Lack of effect of laboratory-provoked anxiety on plasma homovanillic acid concentration in normal subjects.

The present study was undertaken to investigate if acute anxiety can affect plasma concentrations of homovanillic acid (pHVA). Since elevated pHVA levels have been associated with severity of schizophrenic symptoms, the results of this study will help determine if the pHVA elevations are directly related to psychosis or if anxiety is also a contributory factor. Anxiety was provoked in 10 young normal subjects by a combined paradigm of mental arithmetic task and threat of electrical shock. A significant increase in self-ratings of anxiety, blood pressure, and plasma levels of norepinephrine, 3-methoxy-4-hydroxyphenylethyleneglycol and growth hormone indicated that the paradigm used was effective in provoking anxiety; however, anxiety did not affect pHVA concentrations. The results may support the notion that increased pHVA levels in severely ill schizophrenic patients are related to the schizophrenic pathophysiology rather than to anxiety.

Acute effects of haloperidol on cerebral cortex blood flow in normal and schizophrenic subjects.

To evaluate the effects of neuroleptic medications on cerebral blood flow (CBF), cortical perfusion was quantified by the 133xenon technique in 8 unmedicated schizophrenics and 9 healthy controls before, and 1 and 3 hours after, administration of haloperidol (5 mg per os). At 3 hours, the normal subjects, but not schizophrenic patients, showed a significant increase in global mean perfusion (17 +/- 13%). Changes in CBF were not associated with plasma haloperidol levels or the presence of extrapyramidal side effects, and remained significant after controlling for pCO2. The lack of change in CBF in schizophrenic patients following acute haloperidol administration may be due to prior neuroleptic exposure, absence of anxiety, or other nonspecific factors, or may reflect a more fundamental feature of underlying pathophysiology in schizophrenia.

4-Aminopyridine in the treatment of Alzheimer's disease.

The cognitive and behavioral effect of 4-aminopyridine (4-AP) was examined in Alzheimer's disease (AD) using a dose finding/replication study design. Fourteen inpatients, aged 54-89 years (mean 66.1 +/- 10.6 SD), meeting NINCDS criteria for probable AD, were studied. Three doses of 4-AP--2.5 mg b.i.d., 5 mg b.i.d., and 10 mg b.i.d.--or placebo were administered for 4 consecutive days in random order. Symptomatic assessment was performed on the fourth day of each condition using the Alzheimer Disease Assessment Scale (ADAS). Thereafter, the dose on which the best performance occurred was readministered, as was placebo. Of the 13 patients who completed the dose-finding phase, 7 patients had at least one dose of 4-AP that was associated with less severe symptoms than was placebo, and those patients were included in the replication phase. Results indicated no significant difference in total ADAS scores (p greater than 0.05). Examination of the ADAS subscales revealed no significant 4-AP effect on any particular symptom. Possible explanations of the lack of a drug effect in this study include the unselective release of neurotransmitters by 4-AP, poor penetration into the central nervous system (CNS), and the presenile onset of the disease in these patients.

RS 86 in the treatment of Alzheimer's disease: cognitive and biological effects.

Twelve patients who met Research Diagnostic Criteria for Alzheimer's disease (AD) completed a double-blind crossover study comparing oral RS 86, a long-acting and specific muscarinic agonist, with placebo. Cognitive and noncognitive effects were assessed with the Alzheimer's Disease Assessment Scale (ADAS). RS 86 was found to improve ADAS test scores consistently (both cognitive and noncognitive subscales) in seven patients, with a clinically obvious improvement in only two patients. RS 86 produced a significant increase in peak nocturnal cortisol levels, and this increase correlated with improvement on ADAS testing. Similarly, there was a 38% increase in amplitude of the P300 evoked potential with RS 86. The biological findings suggest that RS 86 was effective only to the extent that it enhanced central cholinergic activity.

Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior.

OBJECTIVE: The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients. METHOD: Twenty-eight actively psychotic inpatients, aged 20-60 years, who were under treatment with neuroleptic agents were selected for the study. Each was randomly assigned on a double-blind basis to receive either 5 mg i.m. of haloperidol (N=13) or 1 mg i.m. of flunitrazepam (N=15) during an aggressive event. Verbal and physical aggression was measured over time with the Overt Aggression Scale. Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale. RESULTS: Both flunitrazepam and haloperidol exhibited acute antiaggressive activity. This beneficial effect, as assessed by the Overt Aggression Scale, was obtained within 30 minutes. CONCLUSIONS: Intramuscular flunitrazepam may serve as a convenient, rapid, safe, and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric settings.

Senile degeneration and cognitive impairment in chronic schizophrenia.

OBJECTIVE: This study was an investigation of the role of Alzheimer-type senile degenerative abnormalities in the cognitive impairment of chronic schizophrenia. METHOD: The study group comprised 145 deceased elderly institutionalized psychiatric patients: 66 with schizophrenia, 26 with mood disorders, 36 with dementia, and 17 with other psychiatric diagnoses. The comparison group included 16 deceased elderly individuals without neurologic or psychiatric disease. Psychiatric diagnoses and cognitive status were established by standardized review of medical records. Neuritic senile plaques and neurofibrillary tangles were identified immunohistochemically and counted, by investigators blind to clinical information, in standardized regions of each brain. RESULTS: Of the subjects with schizophrenia, 68% had definite cognitive impairment, but only 8% satisfied neuropathological criteria for Alzheimer's disease. Among the schizophrenia subjects without Alzheimer's disease, definite cognitive impairment was associated with higher levels of plaques and tangles. The schizophrenia subjects without definite cognitive impairment had fewer plaques and tangles than the unimpaired nonpsychiatric subjects. CONCLUSIONS: Most cases of cognitive impairment in schizophrenia could not be attributed to Alzheimer's disease. An association of mild Alzheimer-type pathology with definite cognitive impairment was unique to schizophrenia. Enhanced sensitivity to the effects of aging on the brain may be a manifestation of diminished cognitive reserve in schizophrenia.

Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients.

Fifty-nine elderly residents of long-term care facilities who had DSM-III diagnoses of dementia were studied in an 8-week randomized, double-blind comparison trial of haloperidol, oxazepam, and diphenhydramine to test the efficacy of these agents in the treatment of clinically significant behavioral disturbances in patients with dementia. All three agents demonstrated modest but significant efficacy as measured by clinician ratings of agitated behavior and activities of daily living. The absolute magnitude of improvement was greater for haloperidol and diphenhydramine than for oxazepam, but differences among groups did not approach statistical significance. Frequencies of acute adverse events during the trial were similar across the drug treatment groups. Although these drugs may differ in terms of long-term safety and efficacy, they appear to be equivalent for short-term management of agitated behavior in severely demented patients.

Eye tracking impairment in clinically identified patients with schizotypal personality disorder.

Eye tracking accuracy, which has been found to be impaired in schizophrenic patients and their relatives, was assessed in 26 patients with schizotypal personality disorder, 17 control subjects with other non-schizophrenia-related personality disorders, 29 normal control subjects, and 44 schizophrenic patients. Both schizotypal and schizophrenic patients, but not control subjects with other personality disorders, demonstrated significantly more impaired tracking than the normal control subjects. These results suggest that patients with clinically defined schizotypal personality disorder may be biologically related to schizophrenic patients as part of a spectrum of schizophrenia-related disorders.

Sexual dysfunction in male schizophrenic patients.

BACKGROUND: Neuroleptic treatment in schizophrenic patients is associated with sexual dysfunction. However, it is not clear to what extent the psychiatric disorder and/or the pharmacologic treatment are responsible for the sexual impairment. The aim of the present study was to evaluate the sexual function of untreated and treated male schizophrenic patients in comparison with healthy subjects. METHOD: Participants included 122 male subjects: 20 drug-free schizophrenic patients, 51 neuroleptic-treated (depot form) schizophrenic patients, and 51 normal controls. A detailed structured interview was used to quantitatively and qualitatively assess sexual function. RESULTS: A high frequency of sexual dysfunction was reported by both schizophrenic groups of patients. Impairments in arousal items (erection) and orgasm during sex were reported mainly by the treated patients. Desire parameters were reduced in both schizophrenic groups, but reduction in the frequency of sexual thoughts was confined to the untreated one. The schizophrenic patients were more involved in masturbatory activity in comparison with the control subjects. Treated patients disclosed dissatisfaction with their sexual function. CONCLUSION: Untreated schizophrenic patients exhibit decreased sexual desire. Neuroleptic treatment is associated with restoration of sexual desire yet it entails erectile, orgasmic, and sexual satisfaction problems. Clinicians' awareness and open discussion of sexual problems with patients may improve comprehension and compliance.

Painful ejaculation associated with antidepressants in four patients.

BACKGROUND: Painful ejaculation associated with tricyclic antidepressants is rarely reported in the medical literature. METHOD: Painful ejaculation following the administration of imipramine and clomipramine is described in four patients. RESULTS: The phenomenon occurred in all patients during the first 3 weeks of treatment and disappeared within several days when the tricyclic dosage was reduced or the medication was withdrawn. CONCLUSION: Painful ejaculation was apparently evoked by tricyclic antidepressant administration. Clinicians should be aware of this underreported side effect.

The active uptake of serotonin by platelets of schizophrenic patients and their families: possibility of a genetic marker.

The active uptake of serotonin (5-HT) blood platelets of 20 schizophrenic patients and their families was studied. The uptake was studied over a wide range of 5-HT concentrations (0.1-20 microM), and Km and Vmax of the uptake process were calculated. Of 20 patients, 18 exhibited a lower rate of uptake than the family average at 5-HT concentrations lower than the Km value. At a 5-HT concentration of 0.1 microM, the average 5-HT uptake of patients was 2.15 pmol/10(8) platelets/min, while that of families was 2.99 pmol/10(8) platelets/min (33% difference). At a high 5-HT concentration, only the drug-treated patients had lower Vmax than the family average, and this might be attributed to the effect of the drugs. Km of patients and families were very similar. In eight families, one or more of the family members showed 5-HT uptake patterns very similar to that of the patient. We termed these healthy family members "schizophrenic risks". Our findings indicate the involvement of some genetic factors in this disease.

Increased uptake of serotonin by blood platelets from patients with bipolar primary affective disorder-bipolar type.

Active uptake of serotonin (5-HT) by blood platelets with bipolar primary affective disorder-bipolar type has been compared to that of their family members and healthy controls, and Km and Vmax values were calculated for each subject. The uptake of patients' platelets, as reflected by Vmax, was found to be significantly higher than that of healthy controls (P less than 0.05) and non significantly higher than that of family members (P less than 0.05). The average value obtained (in pmol/10(8) platelets/5 min) were 253.4 (patients), 199.7 (families), and 171.5 (controls). The increased uptake by patients' platelets was not dependent on the state of disease. In two families, daughters of the patients exhibited the same uptake pattern as their ill mothers. The Km values for patients, family members, and controls were all about 1.06 x 10(-6) M. This study raises the possibility that the differences between patients and healthy individuals might be attributed to genetic factors. The meaning and interpretation of the findings are discussed.

Acute administration of alprazolam has no effect on plasma homovanillic acid concentration in normal subjects.

Alprazolam has been suggested as an adjuvant to neuroleptic drugs in the treatment of schizophrenic patients. In an attempt to investigate whether alprazolam has an effect on dopaminergic neurotransmission, plasma homovanillic acid concentrations were measured for 24 h following a challenge with 3 mg of alprazolam or placebo in eight healthy subjects. Alprazolam had no effect on plasma homovanillic acid which may suggest that this agent is devoid of activity at the dopaminergic system in normal subjects.

Reliability of post-mortem chart diagnoses of schizophrenia and dementia.

The reliability of psychiatric diagnosis has a direct effect on the validity of post-mortem analyses of neuropathological data, yet little is known about the reliability of retrospective diagnostic procedures which rely on review of medical records. In this paper, we report on the reliability of DSM-III-R psychiatric diagnoses assigned by a pool of 8 raters to a set of 106 state hospital charts of elderly, chronic patients who had died while institutionalized and were autopsied. Diagnoses were grouped by general diagnostic class, and Kappa coefficients computed for agreement among raters, as well as for agreement between ultimate consensus diagnoses and those made while subjects were living. Interrater agreement for those diagnoses that occurred most frequently in this sample (e.g. Schizophrenia and Dementia) was excellent, and comparable to the the agreement observed for ratings of live patients. Interrater agreement for less frequently occurring diagnoses (e.g. Mental Retardation, Mood Disorders, other non-Schizophrenic Psychoses) ranged from excellent to poor. We found high agreement between our rates diagnoses and those assigned by state hospital personnel while patients were living, although post-mortem review produced lower rates of diagnosis of both schizophrenia and Alzheimer-type dementias. Overall, results suggest that the reliability of chart review diagnosis is comparable to that obtained from interviews of live patients when experienced raters are used and diagnostic base rates are high enough to produce stable estimates of reliability.

Elevated adhesiveness/aggregation of peripheral blood leukocytes in patients with major depression.

A simple slide test was used to determine the effects of major depression (MD) and heterocyclic antidepressants on leukocyte adhesiveness/aggregation (LAA) in the peripheral blood. Eighty subjects were categorized into four equal groups: untreated-MD patients, treated-MD patients, nondepressed patients treated with antidepressants and healthy controls. Significantly higher LAA values were observed both in untreated- and treated-MD patients, 13.8+/-1.7% and 13.5+/-1.9% respectively, compared to nondepressed-treated patients and healthy controls, 5.4+/-0.9% and 6.4+/-0.7% respectively (P < 0.0001). Increased LAA was associated with the depressive episode, was not affected by antidepressants and may potentially serve as a useful laboratory state marker for MD.

Cyproheptadine treatment of sexual dysfunction induced by serotonin reuptake inhibitors.

Treatment of serotonin reuptake inhibitors (SRIs) is associated with sexual dysfunction. The cause of this dysfunction is unclear but may be related to stimulation of the serotonergic system. In the present article, we describe seven patients in whom iatrogenic sexual dysfunction induced by SRIs was treated with cyproheptadine, a 5HT-2 antagonist with antihistaminergic and adrenolytic properties. Seven obsessive-compulsive male patients, aged 29-54 years, who developed sexual dysfunction following treatment with SRIs (fluoxetine, fluvoxamine, and clomipramine) were instructed to take cyproheptadine (4-12 mg) 1-2 h before commencing sexual activity. Five of the seven patients displayed improvement in sexual function, although the improvement was transitory in two. The two remaining patients did not respond. All patients exhibited sedation on the day following cyproheptadine administration. Our preliminary observation suggests that some patients with sexual dysfunction associated with SRI treatment, mainly decreased libido and anorgasmia, may benefit from cyproheptadine administration. The role of 5HT-2 antagonists in SRI-induced sexual dysfunction merits further investigation.

Lithium and male sexual function in affective patients.

The aim of the present study was to evaluate sexual function and behaviour in male patients who take lithium. Participants included 35 bipolar and schizoaffective men, aged 43.3 +/- 9.6 years, who were in euthymic state and were receiving lithium as the sole medical treatment. Eleven patients (31.4%) reported sexual dysfunction on at least two items of the sexual function questionnaire. Notable results were reduction in frequency of sexual thoughts and loss of erection during sex in 23 and 20% of patients, respectively. Difficulties in achieving and maintaining erections (ease of arousal) were reported in 14% of patients. Nevertheless, almost all patients reported preserved pleasure during sexual activity and were satisfied with their sexual performance. There was no difference in serum lithium levels in patients with and without sexual dysfunction. No statistical correlation was found between sexual function scores and serum lithium levels. Lithium therapy may impair desire and arousal, yet it does not appear to have a major impact on patient self-satisfaction or subjective sense of pleasure during sexual activity. The degree of sexual dysfunction as reported in the present study was not a source of distress to patients and did not cause noncompliance.

The serotonin antagonist mianserin for treatment of serotonin reuptake inhibitor-induced sexual dysfunction in women: an open-label add-on study.

The aim of this study was to determine if the serotonin antagonist mianserin improves antidepressant-induced sexual dysfunction in women. The work was prompted by an earlier study of men by our team of researchers. The study population included 16 women aged 20-65 years undergoing treatment at a psychiatric outpatient clinic, who presented with sexual dysfunction subsequent to intake of a serotonin reuptake inhibitor (SRI) for depression. Sexual function (four domains) was evaluated by semistructured interviews before and after the administration of mianserin 15 mg/d for 3 weeks. The most prominent sexual dysfunction was anorgasmia. Clinically significant improvement was noted in all domains in two thirds of the patients, in most cases in the first or second week of treatment. None of the patients with panic disorder (PD) responded to mianserin, in contrast to those with affective disorder or obsessive compulsive disorder (OCD), indicating a possible relevance of the psychiatric diagnosis to mianserin effectiveness. There were no major adverse effects and no changes in the patients' stabilized psychiatric status. We conclude that mianserin is beneficial in reversing sexual function caused by SRI intake. Further large-scale, placebo-controlled studies are needed to confirm these findings.

Effect of amantadine on sexual dysfunction in neuroleptic-treated male schizophrenic patients.

Twelve male schizophrenic outpatients treated with neuroleptics took part in an open-label drug study to assess the impact of co-administration of amantadine hydrochloride (100 mg daily for 6 weeks) on sexual function. Amantadine improved the patients' scores in three out of four areas of sexual function: desire (p < 0.02), erection (p < 0.05), and satisfaction from sexual performance (p < 0.05); there was no change in ejaculatory function. Amantadine may be effective for improving sexual function in male schizophrenic patients receiving neuroleptic medication.

Mianserin, a 5-HT2a/2c and alpha 2 antagonist, in the treatment of sexual dysfunction induced by serotonin reuptake inhibitors.

Sexual dysfunction is commonly encountered in patients treated with antidepressants. The exact mechanism responsible for the sexual impairment is as yet unclear, although activation of the serotonergic system has been implicated. In the present study, we examined the effect of the 5-HT2a/2c and alpha 2 antagonist mianserin in the treatment of patients with sexual dysfunction induced by serotonin reuptake inhibitors (SRIs). Mianserin 15 mg was coadministered to 15 male subjects with new-onset sexual dysfunction who were under treatment with SRIs. Four major domains of sexual activity-desire, erection, orgasm, and satisfaction-were assessed once weekly for 4 weeks. At the end of the study, 9 of the 15 subjects reported a marked improvement in their sexual functioning, 2 reported partial improvement, and only 4 subjects showed no improvement at all. The beneficial effects were prominent in the areas of orgasm and satisfaction and were usually noted within the first and second week of mianserin treatment. The addition of mianserin to the treatment regimen was not associated with either improvement or worsening of the basic psychiatric clinical status. It appears that the coadministration of low-dose mianserin may be an additional option in the treatment of sexual dysfunction induced by SRIs.