Psychiatry has long struggled with the problem of how to understand the relationship between psychotic symptoms and mood symptoms. In the past, these debates were over conceptualizations of categories based on syndromal definitions of mental illnesses. Ample data now exists that provide insight into the biologic basis for syndromal distinctions. We examine the syndromes of mood disorder with psychotic features, schizoaffective disorder, and schizophrenia with mood features, reviewing their classification, clinical features, course, and treatment. We provide evidence that, clinically, mood disorders and schizophrenia do not separate neatly. We will also review data arising from studies in brain imaging, molecular neurobiology, and genetics. Evidence is accumulating that overlap across diagnostic boundaries for both pathologic and etiologic factors exist, along with disorder-specific factors. The nosology that will carve the reality of psychotic illness at the joints awaits further advances in genetics and neurobiology. Or, alternatively, carving out categories may turn out to be less useful for some purposes than considering dimensions.

Sir: Two studies have reported a substantial reduction of symptoms when the anticonvulsant drug lamotrigine was added to clozapine in patients with treatment-resistant schizophrenia.1,2 We report on 6 inpatients with persistent and severe psychotic symptoms who were treated for 24 weeks with a combination of lamotrigine and clozapine.Method. The study, which was conducted between December 2000 and August 2002, was approved by an independent medical ethics committee, and all patients gave informed consent. Four patients had a diagnosis of schizophrenia, and 2 patients had a diagnosis of schizoaffective disorder according to DSM-IV criteria. Their mean ± SD age was 47.2 ± 7.8 years. All had had therapeutic serum levels of clozapine for at least 6 months. Lamotrigine therapy was initiated at 12.5 mg/day and was titrated on the basis of tolerability and patients' symptoms, by no more than 25 mg/week. All other medication was kept as stable as possible. Symptoms were rated every 4 weeks by the Positive and Negative Syndrome Scale (PANSS) 3 during the 24-week trial.Results. Three patients were withdrawn from the study: 1 was removed after 6 weeks because of abuse of cannabis followed by an immediate deterioration of psychotic symptoms; 1, after 8 weeks owing to an increase in agitation and verbal aggression; and 1, after 12 weeks owing to complaints about sedation.Three patients completed the open clinical trial. Their mean ± SD maximum dose of lamotrigine was 116.7 ± 20.4 mg with a mean ± SD serum lamotrigine level of 1.80 ± 0.56 mg/L. Mean ± SD serum levels of clozapine decreased nonsignificantly from 409 ± 38 µg/L at baseline to 328 ± 102 µg/L at endpoint (t = 1.6, df = 2, p = .26).None of the 6 patients showed more than a 20% reduction in PANSS total score at endpoint or at any point during the trial. The mean ± SD PANSS total score decreased nonsignificantly in the last-observation-carried-forward analysis from 82.5 ± 13.6 at baseline to 81.7 ± 13.7 at endpoint (t = 0.28, df = 5, p = .79) and in the completer analysis from 83.0 ± 11.5 to 77.0 ± 5.0 (t = 1.5, df = 2, p = .27).Adding lamotrigine was not effective in our group of patients. Our findings contradict the prompt and substantial improvements reported in the open studies by Dursun et al. 1 and Saba et al. 2 It is not plausible to argue that we were too cautious with regard to the maximum lamotrigine doses (100-125 mg/day) because the mean serum lamotrigine level in responding patients (0.88 mg/L) in the study by Saba et al. 2 was lower than that in our nonresponders (1.80 mg/L). However, it should be stated that small studies are prone to both type I and type II errors.So far, there has been only 1 report of a double-blind, placebo-controlled trial in which lamotrigine was added to clozapine in treatment-resistant patients.4 Tiihonen et al., 4 like us, found no statistically significant change in PANSS total scores. However, they did report a statistically significant mean change of 1 point on the PANSS positive subscale. Although clinically this is a...

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