N.P.Vasavan Nair

Apomorphine-induced penile tumescence in impotent patients — preliminary findings

Apomorphine (Apo), a short acting dopamine (DA) receptor agonist induces penile erections in normal subjects. The erectile response to one or more doses of Apo HCl (0.25, 0.5, 0.75, 1.0 mg sc) or placebo was investigated in eight impotent subjects and penile tumescence monitored using a mercury strain gauge and strip chart recording. Four patients showed a full erection with Apo and one a partial response. Distressing side effects (nausea, sweating) were associated with non-response or partial response. Three responders to Apo were treated with low doses of the long acting DA receptor agonist, bromocriptine (2.5-3.75 mg/d po); all three showed complete recovery of erectile function within two weeks. A subgroup of impotent patients may have impaired central DA function. Testing with Apo may provide a diagnostic and predictive test to identify such patients who may respond to treatment with low doses of bromocriptine or other DA receptor agonist.

Cholecystokinin appears to have antipsychotic properties.

1. According to a currently popular biological hypothesis schizophrenic symptoms are caused by a hyperactivity in dopaminergic neurotransmission. Since cholecystokinin (CCK) is a neuromodulator of dopaminergic neurotransmission, the effects of CCK (0.3 microgram/kg; given in a single dose intravenously) were studied in six chronic paranoid schizophrenic patients. 2. Following 3 baseline assessments on separate days, the effects of CCK treatment were assessed immediately after the injection, daily for one week and weekly thereafter for 5 weeks by the Brief Psychiatric Rating Scale (BPRS) and by the Schizophrenia Subscale of the Present State Examination (SS-PSE). 3. One way analysis of variance revealed statistically significant changes in all BPRS factors as well as in the nuclear syndrome and in the total score of the SS-PSE. Dunnetts tests revealed that the time at which the changes from baseline became statistically significant was as follows: anxiety-depression factor of the BPRS, immediately after the injection; anergia factor of the BPRS, by day 2; thought disturbance factor of the BPRS, immediately after; activation factor of the BPRS, immediately after; hostile-suspiciousness factor of the BPRS, by day 1; total BPRS score, immediately after; nuclear syndrome of the SS-PSE, by day 1; and total score of the SS-PSE, by day 1. 4. It is concluded that further controlled studies of the antipsychotic properties of CCK are warranted.

Apomorphine: clinical studies on erectile impotence and yawning.

1. The erectile response to the short-acting dopamine (DA) receptor agonist, apomorphine (Apo) HCl (0.25, 0.5, 0.75 and 1.0 mg sc), and placebo was evaluated in 28 impotent patients and penile circumference monitored using a mercury strain gauge and strip chart recording. 2. A full erection (increment in penile circumference greater than 2 cm and lasting at least one minute) occurred in 17 patients with Apo; no erection developed after placebo. An erection occurred in 6/8 patients with impaired glucose tolerance, 2/6 patients with diabetes mellitus and in both patients on lithium. 3. Nine patients who responded to Apo were treated in an open trial with bromocriptine; 6 reported improvement in potency. 4. Impairment in DA function may play a role in idiopathic impotence and in impotence associated with impaired glucose tolerance and diabetes mellitus. 5. An erectile response to Apo may predict therapeutic response to bromocriptine or other long acting dopaminergic agents. 6. Lithium, which inhibits DA-sensitive adenylate cyclase, does not prevent Apo-induced erections. This provides further support indicating that Apo induces erections by an effect on D2 receptors. 7. The yawning response to placebo and four doses of Apo HC1 (3.5, 5.0, 7.0, and 10.5 ug/kg sc) was evaluated in five normal men using a polygraphic technique. The yawning response was also assessed in normal young (less than 30 yrs; N = 16) and elderly (greater than 60 yrs; N = 12) volunteers. 8. Under experimental conditions of study, placebo induced spontaneous yawning. This was antagonized by 3.5 and 5.0 ug/kg Apo HC1 but increased by 7.0 ug/kg Apo HC1. These observations are compatible with the view that Apo HC1 in doses of 3.5-5.0 ug/kg stimulates presynaptic DA receptors whereas 7.0 ug/kg stimulates postsynaptic DA receptors. 9. Spontaneous and Apo-induced yawning were significantly decreased in the elderly which suggests that D2 receptor function declines with normal aging.

Cholecystokinin peptides, dopamine and schizophrenia — A review

CCK-IR is co-localized with DA in some DA neurons projecting to limbic structures. The extent of the co-localization is species dependent. The co-localization of CCK and DA is of interest in view of the DA hypothesis of schizophrenia and the putative role of limbic dysfunction in the pathophysiology of this disorder. In animals biochemical, electrophysiological and behavioural studies point to an interaction between CCK and DA. Whereas some investigations point to an inhibitory effect on DA function, which would be compatible with a potential antischizophrenic action, others point to an enhancement or no effect. CCK peptides show a neuroleptic-like profile in several screening tests for neuroleptics but not in all studies. In man there is endocrinological evidence for an inhibitory effect of CCK-33 and CCK-8 on DA function. However, alternate explanations are possible. CSF CCK-IR is unchanged or decreased in schizophrenia. Autopsy investigations have shown significant decreases, increases or no change in brain CCK-IR concentrations and a decrease in CCK-33 binding in schizophrenia. Eight of 11 clinical trials with CER, CCK-8 or CCK-33 have shown a therapeutic effect in schizophrenia; only two of these eight trials have been double-blind studies. The three controlled investigations which have shown no effect have used only small patient populations. None of the trials have used an active placebo. It is difficult to reconcile the apparent long duration of antipsychotic activity with the short half-life of the peptides and problems of the peptides in crossing the blood brain barrier. Despite these apparent anomalies information to date is sufficiently impressive to warrant further detailed investigation of CCK-DA-interactions and the evaluation of the clinical effects of a variety of CCK peptides and related compounds, natural and synthetic, which may more easily cross the blood brain barrier and which may show regional selectivity in site of action in brain.

Allostatic load associations to acute, 3-year and 6-year prospective depressive symptoms in healthy older adults

Allostatic load represents the strain that chronic stress exerts on interconnected biological systems. Associated algorithms are related to numerous deleterious physical outcomes in older populations, and yet few studies have assessed associations to mental health outcomes like geriatric depression. Using data from the Douglas Hospital Longitudinal Study of Normal and Pathological Aging, we assessed whether using an allostatic load index derived from seven biomarkers could detect self-rated depressive symptoms in 58 healthy older adults followed longitudinally over a 6-year period. Our results revealed that increased allostatic load was associated with increased depressive symptoms on the same year of assessment. After 3 years, AL was prospectively associated with depressive symptoms, but entering age and sex as covariates attenuated this effect to a trend. Only age emerged as a significant predictor of depressive symptoms over 6 years. These findings suggest that increased AL in older age is only associated with depressive symptomatology acutely. Over longer periods of time, however, the physical and psychological sequelae of advanced age may contribute to increased depressive symptoms via pathways otherwise undetectable using allostatic load indices of sub-clinical physiological dysregulations.

Cardiovascular, Neuroendocrine, and Monoaminergic Responses to Psychological Stressors: Possible Differences between Remitted Panic Disorder Patients and Healthy Controls

Both clinical symptomatology and stress research suggest that panic attacks might be partially attributable to exaggerated psychophysiological responses to environmental stressors. In the present study, we aimed to explicitly test this idea by measuring the physiological responses to a mild psychological stressor in both healthy controls (n = 8) and fully remitted, medication-free panic disorder patients (n = 8). One hour before the stressor, former patients, compared to healthy controls, exhibited higher diastolic blood pressure. From a blood sample taken 30 min before the stressor, patients, compared to controls, had lower paroxetine platelet binding site densities. During the stressor, patients, compared to controls, had greater increases in plasma levels of cortisol. These preliminary findings suggest that remitted panic disorder patients might have disturbed physiological responses to mild psychological stressors. These disturbances might be related to the development of future episodes.

Neuroendocrine Study of Serotonin Function in Female Borderline Personality Disorder Patients: A Pilot Study

Preliminary findings suggest that patients with borderline personality disorder (BPD) have disturbed serotonin (5-hydroxytryptamine (5HT) neurotransmission. At least some patients have decreased cerebrospinal fluid (CSF) concentrations of the 5HT metabolite, 5-hydroxyindoleacteic acid (5HIAA) (Gardner et al 1990), decreased prolactin responses to both fenfluramine (Coccaro et al 1989), and meta-chlorophenylpiperazine (mCPP) (Hollander et al 1994), and increased cortisol release following mCPP (Hollander et al 1994). Serotonergic disturbances in BPD patients might be different in men and women. Hollander et al (1994) reported that men, but not women patients differed from healthy controls in their mCPP-stimulated release of prolactin and cortisol. As the authors noted, a gender difference might be attributable to circulating ovarian hormones. Perhaps related to this hypothesized difference, prepubertal boys (males who might be hormonally more similar to women than men) with attention deficit hyperactivity disorder (ADHD) plus aggressive features have increased, rather than decreased, prolactin responses to fenfluramine (Halperin et al 1994). The possibility of a gonadal hormone mediated difference in 5HT function among BPD patients indicated the need for an explicit test. Moreover, the relative absence of physiologic studies of BPD women is striking given that the majority of patients are women. Therefore, we investigated 5HT functioning in BPD women as assessed by fenfluramine stimulated pituitaryadrenal activity, and all were tested during their luteal phase. We hypothesized that, if women BPD patients have disturbed serotonergic activity, then, compared to healthy controls, they would have different plasma levels of prolactin and cortisol following the administration of fenfluramine.

The effect of electroconvulsive therapy on endorphins in depression

The time course study of the endorphin response to electroconvulsive therapy (ECT) was carried out in 10 patients (including one control who did not receive active ECT) at the first and sixth ECT. Results showed a significant rise of plasma endorphin levels after ECT. This increase returned to the pre-ECT level within 1 hr after ECT. There was a pre-rise of plasma endorphin level, which probably was stress related and which was also observed in the control case.

Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons

The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release. At high doses, sulpiride increases both dopamine metabolism and release. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent.

Effect of lithium and neuroleptic combination on lithium transport, blood pressure, and weight in bipolar patients.

Patients treated with a combination of lithium (Li) and neuroleptics are reported to be at greater risk for toxicity. Previous findings suggested that treatment with a combination of Li and neuroleptics would increase the lithium ratio (LR) and intraerythrocyte Li levels. We studied 67 bipolar patients who were treated with Li alone (20 patients) or Li combined with haloperidol (17 patients), or Li combined with chlorpromazine (30 patients). Results revealed that the neuroleptic groups showed significantly lower LR and intracellular Li concentration as compared with those on Li alone. There was no significant difference in Li dosage among these three groups. No difference was found among these three groups with respect to mean blood pressure and weight. The number of hypertensive patients in the Li only group was twice as high as that in either of the two other groups, and the LR of the former was significantly higher than those of the latter groups.