Faculty Bibliography

Evidence from lesioning studies and neuroimaging has linked negative symptoms to dysfunction of the prefrontal cortex, the limbic system, and the basal ganglia. Although such symptoms have been most strongly associated with dopaminergic hypoactivity in the prefrontal cortex, other neurotransmitters including norepinephrine, serotonin, and the excitatory amino acids may also play a role. In some patients moderate doses of conventional neuroleptics clearly improve negative symptoms; the response of such symptoms is relatively greater with clozapine and probably with certain serotonin-dopamine antagonists. Recent studies demonstrating improvement of negative symptoms when conventional neuroleptics are augmented with selective serotonin-reuptake inhibitors or with agents active at the glycine-modulatory site of the glutamatergic N-methyl-D-aspartate receptor complex suggest that further amelioration of primary negative symptoms may be possible through pharmacological strategies involving multiple neurotransmitter systems.

Schizophrenic outpatients (62 females, 59 males) were evaluated to examine the relationships between menstrual status, gender, clinical measures of psychopathology and drug side effects. Menstrual status was determined for 55 female patients. Blood from 44 female subjects, drawn before the AM dose of neuroleptic, was assayed for prolactin concentrations. In 27 premenopausal women (age < 45 years), six (22%) reported irregular menses and one (4%) reported amenorrhea. Women with irregular menses did not differ in their prolactin levels or neuroleptic dose, from women with regular menses. Amenorrheic women (n = 22) were significantly older than men (n = 59) and menstruating women (n = 33). After controlling for age, menstruating women did not differ in clinical measures of psychopathology, drug side effects, or neuroleptic dose compared to amenorrheic women or men. Comparison of 15 age-matched pairs of menstruating females and amenorrheic females revealed significantly lower levels of akathisia and depression in the menstruating group and a trend towards lower serum prolactin concentrations (P = 0.08). In female subjects, prolactin levels correlated significantly with neuroleptic dose (r = 0.36, P < 0.005). Our results only partially support hypothesized relationships between menstrual status, prolactin levels and neuroleptic effects and serve to emphasize the importance of controlling for age when comparing these clinical variables.

The excitatory amino acids, glutamate and aspartate, are of interest to schizophrenia research because of their roles in neurodevelopment, neurotoxicity and neurotransmission. Recent evidence suggests that densities of glutamatergic receptors and the ratios of subunits composing these receptors may be altered in schizophrenia, although it is unclear whether these changes are primary or compensatory. Agents acting at the phencyclidine binding site of the NMDA receptor produce symptoms of schizophrenia in normal subjects, and precipitate relapse in patients with schizophrenia. The improvement of negative symptoms with agents acting at the glycine modulatory site of the NMDA receptor, as well as preliminary evidence that clozapine may differ from conventional neuroleptic agents in its effects on glutamatergic systems, suggest that clinical implications may follow from this model. While geriatric patients may be at increased risk for glutamate-mediated neurotoxicity, very little is known about the specific relevance of this model to geriatric patients with schizophrenia.

OBJECTIVE: The effects of D-cycloserine added to clozapine were assessed and compared with previous results for D-cycloserine plus conventional neuroleptics. METHOD: Ten schizophrenic outpatients receiving clozapine entered consecutive 2-week trials of placebo and D-cycloserine at 5, 15, 50, and 250 mg/day. Clinical evaluations were videotaped and scored by a rater blind to the sequence of assessments. RESULTS: There was a significant dose effect of D-cycloserine on scores on the Scale for the Assessment of Negative Symptoms (SANS); the 50-mg dose produced a mean 21% increase in SANS score. The patients had significantly higher baseline serum glutamate concentrations than the patients receiving typical neuroleptics in the previous trial. Baseline glutamate level and change in glycine level significantly correlated with response of negative symptoms to 50-mg D-cycloserine. CONCLUSIONS: The improvement of negative symptoms with D-cycloserine previously observed in patients receiving typical neuroleptics did not occur in patients treated with clozapine.

BACKGROUND: Some treatment-resistant schizophrenic patients improve enough to remain out of the hospital but continue to have significant positive or negative symptoms. METHOD: The goal of this study was to assess the safety and potential efficacy of risperidone as an adjunct for schizophrenic patients treated with clozapine. In an open 4-week trial involving 12 DSM-III-R-diagnosed patients, the addition of risperidone to clozapine was well tolerated and did not affect serum clozapine concentrations significantly. RESULTS: Total Brief Psychiatric Rating Scale (BPRS) scores and subscales measuring positive symptoms, negative symptoms, and depressive symptoms were significantly reduced from baseline. Ten of 12 participants had a 20% or greater reduction in the total BPRS score. CONCLUSION: In this open trial, the addition of risperidone to clozapine was well tolerated and produced significant reduction of symptoms, suggesting that this may be a useful clinical approach. Because this was an open trial, the improvement we observed must be replicated in a controlled trial.

Clozapine, used in the treatment of patients with schizophrenia resistant to other neuroleptic medication, is metabolized by the hepatic microsomal system to demethyl-clozapine and clozapine-N-oxide. Changes in clozapine serum concentrations have been documented after initiation of therapy with medications known to induce or inhibit liver microsomal enzymes. These interactions are of clinical importance when diminished efficacy or increased toxic effects of clozapine therapy occur. A 34-year-old schizophrenic man had increased clozapine serum concentrations, leukocytosis, and adverse effects as a result of concomitant erythromycin therapy given for suspected lower respiratory tract infection. Symptoms included somnolence, difficulty in coordination and ambulation, slurred speech, disorientation, and incontinence. The symptoms resolved after treatment with clozapine and erythromycin were discontinued, and treatment with clozapine was gradually resumed.

Although low levels of social support have been related to mortality from coronary heart disease, little is known about the role of social support among Mexican Americans. The authors therefore examined the relationship between social support and long-term survival in the Corpus Christi Heart Project. They developed a social support scale that used data collected during in-hospital interviews of 292 Mexican Americans and 304 non-Hispanic Whites who survived a myocardial infarction for more than 28 days. The scale incorporated three measures: marital status; if not married, whether living alone; and whether advised to seek help. During an average follow-up period of 43 months, 115 participants died. Survival following myocardial infarction was greater for those with high or medium social support than for those with low social support. With age, gender, ethnicity, education, employment, smoking, diabetes, hypertension, and hypercholesterolemia included in a proportional hazards regression model, the relative risk of mortality was 1.89 (95% CI, 1.20-2.97) for those with low social support. But when the two ethnic groups were analyzed separately, low social support was no longer a significant predictor of mortality for non-Hispanic Whites, whereas for Mexican Americans, the relative risk of mortality was 3.38 (95% CI, 1.73-6.62) for those with low social support.

OBJECTIVE: This study was undertaken to assess the relationships among CSF concentrations of substrates of mitochondrial energy metabolism, neuroleptic medication, and neurological side effects. METHOD: CSF was obtained from 25 patients with schizophrenia; seven were unmedicated and 11 had tardive dyskinesia. CSF concentrations of four substrates of mitochondrial energy metabolism (Krebs cycle)--alanine, aspartate, lactate, and pyruvate--were determined. Tardive dyskinesia was measured with the Abnormal Involuntary Movement Scale (AIMS), and parkinsonism was measured with the Simpson-Angus Rating Scale. RESULTS: CSF concentrations of alanine were significantly elevated in the medicated patients when tardive dyskinesia status was controlled for. CSF aspartate concentrations were significantly elevated in patients with tardive dyskinesia when medication status was controlled for and were significantly correlated with total scores on the AIMS. CONCLUSIONS: These results are consistent with a model linking neuroleptic-induced neurological side effects with impairment of mitochondrial energy metabolism, possibly mediated by inhibition of complex 1 of the electron transport chain.

OBJECTIVE: The authors conducted a dose-finding study of D-cycloserine, a partial agonist at the glycine site of the N-methyl-D-aspartate subtype of the glutamate receptor, added to conventional neuroleptics for schizophrenic patients with prominent negative symptoms. METHOD: Nine patients with schizophrenia completed consecutive 2-week trials of placebo and four doses of D-cycloserine. Clinical assessments were videotaped and were scored by a rater who was blind to temporal sequence. RESULTS: D-Cycloserine at a dose of 50 mg/day produced a significant reduction (mean = 21%, SD = 28%) in negative symptoms and significantly improved reaction time as measured by Sternberg's Item Recognition Paradigm, a test mediated in part by prefrontal cortex. CONCLUSIONS: This preliminary evidence suggests that D-cycloserine may improve negative symptoms and cognitive deficits over a narrow dose range when added to conventional antipsychotic agents.