Philip J. Wilner

Neuropsychologic effects of lithium discontinuation.

This study investigated the effects of blind lithium discontinuation and resumption on measures of cognition, creativity, and fine motor performance in 46 lithium-maintained euthymic outpatients. Scores on memory measures, tests of tapping speed, and associative productivity all improved significantly during the time off of lithium. In an effort to further explain these results, analyses were undertaken with six possible intervening variables: age, sex, lithium concentration in plasma, thyroid function, duration of lithium maintenance, and depressive symptoms. Significant group and interactive effects are reported and discussed. A multiple regression analysis suggested that lithium has a greater neuropsychologic effect in younger, less-depressed patients having higher lithium concentrations in plasma.

Personality pathology among married adults with bipolar disorder

The comorbidity of DSM-III-R axis II personality disorders in patients with bipolar disorder has received less attention than for unipolar depression perhaps because of the potential confounding of state vs. trait qualities. The current study took steps to separate pathological traits of personality from behaviors evidenced during discrete affective episodes in a sample of married, outpatient bipolar patients. Data indicated that 22% of our patients met criteria for a categorical diagnosis of personality disorder. Axis II pathology as represented by both categorical and dimensional scores was associated with increased psychiatric symptoms during subsequent treatment and poorer social adjustment.

Acute effects of single and repeated electroconvulsive therapy on plasma catecholamines and blood pressure in major depressive disorder

The role of activation of adrenergic neurons by electroconvulsive therapy (ECT) in its antidepressant action was studied by examining acute sympathetic nervous system (SNS) responses to ECT during a course of treatment in patients with melancholia. ECT had an acute dose-dependent effect on plasma norepinephrine (NE) level and blood pressure. The postictal increase in plasma NE and blood pressure was independent of electrical seizure duration. Acute levels of NE and epinephrine after ECT correlated positively with ECT dosage. No cumulative effect of repeated ECT was found on the SNS responses. ECT does activate the SNS in a dose-dependent fashion. However, alternative strategies seem necessary for studying the action of ECT on noradrenergic neurons to identify effects that are cumulative, correspond more closely to the time course of its antidepressant action, and correlate with clinical outcome.

Subsensitivity of adenylyl cyclase-coupled receptors on mononuclear leukocytes from drug-free inpatients with a major depressive episode

Previous studies have demonstrated blunted beta-adrenergic responsivity in leukocytes from depressed patients. We sought to determine if this blunted cyclic adenosine monophosphate (AMP) response is specific for beta-adrenergic receptors (homologous), or whether other adenylyl cyclase-coupled receptors are also involved (heterologous), in order to localize this effect at the level of the receptor versus the coupling protein or the transducer, adenylyl cyclase. We studied adenylyl cyclase-mediated responses in peripheral blood mononuclear cells from 95 drug-free patients with a major depressive episode and 69 healthy controls. We found a similar degree of decrease in the peak cyclic AMP response to activation of the beta-adrenergic receptor (28%) and the prostaglandin receptor (34%) in the depressed patients, which indicated heterologous desensitization. Forskolin cyclic AMP responses were not blunted. Blunting of cyclic AMP responses to isoproterenol did not appear to correlate with levels of plasma norepinephrine and epinephrine or hypothalamic-pituitary-adrenocortical function. The absence of a decrease in the peak forskolin-generated cyclic AMP response, which involves direct activation of adenylyl cyclase, suggests an abnormality at the level of the coupling protein in these adenylyl-coupled receptors in depressed patients. Future studies need to determine whether this leukocyte signal transduction defect in depression also involves brain adenylyl cyclase-coupled receptors.

The Therapeutic Alliance in Randomized Controlled Clinical Trials

The therapeutic alliance, familiar to those who treat patients and conduct clinical trials, is considered by many to be a non-specific effect in research studies. The concept of the therapeutic alliance has its roots in the doctor-patient relationship and has been discussed extensively in the context of psychodynamic psychotherapy. Research has demonstrated that the strength of the alliance is a strong predictor of outcome in psychotherapy and has emphasized its importance in ensuring compliance in pharmacotherapy. However, little empirical research has been conducted which examines the impact of the therapeutic alliance on patient compliance and retention in randomized controlled clinical trials. Moreover, tension and debate exist between those who see the therapeutic alliance as both a necessary and positive component of a clinical trial and those who view it as a confounding variable. Those who view it as a confounding variable argue that this alliance may serve to influence patients’ participation and make difficult the assessment of treatment effects. We report our observations from one study of adults with schizophrenia who were enrolled in a clinical trial of a new antipsychotic medication. We hypothesize that there is an association between the strength of the therapeutic alliance and subsequent compliance and retention of patients enrolled in clinical drug trials. The relationship among these constructs could be tested empirically as could the association between the therapeutic alliance and the assessment of clinical response.

Peripheral Blood Cell Biological Markers in Depression

The classical monoamine hypotheses of depressive illness have postulated a deficiency of norepinephrine and/or serotonin at functionally important receptors in the central nervous system (CNS).1,2 An alternative “receptor hypothesis” would explain reduced transmission by a deficiency in signal amplification by the receptor complex. This focus on the receptor gained impetus from studies showing that virtually all effective somatic antidepressant treatment modalities shared the common effect of down-regulation and/or desensitization of β-adrenergic receptor complexes.3,4 Moreover, a significant number of antidepressants down-regulate 5- HT2 (serotonin; 5-hydroxytryptamine) receptors, although, in contrast, electroconvulsive shock up-regulates 5-HT2 receptors.4,5

Studies of sympathetic nervous system (SNS) dysregulation in major depression (MDD)

Excessive norepinephrine (NE) release has been found in patients with MDD after postural challenge. We have further evaluated SNS function by measurement of epinephrine (EPI) release in addition to NE, heart rate (HR), and blood pressure (BP) responses to postural challenge. Patients (N = 44) had significantly higher levels of EPI at rest and at three minutes of standing (p < .05) than controls (N = 40). We did not find significant differences in NE levels. HR was significantly higher in the depressed group at three minutes (p < .05), paralleling the EPI rise. BP was comparable in both groups. Within groups EPI release did not correlate with NE release in the depressed group, but did for controls (p < .05). These findings suggest that patients had a faster sympathomedullary response to a postural challenge and have dysregulated adrenomedullary reactivity or altered central regulation of the SNS.