ Indeed, schizophrenia may be associated with gradual neurodegeneration.²¹