Paul Cosyns

Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder

Chronic electrical stimulation instead of bilateral capsulotomy was done in four selected patients with long-standing treatment-resistant obsessive-compulsive disorder. In three of them beneficial effects were observed.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

LONG‐TERM ELECTRICAL CAPSULAR STIMULATION IN PATIENTS WITH OBSESSIVE‐COMPULSIVE DISORDER

OBJECTIVEBecause of the irreversibility of lesioning procedures and their possible side effects, we studied the efficacy of replacing bilateral anterior capsulotomy with chronic electrical capsular stimulation in patients with severe, long-standing, treatment-resistant obsessive-compulsive disorder. METHODSWe stereotactically implanted quadripolar electrodes in both anterior limbs of the internal capsules into six patients with severe obsessive-compulsive disorder. Psychiatrists and psychologists performed a double-blind clinical assessment. A blinded random crossover design was used to assess four of those patients, who underwent continuous stimulation thereafter. RESULTSThe psychiatrist-rated Yale-Brown Obsessive Compulsive Scale score was lower in the stimulation-on condition (mean, 19.8 ± 8.0) than in the postoperative stimulator-off condition (mean, 32.3 ± 3.9), and this stimulation-induced effect was maintained for at least 21 months after surgery. The Clinical Global Severity score decreased from 5 (severe; standard deviation, 0) in the stimulation-off condition to 3.3 (moderate to moderate-severe; standard deviation, 0.96) in the stimulation-on condition. The Clinical Global Improvement scores were unchanged in one patient and much improved in the other three during stimulation. During the stimulation-off period, symptom severity approached baseline levels in the four patients. Bilateral stimulation led to increased signal on functional magnetic resonance imaging studies, especially in the pons. Digital subtraction analysis of preoperative [18F]2-fluoro-2-deoxy-d-glucose positron emission tomographic scans and positron emission tomographic scans obtained after 3 months of stimulation showed decreased frontal metabolism during stimulation. CONCLUSIONThese observations indicate that capsular stimulation reduces core symptoms 21 months after surgery in patients with severe, long-standing, treatment-refractory obsessive-compulsive disorder. The stimulation elicited changes in regional brain activity as measured by functional magnetic resonance imaging and positron emission tomography.

Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression

Recent studies from this laboratory have provided some evidence that major depression, in particular melancholia, may be accompanied by an immune response. The present study was designed to investigate whether severe depression is characterized by increased interleukin-6 (Il-6) activity and whether Il-6 production is related to altered levels of acute phase reactants and to abnormal function of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements were made in 8 healthy control subjects and 24 depressed inpatients of Il-6 production in culture supernatants of mitogen-stimulated peripheral leukocytes and plasma levels of haptoglobin (Hp), transferrin (Tf), and postdexamethasone cortisol. Il-6 activity was significantly higher in melancholic subjects than in healthy control subjects and in patients with minor depression or nonmelancholic major depression. Il-6 production was significantly correlated with Hp (positively) and Tf (negatively) plasma levels. There were significant and positive correlations between Il-6 activity and postdexamethasone cortisol values. The findings may suggest that increased Il-6 activity in severe depression is related to hypotransferrinemia, hyperhaptoglobinemia, and hyperactivity of the HPA axis.

Fatty acid composition in major depression: decreased ω3 fractions in cholesteryl esters and increased C20:4ω6C20:5ω3 ratio in cholesteryl esters and phospholipids

Abstract Recently, there were some reports that major depression may be accompanied by alterations in serum total cholesterol, cholesterol ester and ω3 essential fatty acid levels and by an increased C 20: 4ω6 C 20: 5ω3 i.e., arachidonic acid/eicosapentaenoic, ratio. The present study aimed to examine fatty acid composition of serum cholesteryl esters and phospholipids in 36 major depressed, 14 minor depressed and 24 normal subjects. Individual saturated (e.g., C14:0; C16:0, C18:0) and unsaturated (e.g., C18:1, C18:2; C20:4) fatty acids in phospholipid and cholesteryl ester fractions were assayed and the sums of the percentages of ω6 and ω3, saturated, branched chain and odd chain fatty acids, monoenes as well as the ratios ω6 ω3 and C 20:4ω6 C 20:5ω3 were calculated. Major depressed subjects had significantly higher C 20:4ω6 C 20:5ω3 ratio in both serum cholesteryl esters and phospholipids and a significantly increased ω6 ω3 ratio in cholesteryl ester fraction than healthy volunteers and minor depressed subjects. Major depressed subjects had significantly lower C18:3ω3 in cholesteryl esters than normal controls. Major depressed subjects showed significantly lower total ω3 polyunsaturated fatty acids in cholesteryl esters and significantly lower C20:5ω3 in serum cholesteryl esters and phospholipids than minor depressed subjects and healthy controls. These findings suggest an abnormal intake or metabolism of essential fatty acids in conjunction with decreased formation of cholesteryl esters in major depression.

Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response.

There is now some evidence that major depression may be accompanied by an immune response. The latter condition is suggested by elevated secretion of neopterin and interferon-gamma (IFN gamma) and by lower L-tryptophan (L-TRP) plasma levels. This study investigated the plasma levels of neopterin, L-TRP, and the L-TRP/competing amino acids (CAA) ratio in 30 normal control subjects and 47 depressed subjects (16 minor depressed, 13 simple major depressed, and 18 melancholic subjects), and IFN gamma secretion by mitogen-stimulated peripheral blood mononuclear cells in 7 normal control subjects and 13 major depressed subjects. Plasma neopterin levels were significantly higher in depressed subjects than in normal controls; 61% of melancholic patients had increased neopterin levels (> or = 7 nmol/l) with a specificity of 90%. Patients with major depression had significantly lower L-TRP and L-TRP/CAA values compared with normal control subjects. The amino acid values were significantly and negatively correlated with plasma neopterin levels. Major depressed subjects exhibited significantly higher IFN gamma secretion than did normal control subjects. The results further support the hypothesis that major depression is accompanied by an immune response and that the lower L-TRP availability in that illness may be an epiphenomenon of immune activation.

The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression

BACKGROUND It is now well established that major depression is accompanied by an immune-inflammatory system response and that indicators of the latter are inversely correlated with lower availability of plasma tryptophan in depression. Inflammation and infection can alter sleep architecture, whereas sleep disturbances can impair immune functions. AIMS AND METHODS The aims of the present study were to examine: (i) immune-inflammatory markers, i.e. serum interleukin-6 (IL-6), IL-8, IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA), gp130, and prostaglandin E2 (PGE2) production by mitogen-stimulated whole blood and the availability of plasma tryptophan in patients with primary sleep disorders, major depression and healthy volunteers; and (ii) the relationships between the availability of tryptophan and indicators of the immune-inflammatory response system. RESULTS Mitogen-stimulated release of PGE2, and serum IL-6 and IL-8, were significantly increased in both depressed and sleep disordered patients compared to normal controls. Serum IL-1RA was significantly higher in depressed patients than in normal controls. Patients with depression and sleep disorders had a significantly lower availability of tryptophan than normal controls. There were significant and inverse relationships between the availability of plasma tryptophan and serum IL-1RA, IL-6 and IL-8. CONCLUSIONS The results suggest that (i) there is an activation of the immune-inflammatory response system in primary sleep disorders and depression; and (ii) the decreased availability of plasma tryptophan may be related to the inflammatory system response.

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the biological treatment of paraphilias

Abstract Objectives. The primary aim of these guidelines was to evaluate the role of pharmacological agents in the treatment and management of paraphilia, with a focus on the treatment of adults males. Because such treatments are not delivered in isolation, the role of specific psychosocial and psychotherapeutic interventions was also briefly covered. These guidelines are intended for use in clinical practice by clinicians who diagnose and treat patients with paraphilia. The aim of these guidelines is to improve the quality of care and to aid physicians in clinical decisions. Methods. The aim of these guidelines was to bring together different views on the appropriate treatment of paraphilias from experts representing different continents. To achieve this aim, an extensive literature search was conducted using the English language literature indexed on MEDLINE/PubMed (1990–2009 for SSRIs) (1969–2009 for antiandrogen treatments), supplemented by other sources, including published reviews. Results. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for its efficacy, safety, tolerability and feasibility. Conclusions. An algorithm was proposed with six levels of treatment for different categories of paraphilias.

Construct validity of the Beck Depression Inventory in a depressive population

This study investigates the construct validity of the Beck Depression Inventory (BDI) in a large population of DSM-III unipolar depressive inpatients. The BDI correlates weakly with the Hamilton scale and differentiates between minor, major and melancholic/psychotic unipolar depressive subgroups. Factor analysis of the BDI resulted in psychological/cognitive (BDIPSY) and somatic/vegetative (BDISOM) subscales. The BDISOM subscale displayed a narrower relationship with the depression construct, as evidenced by a better differential validity and by significant effects for the DST non-suppression response. The present findings generally lend support to the construct validity of the BDI in depressive populations.

Lower serum prolyl endopeptidase enzyme activity in major depression: Further evidence that peptidases play a role in the pathophysiology of depression☆

Prolyl endopeptidase (PEP) is a serine proteinase, which may cleave peptides that are involved in the pathophysiology of major depression, such as arginine vasopressin, beta-endorphin, luteinizing hormone-releasing hormone, thyrotropin-releasing hormone, and maybe corticotropin-releasing hormone. PEP may be involved in activation of cell-mediated immunity, autoimmune and inflammatory responses, which repeatedly occur in severe depression. The present study investigates serum PEP activity in 33 normal controls, 16 minor, 14 simple major, and 18 melancholic depressed subjects. Pre-dexamethasone and post-dexamethasone (DST) intact adrenocorticotropic hormone (ACTH) and cortisol values were determined in 33 depressed subjects. Serum PEP activity was significantly lower in depressed subjects compared to normal controls and in melancholic depressed subjects compared to minor and simple major depressed subjects. Up to 61.1% of the melancholic patients had serum PEP activities below the mean PEP values of normal controls minus two SDs. In the depressed study group, significant negative correlations between serum PEP activity and severity of illness, post-DST cortisol, and ACTH values were observed. There was a trend toward higher serum PEP activity with increasing age. It is hypothesized that lower serum PEP activity, and lower serum activity of other peptidases, may play a role in the neuroendocrine and immune pathophysiology of major depression.