Philip G. Janicak

Plasma and CSF HVA before and after pharmacological treatment

Plasma and cerebrospinal fluid (CSF) levels of the major dopamine metabolite homovanillic acid (HVA) were measured in psychiatric patients after an average washout period of 19 days, and again after 4 weeks of pharmacological treatment. Absolute values of plasma HVA did not correlate with absolute values of CSF HVA either at baseline or after treatment. However, changes in plasma HVA were highly correlated with changes in CSF HVA. Further, while baseline levels of plasma and CSF HVA were not significantly correlated with baseline clinical measures, clinical improvement was associated with decreases in both plasma and CSF HVA. This reached statistical significance for the plasma HVA level/clinical response relationship.

The effect of diagnosis and age on the DST: a metaanalytic approach

The authors present new data on the results of the pretreatment Dexamethasone Suppression Test (DST) in 164 drug-free inpatients, as well as on the effects of age on postdexamethasone cortisol values. Nonsuppression rates were 18% in schizophrenic patients (n = 44), versus 46% in patients with a major depression (n = 56). In addition, a significant correlation was found between age and the 4:00 PM postdexamethasone cortisol value among the depressed patients (r = 0.33). The authors then applied a metaanalysis to summarize 25 other studies that have addressed the schizophrenia/major depression dichotomy as it relates to the DST outcome. Nonsuppression rates were consistently different in schizophrenic patients (19%) when compared to patients with a major depression (51%) or normal controls (7%). These differences were highly significant as measured by the Mantel-Haenszel chi-square statistic. A metaanalysis applied to a series of correlations obtained from 14 other studies reporting an age/postdexamethasone cortisol relationship in affective patients indicated a modest, but significant correlation (r = 0.24) in a total of 1284 patients (p less than 1 x 10(-8)).

Relatives of unipolar and bipolar patients have normal pursuit.

Impaired smooth pursuit eye movements are significantly less prevalent among the first-degree relatives of patients who have major affective disorders than among the first-degree relatives of schizophrenics. The distribution of normal and abnormal smooth pursuit among the relatives of unipolar and bipolar patients does not differ from that of normal individuals having no family history of major psychosis. Smooth pursuit impairment is thus specific to relatives of schizophrenic patients and is not characteristic of relatives of patients with major affective disorders.

Increased 3H-Clonidine binding in the platelets of patients with depressive and Schizophrenic disorders

To examine whether alpha 2-adrenergic receptor function is altered in affective and schizophrenic disorders, we determined 3H-clonidine binding in platelets obtained from 33 normal control subjects and from 24 patients with depressive, 22 patients with schizophrenic, 18 with bipolar, and 8 patients with schizoaffective disorders during a drug-free period. The maximum number of binding sites (Bmax) and apparent dissociation constant (Kd) for high affinity 3H-clonidine binding was computed by Scatchard analysis. Comparison of the diagnostic groups indicated that the Bmax in depressed, schizophrenic, and schizoaffective patients was significantly higher than in normal controls, but there were no significant Bmax differences between bipolar patients and controls. Comparison of the Kd among the diagnostic groups indicated no significant differences among the groups or between patient diagnostic groups and normal controls. Baseline Bmax in schizophrenic patients was significantly correlated with the decrease in Brief Psychiatric Rating Scale (BPRS) scores after treatment, suggesting a relationship between baseline Bmax and clinical response. Treatment with lithium caused a significant decrease in the baseline Bmax, whereas treatment with desipramine or trifluoperazine did not cause significant changes in the baseline Bmax. Our results thus indicate an increase in the number of alpha 2-adrenergic receptors in depressed and schizophrenic patients as compared to normal controls.

CSF and plasma MHPG, and the CSF MHPG index: Pretreatment levels in diagnostic groups and response to somatic treatments

The authors report a significant positive correlation between levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in cerebrospinal fluid (CSF) and plasma in drug-free affective disorder patients (major depression, mania, and schizoaffective disorder), but not in schizophrenia. Recent kinetic studies on the relationship between plasma and CSF MHPG discourage the interpretation of independent CSF MHPG levels without correction for the diffusion of MHPG across the blood-brain barrier. The authors therefore examine pretreatment CSF and plasma MHPG levels, and the CSF MHPG index (CSF MHPG corrected for by using simultaneously obtained plasma MHPG according to the method of Kopin et al. [1983]). No significant differences were found in these pretreatment MHPG measures among the four diagnostic groups. Changes in these MHPG indices, and their correlations with behavioral rating scores, are also examined with respect to response to the four major somatic therapies (neuroleptics, lithium, antidepressants, and electroconvulsive therapy).

Prediction of haloperidol steady-state levels in plasma after a single test dose.

Because of large interindividual variabilities in the pharmacokinetics of haloperidol (HPDL), empirically adjusting the dose to achieve steady-state levels in plasma (Css) is a time-consuming process. We report a method to individualize dose to achieve a desired Css from an observed drug level 24 hours after a single 15-mg test dose of HPDL. Drug-free schizophrenic and schizo-affective patients were blindly and randomly assigned to achieve a low (< 5 ng/ml), medium (10-18 ng/ml), or high (> 25 ng/ml) Css range of HPDL. On day 1 of the study, each patient received an oral test dose of HPDL (15 mg), and blood was drawn 24 hours later to determine drug levels in plasma (C24h). The first 34 patients (group I) were then maintained empirically on 2, 5 to 8, or 10 to 15 mg twice daily of oral HPDL concentrate for 5 days to achieve a low, medium, or high Css range, respectively. For the next 58 patients (group II), the dose of HPDL to achieve the assigned Css range was computed by using C24h in a prediction formula. Application of the C24h correctly predicted the maintenance dose required to achieve the Css in 73.2% of the cases. Further, there was a highly significant correlation (R2 = 0.877, p < 0.0001) between the predicted dose and the actual dose required to achieve the targeted Css range. On the basis of these results, we have formulated a nomogram to help predict the maintenance dose required to achieve low, medium, or high HPDL targeted ranges at various C24h values.

Treatment-Resistant Depression: An Update on Diagnosis and Management

World Health Organization predicts that this disorder will be the second leading cause of disability worldwide by the year 2020. Premature death in this population is associated with an increased risk of suicide, as well as a complex interrelationship with other medical disorders such as heart disease and impaired cognition. Data from the National Comorbidity Study indicate that the annual prevalence of major depression in U.S. adults approaches 15 million individuals. Of this population, approximately half are accurately diagnosed, and one-quarter adequately benefit from or can tolerate existing therapies. Further, the longer a patient remains depressed, the more difficult it is to reverse the mood state and the higher the risk of adverse socioeconomic and medical consequences. This article will consider the evolving concept of treatment-resistant depression (TRD) and review recent evidence-based approaches to its management. CHARACTERIZING TREATMENT-RESISTANT DEPRESSION Definition Acritical first step is the accurate identification of treatment resistance. Although the logical assumption is inadequate response to therapy (e.g., psychotherapy, pharmacotherapy, various combinations of these approaches), this can be difficult to ascertain, since a substantial proportion of patients may experience poor response because of a variety of factors other than true treatment resistance. In this context, several issues must be considered, including: After reading this article, the practitioner should be able to:

The Efficacy of Transcranial Magnetic Stimulation for Major Depression: A Review of the Evidence

Major depression is a leading cause of disease burden worldwide. Although various treatment approaches exist, including pharmacological (eg, antidepressant agents), psychotherapeutic (eg, cognitivebehavioral therapy), and neuromodulatory (eg, electroconvulsive therapy [ECT]), a substantial number of patients do not adequately bene!t from or cannot tolerate these existing options. This has led to a re-emergence of other neurostimulation strategies, the best studied to date being transcranial magnetic stimulation (TMS). This article reviews the rationale for TMS in treating depression with a brief description of the basic principles underlying magnetic stimulation; a discussion of its putative mechanism of action; and its recommended treatment parameters. We then focus on the evidence base to support its use as both a monotherapy and adjunctive therapy for the acute and maintenance treatment of major depression. These data came from controlled trials comparing TMS to a sham procedure and naturalistic outcome studies for acute depression; studies directly comparing TMS to ECT for major depression; and open-label studies, retrospective analyses, naturalistic outcome studies, and case reports that consider the durability of TMS’ eect after acute response. The results of these studies have led to a growing use of TMS in clinical practice for treatment-resistant depression. [Psychiatr Ann. 2014; 44(6):284–292.] Philip G. Janicak, MD, is Professor of Psychiatry, and Director, Transcranial Magnetic Stimulation Center, Rush University Medical Center. Linda Carpenter, MD, is Professor, Brown Department of Psychiatry and Human Behavior, and Chief, Butler Hospital Mood