When Clozapine is not enough: Augment with lamotrigine?
Stabilizing glutamate transmission may benefit some patients with treatment-resistant schizophrenia
Table 2
How symptom scores changed with add-on lamotrigine in the meta-analysis of controlled trials
| PANSS subscales: Individual items scored 1 to 7, with 1=absent and 7=extreme | Change [95% CI]* |
|---|---|
| Positive symptom subscale (max 49) Delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness, hostility | -5.10 [-8.86, -1.34] |
| Negative symptom subscale (max 49) Blunted affect, emotional withdrawal, poor rapport, passive-apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking | -5.25 [-7.07, -3.43] |
| General psychopathology subscale (max 112) Somatic concern, anxiety, guilt feelings, tension, mannerisms and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance | -10.74 [-16.53, -4.96] |
| * See text for limitations of the meta-analysis | |
| CI: confidence interval; PANSS: Positive and Negative Syndrome Scale | |
| Source: Reference 6 | |
Only treatment-resistant patients?
In controlled trials, lamotrigine augmentation has had the greatest effect on positive and negative symptoms in treatment-resistant schizophrenia patients, especially those on clozapine. Could lamotrigine augmentation be of benefit only in treatment-resistant schizophrenia?
Analysis of trial findings. As mentioned, outpatients who comprised the majority of subjects in the 2 large “negative” (or possibly failed) trials32 might have been less treatment-resistant than subjects in the other trials. Lower mean lamotrigine dosages (205 mg/d and 241 mg/d) also were used in the 2 negative trials and in the trial by Akhondzadeh et al (150 mg/d)31—compared with up to 400 mg/d in the trial by Kremer et al.30 This suggests that insufficient dosing might have caused the nonsignificant findings.
Given schizophrenia’s heterogeneity, treatment-resistant patients may represent a subgroup that has greater glutamatergic dysfunction, whereas patients who respond more completely to antipsychotics may have greater dopaminergic dysfunction. Thus, lamotrigine augmentation might be more beneficial in the subset of treatment-resistant patients. Lamotrigine or other glutamate stabilizers have been proposed to act as neuroprotective agents, slowing functional decline in chronic schizophrenia34 (although long-term studies needed to test this hypothesis are unlikely to occur because of cost and time constraints).
Another hypothetical, yet intriguing, explanation for the greater effects of lamotrigine augmentation in patients on clozapine is a pharmacodynamic interaction between these 2 drugs. Clozapine (and possibly olanzapine) have been shown to enhance cortical glutamatergic transmission.25 We propose that clozapine-induced boosting of glutamate in concert with stabilization of the glutamate system by lamotrigine improves neuronal functioning. Clinical trial data regarding lamotrigine augmentation of antipsychotics other than clozapine are needed to determine if the relationship between clozapine and lamotrigine is unique.
Related resources
- Lamotrigine prescribing information and patient handout. www.lamictal.com/bipolar/hcp/prescibing_information. html.
- Augmentation strategies for schizophrenia. IPAP Schizophrenia algorithm flowchart (online interactive version), node 11. www.ipap.org/algorithms.php.
Drug brand names
- Carbamazepine • Carbatrol, Equetro, Tegretol
- Clozapine • Clozaril
- Divalproex • Depakote
- Ketamine • Ketalar
- Lamotrigine • Lamictal
- Olanzapine • Zyprexa
- Risperidone • Risperdal
- Valproate • Depacon, Depakene
Disclosures
Dr. Gray reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Risch receives research support from the National Institute of Mental Health and is a speaker for AstraZeneca and Pfizer Inc.
