James E. Shipley

Muscarinic cholinergic hyperactivity in schizophrenia : relationship to positive and negative symptoms

Based on the implication of increased muscarinic ACh activity in the production of negative symptoms, the association of decreasing cholinergic activity with positive symptoms, and the covariance of positive and negative symptoms in the psychotic phase of schizophrenia, a model of (DA) dopaminergic/(ACh) cholinergic interactions in schizophrenia was recently formulated. It suggests that DA/ACh balance is of central importance in schizophrenic pathophysiology and that muscarinic ACh activity increases in an attempt to maintain this balance in the face of increasing DA activity that occurs in the psychotic phase of the illness. The model further suggests that the muscarinic system exerts a damping influence on the emergence of positive symptoms associated with DA hyperactivity, but that this compensatory increase in muscarinic activity is accompanied by an intensification of negative symptoms. In the present study, we tested two important postulates of this model. We tested the prediction that muscarinic activity is increased in schizophrenia by comparing the effect of biperiden, an antimuscarinic M-1 agent, on REM latency in 12 drug-free schizophrenic inpatients and matched normal controls. We found that biperiden caused a smaller increase in REM latency in schizophrenic patients, suggesting that muscarinic activity is increased in schizophrenia. We tested the prediction that an anticholinergic agent would increase positive symptoms and decrease negative symptoms by studying the effect of 8 mg of biperiden/day for 2 days on positive and negative symptoms (assessed by the BPRS) in 30 medication-free schizophrenic inpatients.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of effects of desipramine and amitriptyline on EEG sleep of depressed patients

Despite their widespread use, there are few data concerning the effects of tricyclic antidepressants on EEG sleep in depression. The present study documented the effects of desipramine (DMI, n=17) and amitriptyline (AT, n=16) upon EEG sleep in hospitalized depressed patients as part of a double-blind protocol involving 28 days of active treatment. Compared to placebo, patients receiving DMI showed somewhat worsened sleep continuity, particularly after 1 week of administration when the dose was 150 mg/day. On the other hand, sleep architecture and REM measures showed a rapid suppression of REM sleep, and then partial tolerance for this effect was observed with continued administration of DMI for 3 weeks. DMI was a more potent suppressor of REM sleep, while AT was more sedative. Based on these differences in effects upon EEG sleep, a discriminant function was derived and resulted in a correct classification of 87.5% of AT cases and 76.5% of DMI cases. These results are discussed in terms of the differences in pharmacological profiels for uptake blockade and anticholinergic potency for these two compounds.

Differential effects of amitriptyline and of zimelidine on the sleep electroencephalogram of depressed patients

The effects of amitriptyline (n = 14) or zimelidine (n = 13) on the sleep electroencephalogram of hospitalized depressed patients were assessed in a double‐blind protocol involving 28 days of active dosing. Zimelidine induced no immediate improvement in sleep continuity, and even after 3 wk on zimelidine subjects tended to have longer sleep latency, more awakenings, and lighter non‐rapid eye movement (REM) sleep than before taking the drug. Zimelidine did, however, induce a rapid and persistent alteration of sleep architecture and selected REM measures. REM sleep, which was suppressed over the first two nights on zimelidine, was maximally suppressed after 1 wk, but by 3 wk there was some tolerance for selected REM measures. While zimelidine induced none of the sedative effects of amitriptyline, both were equivalent in their REM‐suppressant effects. These findings are discussed in terms of the differences in uptake blockade and anticholinergic potency in these two drugs.

Failure to Normalize the Dexamethasone Suppression Test: Association with Length of Illness

It is well-documented that a subgroup of patients with major depressive disorder (MDD) have a state-dependent alteration of their hypothalamopituitary-adrenocortical (HPA) axis, most consistently demonstrated by nonsuppression of plasma cortisol following the Dexamethasone Suppression Test (DST) (Carroll et al. 1981). Although the sensitivity and specificity of this test vary considerably, recent studies of the nonsuppressor subgroup indicate that the test might have prognostic importance. Some investigators (Greden et al. 1980, 1983; Albala et al. 1981; Holsboer et al. 1982, 1983) have shown that conversion to a normal DST (suppression) in this subgroup of patients is associated with a favorable clinical response. As part of a longitudinal investigation of monoamine receptor and neuroendocrine regulation in patients with MDD, we examined the DST results pre and post treatment. We report our results in an attempt to characterize those patients who manifest nonsuppression prior to treatment and either

Orbital or medial frontal cortical lesions have different effects on tail pressure-elicited oral behaviors in rats

Three groups of rats were tested with daily tail pressure (TP) tests until reliable and stable baseline eating, gnawing or licking was observed. One group then received bilateral aspiration of the medial frontal cortex, a second group received orbital frontal cortical lesions, and a third group received control lesions of the motor cortex. Daily TP tests were continued postoperatively. There was no disruption of TP-elicited oral behaviors after medial frontal or motro cortex lesions. In contrast, orbital frontal lesions abolished TP behaviors on the first day postoperatively, and there was a slow recovery of TP until day 5 when the elicited behaviors were about 80% of preoperative levels. The time course of recovery of TP-elicited oral behavior closely paralleled the recovery of elective eating after orbital frontal lesions, both in the group given TP and in another group given orbital lesions but not TP. These data demonstrate a marked difference between the medial and orbital divisions of the prefrontal cortex in the mediation of stress-induced oral behavior, and we discuss our data in terms of the possible role of dopamine terminals in these regions.

Polysomnography and prediction of treatment response in depressed adolescents

To test the hypothesis that an increase in REM latency following initiation of antidepressant treatment will predict favorable outcome, we measured REM latencies of depressed adolescents at medication-free baseline and after two nights of antidepressant treatment. Subjects to date include three adolescents, two with a DSM-III-R diagnosis of dysthymia and one with major depressive episode plus dystbymia. Severity of depression was followed with the Children’s Depression Rating Scale (CDRS). Treatment consisted of amitriptyline or imipramine, 50 mg qHS. Two adolescents eventually responded to antidepressants, whereas one did not. The REM latency of the responders increased an average of 183 minutes, whereas the REM latency of the nonresponder increased only four minutes. Sample size is too small for broad interpretation, but the mean increase in REM latency from the baseline nights to the post-medication nights predicted eventual clinical response (p = .Ol). These findings support several studies of depressed adults and one among depressed children, but clearly require replication with a larger sample. If confirmed, the data suggest that an antidepressant challenge of EEG-monitored sleep may be helpful in predicting clinical response in depressed adolescents.

The effect of in or outpatient status on EEG sleep data and postdex controls levels in depressed patients

In a sample of inpatients with major depressive disorder (MDD), we reported that patients with short REM latency (RL) had higher postdexamethasone (postdex) plasma cortisol levels. We now report on the general association of EEG sleep measures and postdex cortisol levels in the above sample, with comparison to a group of 36 outpatients. EEG sleep data averaged over two nights were compared to data for the 1 .O mg DST. After a two-week drug wash-out period, all patients had a SADS/RDC diagnosis of definite MDD and had a HRS > 14. Clinical and demographic data showed the 52 inpatients did not differ from the 36 outpatients with respect to mean age or HRS. Concerning a comparison of EEG sleep measures, however, the inpatient group showed significantly more impaired sleep efficiency (77.4 ? 14.0% vs 83.0 & 11.77%, p < .05) and other measures of sleep continuity, and had greater abnormalities of REM sleep, including a shorter RL (35.0 ? 25.3 minutes vs 56.3 + 27.5 minutes, p < .OOl), and greater REM time (25.1 ? 13.8 vs 18.5 ? 9.3, p < .05) and REM activity (55.2 + 47.5 vs 29.9 + 24.0, p < .Ol) in the first REM period. A significant correlation between sleep measures and cortisol existed only within the inpatient group, in which the maximum postdex cortisol level was correlated positively with%awake(+0.40,p<.01),%stage1(+0.36,pC.01)andnumberof~ousals (+0.32, p < .05), and negatively with time spent asleep (-0.28, p < .05) and sleep efficiency (-0.44, p < .Ol). Cortisol was negatively correlated with REM latency minus awake (-0.44, p C .OOl) but not with REM activity or REM density. These data suggest that the relationship between sleep and postdex cortisol secretion may hold only in a more severely ill (i.e. inpatient) group.