Edward M. DeMet

Sleep deprivation therapy in depressive illness and Parkinson's disease

1. Sleep deprivation is commonly associated with feelings of fatigue and cognitive impairment. 2. Patients with depressive illness, however, often experience mood improvements under these same conditions. 3. Other studies now show that tremor and rigidity, in patients with Parkinsons disease, are also improved by sleep depression therapy. 4. The neural substrates which underlie these effects are unclear. Some recent evidence, however, suggests that sleep deprivation may activate mechanisms which are otherwise typical of conditions of metabolic stress. 5. A common feature of these mechanisms is the suppression of cholinergic activity which is thought to be excessive, in relation to monoamine transmission, in both depression and Parkinsons disease.

Neuroleptic-induced hypothermia associated with amelioration of psychosis in schizophrenia

Body temperature is a regulatory function of the hypothalamus. Recently, DeMet et al. (Society for Neuroscience Abstracts Vol 12, 1986) reported that apomorphine stimulation of dopamine autoreceptors caused a significant decrease in metabolic rate in the posterior heat-conserving area of the hypothalamus. The logical hypothesis to follow is that apomorphine administration should induce a decrement in body temperature; this in fact was demonstrated by Cutler et al. (Commun Psychopharmacol 3:375-382, 1979) in humans. It is well known that neuroleptics also disrupt thermoregulation (Clark: Neurosci Biobehav Rev 3:179-231, 1979) and affect dopamine autoreceptors. Therefore, eight chronic treatment-resistant schizophrenics underwent a 6-week single-blind trial of haloperidol and then a subsequent 6-week double-blind trial of clozapine. Both haloperidol and clozapine significantly lowered oral body temperatures relative to baseline washout temperatures. More interestingly, clozapine relative to haloperidol was found to induce a greater decrement in body temperature and was associated with greater clinical improvement. Possible confounding variables are discussed, as is the possible neurochemical basis for the amelioration of psychosis associated with hypothermia.

Gabapentin as an Adjunct to Standard Mood Stabilizers in Outpatients with Mixed Bipolar Symptomatology

Gabapentin is a new adjunctive medication to antiseizure therapies. Anecdotal evidence suggests that it may also help to alleviate mood symptoms in patients with bipolar illness. An open-label study examined the effects of adjunctive gabapentin in bipolar patients with mixed symptoms who had previously demonstrated only partial treatment responses. Mood ratings and side-effect profiles were followed weekly in 10 patients for 1 month. Decreases in Hamilton depression (P < 0.05) and Bech mania ratings (P < 0.01) were evident in the first week of treatment and were sustained. Potent early improvements were noted in early, middle, and late insomnia. The results suggest that gabapentin may be of benefit to bipolar patients who only partially respond to other mood stabilizers. A favorable side-effect profile and rapid action make this drug an attractive choice as an adjunctive therapy.

Caffeine taste test for panic disorder: adenosine receptor supersensitivity.

The present study introduces a novel measure of adenosine receptor sensitivity that is based on the action of specific receptor blockers (e.g., caffeine) to potentiate the ability to detect threshold quinine concentrations. The test is used to compare gustatory adenosinergic responses to caffeine challenges in normal controls and patients with panic disorder or posttraumatic stress disorder (PTSD). Panic disorder patients had an exaggerated response to the caffeine challenge that was not found in controls or PTSD patients, although the latter had higher anxiety scores on psychometric tests. The results are related to a model in which A1-adenosine receptors up-regulate in an attempt to modulate hyperactive excitatory neuronal systems.

Platelet MAO activity in personality disorders and normal controls

Platelet monoamine oxidase (MAO) activity has been related to several psychiatric disorders and personality dimensions. The purpose of this study was to measure platelet MAO activity in personality disorders and determine its relationship to symptoms analogous to sensation seeking. Twenty-eight males admitted to a psychiatric unit with a DSM-III-R diagnosis of personality disorder were compared to normal controls. Patients with Axis I diagnoses other than adjustment disorder were excluded. There was no difference in MAO activity between patients and normals, although it was lower in borderline patients. MAO activity was inversely correlated with sensation seeking, especially in the patient group, as predicted. The results are consistent with the view that platelet MAO activity is a marker of general psychopathology.

Once-daily high-dose pindolol for SSRI-refractory depression

Selective serotonin reuptake inhibitor (SSRI) augmentation with the 5-HT1A antagonist pindolol has met with mixed results. Recent studies using positron emission tomography (PET) suggest that pindolol doses used in these studies were too low to effect 5-HT1A autoreceptor blockade. To test the hypothesis that a single higher dose of pindolol would effectively augment antidepressant responses in SSRI-refractory patients, nine subjects with major depression unresponsive to paroxetine 40 mg/day given for 2 months or more were randomized to AM pindolol 7.5 mg (n=4) or placebo (n=5). Subjects were administered the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), the Bech-Rafaelsen Melancholia Scale, and the Zung Depression Inventory at baseline and weeks 1, 2, 3, and 4. Subjects receiving pindolol exhibited significant improvements in all ratings beginning at week 2 which continued through week 4. Aside from transient dizziness and a five-point decrease in systolic/diastolic blood pressure associated with pindolol, no adverse effects were reported. Although results must be verified in a larger sample, these findings support previous studies indicating that pindolol can accelerate antidepressant responses during SSRI therapy. In addition, results reported here suggest that a single high dose of pindolol (7.5 mg) is a more effective augmentation strategy in SSRI-refractory patients compared with the same total dose given at 2.5 mg tid.

Seasonal rhythm of platelet 3H-imipramine binding in normal controls

The densities of platelet 3H-imipramine sites were determined by repetitive measures of 11 normal controls over the course of 1 year. A significant seasonal variation was found, with a circannual peak on February 17 and a nadir on August 18. The estimated amplitude of this rhythm was +/- 599.54 fmol/mg, which fluctuated about a yearly mean of 2647.5 fmol/mg. The present results underscore the importance of including seasonally matched controls in the evaluation of potential patient differences in platelet binding.

Increased pupillary sensitivity to pilocarpine in depression.

1. The present study was undertaken to examine the hypothesis that muscarinic receptor sensitivity is increased in depression. 2. Pupillary responses to increasing concentrations of pilocarpine (O.08%-O.23%) given in a 2 ml solution were compared between ten male patients with major depression and a matched group of normal controls. 3. Individual differences in pupil size due to anatomic variability or adrenergic tone were evaluated under conditions of maximum pupil dilation following cholinergic blockade (tropicamide, 0.5 percent). 4. In contrast to controls, depressed patients exhibited significantly greater reductions in pupillary diameter following pilocarpine in doses between 0.095%-0.185%. This was true regardless of whether or not the results were adjusted for differences in dilated pupil size. 5. These results are consistent with the idea that muscarinic sensitivity is increased in depression and indicate that depressed patients may be discriminated from controls on the basis of pupillary sensitivity to pilocarpine.

Cholinergic sensitivity predicts severity of mania

Our laboratory and others have reported that pupillary constrictions following application of the cholinergic agonist pilocarpine are increased in depressed patients. Moreover, mood improvements in manic patients, given lithium or Depakote, are also correlated with increases in pupil sensitivity. The present report describes the relationship between symptom severity and cholinergic sensitivity in a larger group (N=20) of manic patients (bipolar I; 296.4x). Pupil responses to pilocarpine eye drops (0-2%) were recorded using infrared pupillometry. The results were compared with pupil sizes measured under conditions of cholinergic blockade (0.5% tropicamide). Pupil responses were computed as percentages of the maximal range of areas measured under saturating agonist and antagonist conditions. Dose response curves were subjected to a log-logit transformation and ED(50) values were determined by weighted least squares regression. Bech-Rafaelsen mania ratings were found to be linearly related to ED(50) values (r=0.48). Patients with more severe mania required higher concentrations of pilocarpine in order to elicit a 50% reduction in pupil size. The present findings support a putative cholinergic role in the regulation of mood state. Moreover, the results suggest that pupillary responses may provide a simple and non-invasive means to evaluate cholinergic sensitivity in patients with affective disorders.

Diurnal rhythm of 3-methoxy-4-hydroxyphenylglycol (MHPG): relationship between plasma and urinary levels

Plasma and urinary levels of MHPG were determined in six normal volunteers. Samples were obtained at 3-hour intervals for plasma and at 12-hour intervals for urine. Acrophase, amplitude and period were determined for plasma MHPG levels. A sinusoidal pattern was obtained for diurnal plasma MHPG with a peak at 15:00 hrs. +/- 46 min. Urinary MHPG, corrected for creatinine levels, correlated with both 9 AM plasma MHPG and with baseline plasma MHPG. Furthermore, the relationship between plasma and urinary MHPG was linear when the rhythm of urinary levels was assumed to lag 6.2 hours behind the plasma rhythm. It was concluded that free MHPG is evenly distributed in the total body space and that conjugated MHPG is largely restricted to the blood.