Neuroleptic-induced seizures. An in vitro technique for assessing relative risk.

To estimate the relative risk of various neuroleptic medications for patients with epilepsy or likely to have neuroleptic-induced seizures, their action on spike activity in perfused guinea pig hippocampal slices was studied. Within the range of concentrations studied, molindone hydrochloride, butaclamol hydrochloride, pimozide, and fluphenazine dihydrochloride produced the least increase in excitability. There were also differences in the dose-response curves. Chlorpromazine, thioridazine, and pimozide produced an inverted U-shaped curve. For haloperidol and fluphenazine, excitability tended to increase and them plateau. Molindone and butaclamol produced no increase in excitability. Combinations of neuroleptics had synergistic effects, while the anticonvulsant diazepam inhibited neuroleptic-induced excitability. This article discusses the clinical implications of these findings and their effect on theories of which neuroleptics might produce the fewest seizures.

Schizophrenia: evidence of a subgroup with reversed cerebral asymmetry.

Normal right-handed individuals often show neuroanatomical asymmetries of the brain on computed tomography (CT), with wider right frontal and left occipital lobes. We examined the frequency of reversals of this normal asymmetry in a group of 57 right-handed, the schizophrenic patients. Compared to 80 normal right-handeders, the schizophrenics had an increased frequency of both frontal and occipital reversals. We then divided the patients on the basis of whether they had CT evidence suggestive of brain atrophy. Those without evidence of atropy had increased frontal and occipital reversals. Those with evidence of atrophy had no increase in reversals. This suggests that reversals of neuroanatomical asymmetry, and by implication abnormalities of lateralization, are relevant to a subgroup of schizophrenic patients with otherwise normal CT scans.

Psychotic exacerbations and enhanced vasopressin secretion in schizophrenic patients with hyponatremia and polydipsia.

BACKGROUND: For unclear reasons, life-threatening water intoxication often coincides with acute psychosis in polydipsic schizophrenic patients with chronic hyponatremia. In contrast, most polydipsic schizophrenic patients are normonatremic and never manifest hyponatremia. To explore whether the effect of acute psychosis on water balance differs in these 2 schizophrenic subgroups, we compared their responses to drug-induced psychotic exacerbations. METHODS: Matched polydipsic schizophrenic patients with (n = 6) and without (n = 8) hyponatremia were identified based on past and current indexes of fluid intake and hydration. A transient psychotic exacerbation was induced with an infusion of the psychotomimetic methylphenidate hydrochloride (0.5 mg/kg of body weight over a 60-second period). Antidiuretic hormone levels, subjective desire for water, and factors known to influence water balance were measured at 15-minute intervals for 2 hours. RESULTS: Except for the expected differences in plasma osmolality and sodium, basal measures were similar in the 2 groups. Following methylphenidate administration, antidiuretic hormone levels increased more in the hyponatremic patients (P < .02), despite their consistently lower plasma osmolality (P < .007). No known or putative antidiuretic hormone stimulus could account for this finding. Only basal positive psychotic symptoms (P < .09) and plasma sodium (P < .18) were even marginally associated with the peak antidiuretic hormone responses, but neither factor could explain the difference in the response by the 2 groups. CONCLUSION: Psychotic exacerbations are associated with enhanced antidiuretic hormone secretion, for unknown reasons, in schizophrenic patients with hyponatremia and polydipsia, thereby placing them at increased risk of life-threatening water intoxication.

The influence of polydipsia on water excretion in hyponatremic, polydipsic, schizophrenic patients.

To determine whether polydipsia is responsible for the altered water excretion in the subset of polydipsic schizophrenic patients who develop hyponatremia, the regulation of antidiuretic function was assessed in polydipsic schizophrenic patients with hyponatremia (n = 5), polydipsic schizophrenic patients without hyponatremia (n = 5), nonpolydipsic schizophrenic patients (n = 6), and normal controls (n = 8). The severity and duration of polyuria were similar in the two polydipsic groups. After oral water loading, maximal free water clearance was similar across all four groups. Free water clearance diminished, however, at lower plasma osmolalities in the hyponatremic polydipsics (P < 0.02) and at higher plasma osmolalities in the normonatremic polydipsics (P < 0.05) relative to that in the nonpolydipsic schizophrenics and normal subjects. The increase in plasma vasopressin after osmotic stimulation with hypertonic saline was slightly, but significantly (P < 0.02), blunted in both polydipsic groups. Hyponatremia occurs in some polydipsic schizophrenics because the relationship between free water clearance to plasma osmolality/sodium is shifted to the left. Polydipsia per se is not responsible for this still unexplained shift.

A possible role of hippocampal dysfunction in schizophrenic symptomatology.

The author proposes a pathogenesis for the bizarre, repetitive behaviors frequently seen in deteriorated schizophrenics, i.e., polydipsia, hoarding, pacing, etc. It is argued that such behaviors may have a neurobiology similar to schedule-induced behaviors or incentive-conditioned behaviors described in animal models, which involve the hippocampus, nucleus accumbens, and the neurotransmitter dopamine. Such behaviors are augmented by hippocampal lesions, stress, increased drive state, or dopaminergic agents, and reduced by 6-OH dopamine lesions to nucleus accumbens or antipsychotic agents. These repetitive behaviors may reflect the failure of hippocampus to modulate the impact of mesolimbic dopaminergic activity on the nucleus accumbens and thus on motor behavior. Such a hypothesis is consistent with a growing body of neuropathological and brain imaging results demonstrating hippocampal lesions in chronic schizophrenics.

Demeclocycline improves hyponatremia in chronic schizophrenics.

Serum sodium concentration increased significantly in eight hyponatremic schizophrenic subjects treated with demeclocycline. The incidence of severe hyponatremic episodes was significantly reduced. The authors argue that mild impairments in urinary dilution contribute to water intoxication in most chronic psychotics who develop this syndrome. Demeclocycline may help these patients.

Serum dopamine-beta-hydroxylase activity and lateral ventricular size in affective disorders and schizophrenia.

Previous studies have reported a significant negative correlation between cerebrospinal fluid DBH activity and ventricular brain ratio (VBR) in schizophrenic patients. We now report a significant negative correlation between log serum DBH activity and VBR in 28 patients with major depression (r = -0.41, p = 0.04); this correlation was also negative (r = -0.15), but not significant, in 46 schizophrenics. Eight patients (five schizophrenic, three affective disorder) with increased VBR had significantly lower serum DBH activity than the patients with normal VBR. The relationship between low CSF or serum DBH activity and increased VBR may be manifestations of the polygenetic vulnerability common to the major psychoses.

Lateral ventricular size, psychopathology, and medication response in the psychoses.

Using computed tomography, lateral ventricular size was determined in 45 schizophrenic and 22 affective disorder patients, and was found in both patient groups to be greater than that of 62 similarly aged headache controls. While drug-free, the 15 schizophrenics with ventricles 1 standard deviation greater than the age-corrected control mean tended to have less positive symptomatology than the 30 schizophrenics with smaller ventricles. There was no differences between these two schizophrenic groups in negative symptomatology. Amongst the depressed affective disorder patients, those with larger ventricles tended to be diagnosed as psychotic more often than those with smaller ventricles. Response to neuroleptic treatment was assessed in the 35 schizophrenics who had received conventional neuroleptics for at least 5 weeks. Those schizophrenics with ventricles 2 standard deviations greater than the age-corrected control mean showed less improvement than those with smaller ventricles and on some measures appeared to deteriorate. No such relationship between ventricle size and drug response could be detected in the affective disorder patients.

Anterior medial temporal lobe volumes in polydipsic schizophrenic patients with and without hypo-osmolemia: a pilot study.

The volume of certain brain structures, particularly those in the anterior medial temporal lobe, may be reduced to a greater extent in hyponatremic/hypo-osmolemic polydipsic schizophrenics than other schizophrenic patients. To explore if volume reduction is specific to this particular brain region, and if it is fundamentally associated with polydipsia, we imaged the anterior hippocampi/subicula and adjacent temporal lobes in normal males (n = 10) and polydipsic schizophrenic patients with (n = 7) and without (n = 6) hypo-osmolemia. Bilateral hippocampal/subicular (p < .01), but not temporal lobe (p < .30), volumes were diminished in the hypo-osmolemics relative to the other two groups, who resembled each other on these measures. No recognized or putative factor could explain these findings. Thus anterior medial temporal lobe structures appear to be preferentially diminished in hypo-osmolemic polydipsic schizophrenics. Additional studies are needed to more precisely define these anatomic differences and their relationship to these patients' impaired water excretion and severe mental illness.

Ex uno multi: subtyping the schizophrenic syndrome.

We studied 93 chronic schizophrenic inpatients, who met the Research Diagnostic Criteria for schizophrenia. Data on a number of historical, epidemiologic, phenomenologic, biochemical, neuropathological, and treatment-response variables were analyzed, using univariate and multivariate statistical analyses. Patients were classified into pairs of subgroups, according to each of the following seven dimensions: (1) ventricle/brain ratio (VBR) assessed on computed tomography scans (normal vs. abnormal); (2) premorbid adjustment (good vs. poor); (3) therapeutic response to neuroleptics (good vs. poor); (4) platelet monoamine oxidase (MAO) activity (low vs. high); (5) paranoid features (present vs. absent); (6) tardive dyskinesia (present vs. absence); and (7) hemispheric asymmetry on computed tomography scans (normal vs. abnormal). These seven dimensions were chosen because earlier studies had shown that the variables involved were operationally definable and were of potential relevance to the subgrouping of schizophrenic patients. Our results suggested that two biological variables, viz., VBR and platelet MAO activity, might be useful in identifying two rather distinct subgroups among chronic schizophrenic patients. A subgroup with large VBR was associated with poor premorbid adjustment, neurological impairment, and poor therapeutic response to neuroleptics, while the subgroup with low platelet MAO activity was characterized by the presence of paranoid features and tardive dyskinesia. Possible explanations, implications, and limitations of our findings are discussed.

Review of clinical and animal studies comparing the cardiovascular effects of doxepin and other tricyclic antidepressants.

On the basis of early reports suggesting that doxepin has fewer cardiovascular effects than do other tricyclic antidepressants, doxepin continues to be recommended for the treatment of depression in cardiac patients and in the elderly. However, these reports have been criticized, and other evidence has suggested opposite conclusions. To clarify this issue, the author reviewed clinical and animal studies and found that, in general, doxepin has an effect comparable to the effects of other tricyclic antidepressants on cardiac conduction, cardiac rhythm, heart rate, blood pressure, and cardiac mechanics.

Fatal agranulocytosis in a chronic schizophrenic patient treated with carbamazepine.

A chronic schizophrenic patient developed a fatal agranulocytosis 1 month after beginning to take carbamazepine for aggression. Routine hematological monitoring was not carried out. This case highlights the need for psychiatrists' increased awareness of the possible hematological complications of carbamazepine.

Depression in the spouses of demented patients.

The authors present three cases of depression requiring hospitalization in spouses of patients with progressive dementia. They discuss the stress of caring for demented people and the need for clinicians to inquire about depressive symptoms in care givers.

Prevention of episodic water intoxication with target weight procedure.

An effective, practical, and inexpensive method of preventing water intoxication in inpatients is described. The procedure uses the relationship between acute changes in body water and body weight to predict body weights associated with severe hyponatremia.

Late-life onset of panic disorder with agoraphobia in three patients.

Although the onset of panic disorder with agoraphobia is usually thought to occur in early adulthood, the authors describe three cases in which onset occurred after age 65.

Differential memory function with dopaminergic versus anticholinergic treatment of drug-induced extrapyramidal symptoms.

Nine chronic schizophrenic patients being treated with high-potency antipsychotic medication and antiparkinsonian agents were enrolled in a double-blind, crossover trial comparing amantadine and trihexyphenidyl. Memory function was assessed with the Rey Auditory-Verbal Learning Test during each 6-week drug trial. The subjects performed significantly better while receiving amantadine. Examinations of computed tomographic studies of seven subjects revealed a significant inverse correlation between ventricle size and memory while they were taking trihexyphenidyl but not amantadine. This suggests that patients with underlying brain pathology may be particularly vulnerable to the memory-disrupting effects of anticholinergic agents.

Alteration in the recommended dosing schedule for risperidone.

OBJECTIVE: The authors' goal was to study the recommended dose schedule for risperidone. METHOD: They obtained computerized pharmacy data on 1,283 inpatients with the diagnoses of schizophrenia or schizoaffective disorder who were treated with risperidone. Continuance on risperidone was defined as remaining on the drug for 16 days or until discharge. RESULTS: The majority of the patients (84%) continued on resperidone. Use of the recommended dose schedule decreased greatly over time. Patients were more likely to continue on risperidone if they had a higher maximum dose (5.7 mg/day versus 4.7 mg/day), a longer number of days to maximum dose (5.7 days versus 3.9 days), and a maximum rise in dose of 0.5-2 mg/day. CONCLUSIONS: These findings suggest that the recommended dose schedule should be altered to one that recommends a less rapid titration (over 6 days to a week) and that the dose increments consist of 0.5-2 mg/day.

Schizophrenia and cerebral asymmetry detected by computed tomography.

The authors nonblindly assessed occipital cerebral asymmetry on computed tomography (CT) scans of 79 schizophrenic or schizoaffective patients and 100 neurological or medical patients. More of the schizophrenic patients had reversals of the normal asymmetry than did controls. The schizophrenics with CT evidence of brain atrophy has a higher frequency of normal asymmetrics than did controls, and the schizophrenics without atrophy had more reversed asymmetries. The schizophrenics with reversed asymmetry, compared with those with normal asymmetry, had lower verbal than performance IQ. Comparison of occipital asymmetry and lateral ventricular asymmetry indicated that reversed asymmetry in the schizophrenic patients was probably not due to localized atrophy.

The role of cholinergic supersensitivity in the medical symptoms associated with withdrawal of antipsychotic drugs.

From a review of the clinical literature, the authors determined that the medical symptoms of neuroleptic withdrawal occurred more frequently with neuroleptics having potent anticholinergic effects than with those having weak anticholinergic actions. When antiparkinsonian agents were not simultaneously withdrawn, there was a striking difference between these two categories of neuroleptics. Experiments with mice showed that withdrawal of haloperidol, a neuroleptic with weak anticholinergic effects, produced subsensitivity (depression of locomotor activity and seizure thresholds) to the cholinergic effects of physostigmine. These findings support the theory that the medical side effects of neuroleptic withdrawal are due to rebound cholinergic hypersensitivity associated with the anticholinergic actions of these drugs, rather than being related to their dopamine-blocking activity.

Maintenance of training effects on the Wisconsin Card Sorting Test by patients with schizophrenia or affective disorders.

The authors used the Wisconsin Card Sorting Test to study 50 hospitalized psychiatric patients: 28 with schizophrenia, 17 with affective disorders, and five with schizoaffective disorder. The schizophrenic patients performed significantly more poorly than the patients with affective disorders. Both groups of patients improved when given additional instructions. The schizophrenic patients maintained their improvement when retested approximately 6 weeks later. The results suggest that factors other than frontal cortex dysfunction are involved in schizophrenic patients' performance on the Wisconsin Card Sorting Test.