When Clozapine is not enough: Augment with lamotrigine?
Stabilizing glutamate transmission may benefit some patients with treatment-resistant schizophrenia
Figure 2 Inverted U-curve may explain dysfunctional glutamate signaling in schizophrenia
Both too little or too much glutamate may play a role in schizophrenia’s pathophysiology. Glutamate, the major excitatory neurotransmitter of the cerebral cortex, is involved in most cognitive functions. Too little (or glutamate inhibition) can impair cognition, whereas too much can lead to seizures, neurotoxicity, and cell death.
Glutamate stabilization?
Because lamotrigine prevents excessive glutamate release at synapses, it stabilizes neuronal membranes by preventing toxicity from too much glutamate without interfering with glutamate’s normal functions.22 Thus, lamotrigine may have potential to maintain optimal glutamate signaling in patients with schizophrenia.
In 16 healthy volunteers, a 300-mg dose of lamotrigine was significantly more effective than placebo in reducing ketamine-induced positive symptoms, as assessed by the Brief Psychiatric Rating Scale positive symptoms subscale (P < .001). Lamotrigine pretreatment also reduced negative symptoms and improved learning and memory.23
More recently, lamotrigine pretreatment was shown to prevent many ketamine-induced changes on functional MRI.24 Few antipsychotics have clinically significant effects on ketamine-induced symptoms—especially in a single dose—although repeated dosing with clozapine attenuates some ketamine-induced effects.25
Given the limitations of available antipsychotics, adding a drug such as lamotrigine—which may modulate and stabilize the glutamate system—could be effective in treatment-resistant schizophrenia.
What is the evidence?
Case reports and open-label case series first showed that lamotrigine augmentation could be effective in treatment-resistant schizophrenia patients receiving clozapine.26–28 One naturalistic case series also included patients receiving olanzapine or risperidone and suggested greater improvement with lamotrigine augmentation in patients on clozapine.26
Controlled trials. In a placebo-controlled trial, Tiihonen et al29 reported significantly lower ratings of positive symptoms—but not negative symptoms—after 38 treatment-resistant schizophrenia patients on clozapine received adjunctive lamotrigine, 200 mg/d, for 14 weeks (Table 1).
A subsequent controlled trial in which Kremer et al30 added lamotrigine, ≤400 mg/d, showed significant improvements in positive and negative symptoms among 31 treatment-resistant schizophrenia patients who completed the 10-week study. Patients were taking conventional and atypical antipsychotics, including clozapine. All groups improved, but the study was not powered to detect differences among the groups.
Table 1
Lamotrigine augmentation: 5 double-blind, placebo-controlled trials
| Trial duration | Patient diagnosis (number) | Antipsychotic(s) | Lamotrigine (mg/d) | Results |
|---|---|---|---|---|
| 14 weeks (Tiihonen et al, 200329) | Treatment-resistant schizophrenia (n=34) | Clozapine | 200 | Significantly reduced psychosis ratings, with no significant improvement in negative symptoms |
| 10 weeks (Kremer et al, 200430) | Treatment-resistant schizophrenia (n=38) | Conventional and atypical, including clozapine | ≤400 | Significant improvements with all antipsychotics, especially clozapine, in positive and negative symptoms* |
| 8 weeks (Akhondzadeh et al, 200531) | Schizophrenia (n=36) | Risperidone | 150 | Significant improvement in negative symptoms and cognition; less improvement in positive symptoms |
| 12 weeks, multicenter (Goff et al, 200732) | Schizophrenia, schizoaffective patients with residual symptoms (n=217+212) | Conventional and atypical, including clozapine | 100 to 400 | No significant improvement in any symptom domain; improved negative symptoms only in study 1 and cognitive symptoms only in study 2 |
| 24 weeks (Zoccali et al, 200733) | Treatment-resistant schizophrenia (n=51) | Clozapine | ≤200 | Significant improvement in positive and negative symptoms as well as some cognitive symptoms |
| * Significance achieved only in study completers, not in the last-observation-carried-forward analysis | ||||
A third trial by Akhondzadeh et al,31 augmenting risperidone with lamotrigine, 150 mg/d, resulted in modest improvements in negative and cognitive symptoms and slight improvement in positive symptoms.
Multicenter trials. Preliminary trials led to 2 randomized, double-blind, multicenter studies. In a total of 429 schizophrenia outpatients with residual psychotic symptoms on atypical antipsychotics, lamotrigine, 100 to 400 mg/d, or placebo was added for 12 weeks.32 The combined results failed to show significant improvement with adjunctive lamotrigine in any symptom domain compared with placebo. One study showed some improved negative symptoms, and the other showed improved cognitive symptoms.
Possible reasons for these negative results were unclear, although:
- a relatively large placebo response, compared with other studies, suggests a “failed” clinical trial
- the small number of patients receiving clozapine in this study suggests that they may have been less treatment-resistant than those enrolled in prior studies.
Meta-analysis. A meta-analysis of data from these 5 randomized, controlled trials found the “positive, negative, and general psychopathology subscale scores as measured with the PANSS … showed significant difference favoring adjuvant lamotrigine” (Table 2).6 As for study limitations, the authors noted that effectiveness data could be usefully analyzed in <70 of the 537 patients from the controlled trials, and “the small mean decrease in scores may not be really clinically relevant.”6 Thus, they said, caution is warranted in translating these results to clinical practice.
One more trial. Since the meta-analysis, an additional placebo-controlled trial has been reported.33 In this 24-week trial, lamotrigine augmentation, ≤200 mg/d, was statistically more effective than placebo in reducing positive and negative symptoms in 51 stable treatment-resistant patients on clozapine. Cognitive function also improved.
