Faculty Bibliography

OBJECTIVE: To review the literature on efficacy and risks of combining antipsychotics (atypical with atypical or conventional) and suggest a rationale and strategies for future clinical trials. METHOD: A computerized Medline search supplemented by an examination of cross-references and reviews was performed. RESULTS: Empirical evidence for the efficacy of combining antipsychotics is too limited to draw firm conclusions. The practice of augmenting clozapine with more 'tightly bound' D2 receptor antagonists as exemplified by risperidone augmentation of clozapine has some empirical and theoretical support. The risks of augmentation strategies have not been studied systematically. No study has examined the economic impact of combination treatment. CONCLUSION: Further trials of antipsychotic combination therapies are needed before this currently unsupported practice can be recommended. Rationales for combination treatment include a broadening of the range of receptor activity or an increase in D2 receptor occupancy with certain atypical agents. Trial methodology needs to take into account subject characteristics, duration of treatment, optimization of monotherapy comparators, and appropriate outcome measures.

OBJECTIVE: Recognition memory is impaired in patients with schizophrenia, as they rely largely on item familiarity, rather than conscious recollection, to make mnemonic decisions. False recognition of novel items (foils) is increased in schizophrenia and may relate to this deficit in conscious recollection. By studying pictures of the target word during encoding, healthy adults can suppress false recognition. This study examined the effect of pictorial encoding on subsequent recognition of repeated foils in patients with schizophrenia. METHOD: The study included 40 patients with schizophrenia and 32 healthy comparison subjects. After incidental encoding of 60 words or pictures, subjects were tested for recognition of target items intermixed with 60 new foils. These new foils were subsequently repeated following either a two- or 24-word delay. Subjects were instructed to label these repeated foils as new and not to mistake them for old target words. RESULTS: Schizophrenic patients showed greater overall false recognition of repeated foils. The rate of false recognition of repeated foils was lower after picture encoding than after word encoding. Despite higher levels of false recognition of repeated new items, patients and comparison subjects demonstrated a similar degree of false recognition suppression after picture, as compared to word, encoding. CONCLUSIONS: Patients with schizophrenia displayed greater false recognition of repeated foils than comparison subjects, suggesting both a decrement of item- (or source-) specific recollection and a consequent reliance on familiarity in schizophrenia. Despite these deficits, presenting pictorial information at encoding allowed schizophrenic subjects to suppress false recognition to a similar degree as the comparison group, implying the intact use of a high-level cognitive strategy in this population

BACKGROUND: D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor has previously been shown to improve negative symptoms when added to conventional antipsychotics and to worsen negative symptoms when added to clozapine. The purpose of this study was to examine the effects of D-cycloserine when added to risperidone on negative symptoms of schizophrenia. METHOD: Ten patients with schizophrenia who were treated with risperidone completed consecutive two 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 50mg/day was associated with significant reduction in negative symptoms (mean=10%). Ratings of depression, extrapyramidal side effects, and cognitive function were unchanged. Serum concentrations of glutamate and serine increased significantly on this dose of D-cycloserine. CONCLUSIONS: This preliminary study suggests that combination of D-cycloserine, 50mg/day, with risperidone may improve negative symptoms of schizophrenia over a narrow dose range. The degree of improvement appears to be intermediate between improvement of negative symptoms observed with combination of D-cycloserine with conventional antipsychotics and worsening of negative symptoms observed with combination of D-cycloserine with clozapine in previous trials of identical design

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a method to examine cortico-cortical motor excitability and hemispheric asymmetry in unmedicated and medicated schizophrenia patients. METHODS: Fourteen right-handed schizophrenia patients (seven on conventional neuroleptics and seven medication-free) were compared with seven right-handed, age- and gender-matched normal control subjects. Motor threshold for induction of motor-evoked potentials (MEPs) and bihemispheric intracortical inhibition and facilitation were measured with single-pulse and paired-pulse TMS. RESULTS: Medicated patients showed an approximately 5% higher motor thresholds in both hemispheres than unmedicated patients and control subjects. Normal control subjects had a nearly 10% higher threshold for the left than the right hemisphere, whereas the opposite was true for the patient groups (5-10% higher threshold on the right than the left). Medicated patients showed significantly decreased intracortical inhibition relative to unmedicated patients and control subjects. This difference was more pronounced for the right than for the left hemisphere. CONCLUSIONS: Treatment with conventional neuroleptics is associated with increased motor threshold and decreased intracortical inhibition, whereas unmedicated patients did not differ from normal control subjects on these measures; however, schizophrenia may be characterized by a reversed pattern of interhemispheric corticospinal excitability

BACKGROUND: Schizophrenic patients have executive function deficits, presumably on the basis of prefrontal cortex dysfunction. Although they consistently show impaired inhibition, the evidence of a task switching deficit is less consistent and is often based on performance of neuropsychological tests that require several cognitive processes (e.g., the Wisconsin Card Sort Test [WCST]). We investigated inhibition and task switching using saccadic tasks to determine whether schizophrenic patients have selective impairments of these executive functions. METHODS: Sixteen normal and 21 schizophrenic subjects performed blocks of randomly mixed prosaccade and antisaccade trials. This gave rise to four trial types: prosaccades and antisaccades that were either repeated or switched. Response accuracy and latency were measured. Schizophrenic subjects also performed the WCST. RESULTS: Schizophrenic subjects showed abnormal antisaccade and WCST performance. In contrast, task switching was normal and unrelated to either antisaccade or WCST performance. CONCLUSIONS: The finding of intact task switching performance that is unrelated to other measures of executive function demonstrates selective rather than general impairments of executive functions in schizophrenia. The findings also suggest that abnormal WCST performance is unlikely to be a consequence of deficient task switching. We hypothesize that inhibition and task switching are mediated by distinct neural networks, only one of which is dysfunctional in schizophrenia

Evidence implicating dysfunction of glutamatergic neurotransmission rests largely on the finding that antagonists of the NMDA subtype of glutamate receptor, especially the dissociative anesthetics like ketamine, can reproduce the full range of symptoms as well as the physiologic manifestation of schizophrenia such as hypofrontality, impaired prepulse inhibition and enhanced subcortical dopamine release. To test the hypothesis that schizophrenia may result from NMDA receptor hypofunction a number of clinical trials have examined the effects of agents that act on the glycine modulatory site on the NMDA receptor. Glycine, D-serine, and the partial agonist, D-cycloserine, have been shown to improve cognition and decrease negative symptoms in schizophrenic subjects receiving typical antipsychotics. Results with D-cycloserine suggest that clozapine may enhance glycine modulatory site occupancy. Preliminary results with an allosteric modulator of the AMPA subtype of glutamate receptor suggest enhanced cognitive functions in subjects treated with clozapine

Executive functions allow us to respond flexibly rather than stereotypically to the environment. We examined two such functions, task switching and inhibition in the antisaccade paradigm, in two studies. One study involved 18 normal subjects; the other, 21 schizophrenic patients and 16 age-matched controls. Subjects performed blocks of randomly mixed prosaccades and antisaccades. Repeated trials were preceded by the same type of trial (i.e., an antisaccade following an antisaccade), and switched trials were preceded by a trial of the opposite type. We measured accuracy rate and latency as indices of processing costs. Whereas schizophrenic patients had a threefold increase in error rate for antisaccades compared to normals, the effect of task switching on their accuracy did not differ from that in normal subjects. Moreover, the accuracy rate of trials combining antisaccade and task switching was equivalent to a multiplication of the accuracy rates from trials in which each was done alone. Schizophrenic latencies were disproportionately increased for antisaccades, but again they were no different from normal subjects in the effect of task switching. In both groups the effect of task switching on antisaccades was a paradoxical latency reduction. We conclude that the executive dysfunction in schizophrenia is not generalized but selective, sparing task switching from exogenous cues, in which the switch is limited to a stimulus-response remapping. The accuracy data in both groups support independence of antisaccade and task-switching functions. The paradoxical task-switching benefit in antisaccadic latency effects challenges current models of task switching. It suggests either carryover inhibition by antisaccadic performance in the prior trial or facilitation of antisaccades by simultaneous performance of other cognitive operations

BACKGROUND: Recent evidence suggests that effects upon glutamatergic transmission may contribute to the therapeutic action of certain atypical antipsychotic agents. METHODS: Glutamate concentrations were measured in serum and were estimated (Glx/Cr) in cingulate cortex by proton magnetic resonance spectroscopy (MRS) in schizophrenia patients while they were being treated with conventional neuroleptics and then 8 weeks after switching to olanzapine. Serum glutamate concentrations were obtained from 11 subjects, and MRS estimates of Glx/Cr were available from 10 subjects at both time points. RESULTS: Serum glutamate concentrations significantly increased after the switch from conventional agents to olanzapine; brain glutamate (Glx/Cr) did not change significantly; however, brain glutamate (Glx/Cr) concentrations increased significantly in patients who exhibited an improvement in negative symptoms with olanzapine compared with patients with no change or worsening of negative symptoms. CONCLUSIONS: Comparisons performed following the switch from conventional agents to olanzapine are consistent with previous studies of clozapine and provide additional preliminary evidence supporting the hypothesis that effects on excitatory amino acid activity may contribute to olanzapine's efficacy for treating negative symptoms