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.

Decreases in dilated pupil size in depressed patients with age may reflect adrenergic changes.

Some studies have suggested that noradrenergic activity may decrease with age in depressed patients. Pupil size is regulated by a balance between norepinephrine and acetylcholine. The present study compares pupil size in 10 unmedicated patients with unipolar depression (296. 3) and in 16 normal controls. Pupil size after dilation with tropicamide, a cholinergic antagonist, was inversely related to age in the patients (r=-0.87), but did not diminish with age in controls. The results suggest that pupil size may provide an index of diminished noradrenergic function with age in patients with major depression.

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.

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 Parkinson's 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 Parkinson's disease.

Sodium valproate increases pupillary responsiveness to a cholinergic agonist in responders with mania.

BACKGROUND: The cholinergic hypothesis of affective disorders predicts that mania is a hypocholinergic state relative to monoaminergic activity. Treatments that increase cholinergic sensitivity are expected to improve manic symptoms. Valproic acid is an effective treatment for mania. Little, however, is known about the cholinergic effects of this agent. METHODS: Ten male hypomanic or manic patients were treated with valproic acid (1500-2000 mg) for 2 weeks. Cholinergic sensitivity was assessed before, and after treatment using graded concentrations of pilocarpine eyedrops (0.03-2.0%). Pupil size changes were quantified using an infrared pupillometer and ED50 values were referenced to maximal dilation with 0.5% tropicamide. RESULTS: Valproate treatment decreased Bech mania ratings and ED50 values (p < .0001). Improvements in mania after treatment were closely correlated with decreases in ED50 (r = .76; p < .01). This relationship was indistinguishable from one previously observed after lithium treatment. CONCLUSIONS: These results provide support for the cholinergic-adrenergic hypothesis. Moreover, similar pupillary reactions to valproic acid and lithium treatments suggest that these agents may share a common action on muscarinic receptors.

Pupillary cholinergic sensitivity to pilocarpine increases in manic lithium responders.

BACKGROUND: The cholinergic hypothesis of affective disorders predicts that mania is a hypocholinergic state relative to monoaminergic activity. Treatments that increase cholinergic sensitivity are expected to improve manic symptoms. METHODS: Ten male hypomanic or manic patients were treated with lithium carbonate (0.7-1.1 mEq/L) for 2 weeks. Cholinergic sensitivity was assessed prior to, and following treatments, using graded concentrations of pilocarpine eyedrops (.03-2.0%). Pupil size changes were quantified using an infrared pupillometer and ED50 values were referenced to maximal dilation with .5% tropicamide. RESULTS: Lithium treatment decreased Bech mania ratings and ED50 values (p < .001). Improvements in mania with lithium treatment were closely correlated with decreases in ED50 (r = .88, p < .001). CONCLUSIONS: These results support the cholinergic-adrenergic hypothesis and suggest that one possible mechanism for the antimanic effects of lithium may involve increasing cholinergic activity in relation to monoaminergic neurotransmission.

Apomorphine induced alteration in corneofundal potentials in depression.

1. The role of dopamine (DA) in mood regulation remains controversial. 2. Previous studies have examined DA sensitivity by measuring neuroendocrine responses following an agonist challenge. For the most part the results of such tests have failed to provide convincing evidence of a DA abnormality in affective disorders. 3. Neuroendocrine responses, however, are subject to complex regulatory influences and respond to DA systems which differ from those thought to modulate mood. 4. Recent animal and human studies suggest that light-dark adaptive electrical responses of the retinal pigment epithelium may serve as a better model of dopaminergic function. 5. The present study reports neuroendocrine and ocular results prior to, and following, an apomorphine (APO; 0.75 mg sc) challenge in 12 depressed patients and 12 normal controls. 6. Apomorphine administration increased both light and dark retinal potentials in patients whereas those of controls decreased and this group difference was significant (p < 0.002). 7. No group differences were detected in any measure at baseline, or in prolactin, or growth hormone levels after the APO challenge. 8. The results indicate that the retina may serve as a more sensitive indicator of dopamine abnormalities in depressive illness.

Seasonal patterns in platelet ligand binding are related to membrane proteins.

A seasonal pattern of platelet [3H]imipramine (3H-IMI) binding was explained by a similar but inverted pattern in membrane protein levels in repeated measures of 20 normal volunteers. No seasonal pattern was evident when 3H-IMI binding was expressed on the basis of surface area rather than membrane protein. Platelet Bmax levels in 50 depressed patients were lower than those of controls when values were expressed in terms of platelet surface area. The results support previous reports of low Bmax values in unipolar major depression, but indicate that seasonal changes in 3H-IMI binding are due to fluctuations in membrane protein and not to changes in the number of receptive sites. The present findings also have similar implications for other platelet measures expressed in terms of membrane protein.

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.

Antidepressant responses and changes in visual adaptation after sleep deprivation.

The effects of 1 night of total sleep deprivation on mood state and visual light-dark adaptation were studied in 15 patients with major depression and nine normal comparison subjects. Mood improvements were evident in all but one patient, although responders (n = 9) could be easily distinguished from nonresponders (n = 6). No significant group differences were found in ocular responses before treatment. After treatment, however, light-adapted peak corneofundal potentials increased in patient responders and decreased in patient nonresponders and normal subjects. Moreover, changes in peak values were closely correlated (r = -0.74) with changes in scores on the Hamilton Depression Rating Scale. In contrast, dark-adapted trough potentials did not distinguish between diagnostic groups and were not correlated with clinical responses. The results indicate that sleep deprivation induces changes in light sensitivity that are proportional to improvements in depressive state.

REM latency, dexamethasone suppression test, and thyroid releasing hormone stimulation test in posttraumatic stress disorder.

1. Twenty-one patients with post-traumatic stress disorder (PTSD) were included in a study utilizing baseline rapid eye movement (REM) latency measurements, the dexamethasone suppression test (DST), and the protirelin (thyroid releasing hormone; TRH) stimulation test. The DST and TRH stimulation test were repeated after double blind treatment with desipramine. 2. A high number of patients (75%) exhibited a REM latency of 60 min or less and blunted thyroid stimulating hormone (TSH) response to TRH (61.9%) on baseline tests while only one patient showed cortisol escape from dexamethasone suppression. 3. After four weeks of desipramine treatment, significant improvements were reported in the Hamilton Rating Scale for depression, but not for anxiety symptoms, PTSD symptoms, or self-rated depressive symptoms. 4. Desipramine treatment did not affect hormonal responses to TRH. 5. The findings of shortened REM latency and altered TRH stimulation test suggest PTSD and depression may share some pathophysiological abnormalities.

The effect of sleep deprivation on motor impairment and retinal adaptation in Parkinson's disease.

1. Sleep deprivation has previously been reported to result in a temporary improvement of motor deficits in Parkinson's disease patients. 2. The mechanism of this action is unclear but may involve an activation of dopamine pathways. 3. Other studies suggest that light adaptive changes in the retinal pigment epithelium may serve as a model of dopamine sensitivity. 4. The present study examined the effects of one night of total sleep deprivation on RPE potentials and motor abnormalities in Parkinson's patients. 5. Sleep deprivation significantly improved motor deficits and these changes were strongly correlated with increases in light adaptive RPE potentials.

Effects of substance abuse on hallucination rates and treatment responses in chronic psychiatric patients.

BACKGROUND: Few data systematically document the effects of illicit drug exposure on psychotic illness. We examined the effect of substance abuse on rates and treatment responses of hallucinations in a chronic psychiatric population. METHOD: 113 cooperative patients consecutively admitted to a state psychiatric hospital were administered the Structured Clinical Diagnostic Interview for DSM-III-R, a Hallucination Interview, and an inventory of past and current substances of abuse. Demographic information was obtained on 104 of 108 patients who declined interview. Medication dosage was analyzed for one third of the interviewed sample; hospital records, nursing reports, contacts with relatives, and urine drug screens were used to confirm information from patient interviews. Hallucination rates and response were compared by diagnostic groups (chi-square). RESULTS: Noninterviewed patients had more frequent hospitalizations, more patients diagnosed with psychosis not otherwise specified or schizoaffective disorder, and fewer females with comorbid substance abuse than the study population. Among interviewed subjects, those with substance abuse and psychiatric illness had first admissions at an earlier age than patients with no substance abuse (p = .005). Schizophrenics experienced higher rates of visual (p = .04) and olfactory (p = .05) hallucinations when using illicit drugs. Substance abuse was associated with decreased treatment responsiveness of auditory (p < .03) and tactile (p < .004) hallucinations in schizophrenic or manic patients. Compared with nonparanoid patients, there was a trend for paranoid schizophrenics with substance abuse to experience more frequent visual (p = .09) and tactile (p = .06) and more refractory auditory (p = .08) hallucinations. No differences in medication dosages were found between patients with treatment-responsive and treatment-refractory hallucinations. CONCLUSIONS: Abused substances may interact selectively with primary psychiatric illness to increase rates and treatment resistance of specific hallucination modalities; etiologies are discussed.

Disruption of circadian MHPG rhythmicity in major depression.

Plasma concentrations of total (free plus conjugated) 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined every 3 hr for a 24-hr period in 32 unipolar depressed patients, 11 bipolar depressed patients, and 12 healthy subjects. Each subject's circadian MHPG rhythmicity was modeled by a sinusoidal function. Temporal parameters were estimated by linear least squares regression with a fixed 24-hr period. The variabilities associated with estimates of circadian amplitude and acrophase were roughly twice as large in the patients compared to healthy subjects. Phase advances were associated most significantly with the agitated rather than the retarded subtype of depression, and with first episode depressions. Treatment with desipramine (n = 26) did not alter significantly any of the model parameters and had no effect on circadian variability in any patient group. The data overall support a dysregulation theory for depressive illness with phase advances representing one manifestation of such dysregulation.

Decreased seasonal mesor of platelet 3H-imipramine binding in depression.

Seasonal cycles of platelet 3H-imipramine binding were compared in 49 endogenous unipolar depressed patients and 20 normal volunteers. A significant sinusoidal component was detected in the Bmax of binding in both patients and controls with similar amplitudes and seasonal peaks. However, the yearly average (mesor) of the patient group was significantly lower (20.0%) than that of the normal controls. The results support earlier claims of a diminished platelet binding in endogenous depression and indicate that this decrease was still evident in the presence of a 48.2% (controls) to 65.8% (patients) seasonal variation. Control Bmax values were normally distributed about a best-fit mean (cosinor fit). In contrast, patient values appeared to be bimodally distributed with one mode that was similar to controls and one mode that was substantially lower. In general, psychiatric symptoms failed to distinguish between patients with high and low platelet binding and no correlation was found between Bmax and severity of illness (HAM-D).

Relationship between seasonal patterns of platelet serotonin uptake and 3H-imipramine binding in depressed patients and normal controls.

1. Significant seasonal variations were found in the velocity of serotonin (Vmax) uptake and the density of 3H-imipramine binding sites (Bmax) in blood platelets from normal controls. 2. Peak 3H-imipramine (3H-IMI) binding was found in February whereas peak serotonin (5HT) uptake was found in June and these measures were not correlated in paired comparisons. 3. Both Vmax and Bmax values of depressed patients deviated from the normal seasonal pattern with lower uptake and binding in the patient group. 4. A comparison of Vmax and Bmax deviations from the normal patterns of uptake and binding revealed a significant correlation between these measures such that patients with low Vmax values were the same as those with low Bmax values. 5. The results support previous claims that the 3H-IMI binding site may be closely associated with, or identical to, a 5HT transport carrier. 6. A significant correlation between uptake and binding further suggests that a common defect may be responsible for observed decreases in Vmax and Bmax values of depressed patients.

Subclasses of platelet 3H-imipramine binding sites.

The possible presence of multiple high affinity 3H-imipramine (3H-IMI) binding sites on blood platelets was studied using trypsin digestion and cyanoimipramine (CNIMI), a pseudo-irreversible inhibitor of 3H-IMI binding and serotonin uptake. Increasing concentrations of CNIMI resulted in a discontinuous curve with a plateau at intermediate concentrations (0.05-0.35 nM). CNIMI sensitive (0.25 nM) sites accounted for approximately half of total high affinity 3H-IMI binding as defined by displacement with 100 microM desipramine. Similar results were obtained when platelet membranes were pretreated with trypsin (0.21-0.84 mg/ml), and no additional inhibition was evident with a combination of both treatments. The present results suggest that 3H-IMI may bind to two separate types of high affinity sites. One subclass is apparently proteinaceous and sensitive to low concentrations of CNIMI, whereas the other is apparently nonproteinaceous and is CNIMI resistant.

Effects of chronic imipramine treatment on subclasses of platelet 3H-imipramine binding sites and plasma cortisol.

A decreased density of platelet 3H-imipramine (3H-IMI) binding sites has been proposed as a putative trait marker of major depressive illness. However, subsequent studies have demonstrated that the number of such sites is increased so as to be more like normal controls upon chronic treatment with antidepressant drugs. In addition, there is some evidence to suggest that altered 3H-IMI binding may be secondary to elevated plasma cortisol levels which are common in depressed patients and which normalize with remission. The present study compares platelet 3H-imipramine binding, plasma cortisol levels, and clinical improvement of 10 endogenous depressed patients before and after 6 weeks of treatment with imipramine-HCl. Total high affinity 3H-IMI binding sites were further differentiated into two subclasses on the basis of their relative sensitivities to cyanoimipramine (CNIMI) inhibition. Treatment was associated with a significant increase (134%) in CNIMI resistant binding but a decrease (45.2%) in CNIMI sensitive binding. While the former was significantly correlated with posttreatment cortisol levels, no significant correlation was found between cortisol and CNIMI specific binding. Neither site appeared to be directly related to mood state. The significance of these findings to the evaluation of platelet binding as a trait dependent marker is discussed.

Seasonal changes in cyanoimipramine specific platelet 3H-imipramine binding in depression.

Seasonal variations in cyanoimipramine (CNIMI) sensitive and CNIMI resistant subclasses of platelet 3H-imipramine (3H-IMI) binding sites were studied in depressed patients and normal volunteers. Sinusoidal rhythms of the binding of both subclasses were found in patients and controls with peak levels in mid-February. Patient values of CNIMI sensitive binding fluctuated about a yearly average that was 32% lower than the average of controls. Patient deviations from the normal pattern were apparently bimodally distributed, whereas those of controls were normally distributed. CNIMI resistant binding was also normally distributed in controls, but not in depressed patients, although patient mesor values were not lower than those of controls. Platelet binding was not correlated with the severity of illness as measured by the Hamilton Rating Scale for Depression, and individual symptoms failed to discriminate between patients with high and low Bmax values.