Epidemiology of mental health comorbidity in psoriasis.

AIM: The occurrence of mental health comorbidities such as depression, anxiety, and suicidal ideation or behavior is not uncommon in the context of psoriasis. The negative influence of psoriatic disease on a patient's physical and mental well-being, in combination with overlapping pathophysiology, increase the risk for clinically significant psychiatric conditions. These psychiatric conditions, in turn, influence the patient's outlook and potentially, prognosis. Although the healthcare community increasingly recognizes the association of mental health comorbidities with psoriasis, the extent of the correlation is not fully appreciated. To better understand the relationship between mental health comorbidities and psoriasis, including prevalence, risk factors, and response of psychiatric comorbidities to psoriasis treatment, a narrative review of the published literature was conducted. METHODS: Data from epidemiologic, observational, and clinical studies demonstrate a substantially greater mental health comorbidity burden in patients with psoriasis compared with those without psoriasis or patients with other dermatologic conditions. RESULT: The influence of contemporary drug therapies on measures of depression and anxiety are predominantly positive, although further data are needed to better understand the effects of long-term therapy. CONCLUSION: Clinicians should consider the heightened potential for mental health comorbidities when determining an optimal management strategy for their patients with psoriasis.

Depression and suicidality in psoriasis: review of the literature including the cytokine theory of depression.

Psoriasis can be a socially isolating disease due to debilitating physical symptoms and the stigma patients feel because of the appearance of their skin. Mental health comorbidities such as anxiety, depression and suicidal ideation and behaviour (SIB) are prevalent in patients with psoriasis. Patients with mild psoriasis can experience psychiatric comorbidities; however, disorders such as depression and SIB are more common in patients with severe psoriasis or psoriatic arthritis. Psychiatric disorders can both result from and contribute to progression of psoriasis, suggesting that psoriasis and psychiatric conditions, such as depression, may have overlapping biological mechanisms. Proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are elevated in both psoriasis and depression, indicating that the inflammatory process may be involved in the progression of both diseases. Elevated cytokine levels in the central nervous system cause physiologic and biochemical changes that may contribute to the development of depression. In this review of the literature, we discuss the evidence that supports the association of psoriasis with mental health disorders and the tools used to detect the presence of these comorbidities. Additionally, we review the most prominent hypotheses on the mechanisms by which the inflammatory response and elevated cytokines can cause depression. These results highlight the role that systemic inflammation plays in the various mental health comorbidities associated with psoriasis, including depression and SIB.

Impact of fatigue on outcome of selective serotonin reuptake inhibitor treatment: secondary analysis of STAR*D.

OBJECTIVE: To explore relationships between baseline and changes in fatigue during treatment with outcomes in patients with major depressive disorder (MDD) receiving citalopram monotherapy. RESEARCH DESIGN AND METHODS: Secondary analyses of data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Level 1 treatment phase (≤14 weeks citalopram monotherapy). Fatigue was assessed with item 14 on energy level from the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR16; scored 0-3: 0 = no fatigue, 3 = maximal fatigue); prospective fatigue: assessment of fatigue at Level 1 entry and exit (no fatigue, treatment-emergent fatigue, remitted fatigue, or residual fatigue). CLINICAL TRIAL REGISTRATION: Http://clinicaltrials.gov, NCT00021528. MAIN OUTCOME MEASURES: Remission of depressive symptoms (17-item Hamilton Rating Scale for Depression ≤7 or QIDS-SR16 ≤5); Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form; Short-Form Health Survey Mental and Physical subscales; and Work and Social Adjustment Scale (WSAS). RESULTS: At baseline, of 2868 patients included in the analyses, 5.5% had a QIDS-SR16 item 14 score of 0; 22.9%, a score of 1; 53.6%, a score of 2; and 18.0%, a score of 3. During Level 1 treatment, 3.5% of patients had no prospective fatigue, 2.1% had treatment-emergent fatigue, 33.6% had fatigue remitting during treatment, and 60.8% had residual fatigue. Female gender, unemployment, fewer years of education, and lower monthly income were significantly associated with higher rates of baseline fatigue (all P < 0.0001). Higher levels of baseline or prospective fatigue were associated with reduced likelihood of remission, decreased overall satisfaction (P < 0.0001), and reduced mental and physical function at outcome (P ≤ 0.05). Patients with higher baseline or prospective fatigue reported higher WSAS total scores (P < 0.0001), indicative of more severe functional impairment. CONCLUSIONS: Lower baseline fatigue and remission of fatigue during antidepressant treatment in patients with MDD are associated with higher rates of remission of depressive symptoms and better function and quality of life. Study limitations include use of the STAR*D Level 1 sample (citalopram as only antidepressant), use of a proxy measure of energy/fatigue (item 14 from the QIDS-SR16), and the secondary post-hoc analysis design.

Predictors of remission with placebo using an integrated study database from patients with major depressive disorder.

OBJECTIVE: To identify predictors of remission with placebo treatment in double-blind randomized controlled trials (RCTs) in major depressive disorder (MDD). METHOD: A total of 1017 placebo-treated patients with baseline Hamilton Depression rating scale (HAMD) total ≥15 from eight duloxetine RCTs were included. Remission was defined as endpoint (7-8 weeks) HAMD total ≤7. Data were randomly split into training data (N = 813, 80%) for model selection and test data (N = 204, 20%) for validation. Logistic regression and classification and regression tree (CART) methods were used to identify predictors of remission. Predictive accuracy of models was assessed by Receiver Operator Characteristic (ROC) curves. RESULTS: Baseline predictors for remission with placebo consistently identified with the logistic regression and CART analysis were less severe depressive symptoms (based on HAMD core symptoms), younger age, less anxiety (based on HAMD anxiety/somatization), and shorter current MDD episode duration. Associated cut-off values from the CART method characterized patient groups according to their remission likelihood. However, the predictive accuracy was modest for both methods with areas under the ROC curve of 0.6-0.65 based on test data. CONCLUSION: The derived models, although of limited value for predicting remission in individual patients, may be useful for adjusting for placebo effects in clinical trials.

Neurostimulation therapies in depression: a review of new modalities.

OBJECTIVE: In response to an increased understanding of the neurobiology of severe psychiatric disorders, new therapeutic modalities are entering clinical practice that involve the direct stimulation of the brain. METHOD: We provide a review of published literature regarding the clinical use of vagus nerve stimulation (VNS) therapy, transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) in psychiatric disorders, with an emphasis on treatment-resistant depression (TRD). RESULTS: Vagus nerve stimulation is approved for use in both the EU and US for TRD. TMS has been approved for TRD in Canada, Australia, New Zealand, the European Union and Israel, but not yet in the United States. DBS remains in the early stages of investigation. CONCLUSION: While additional studies are clearly warranted, treatments that directly stimulate the brain appear to hold great therapeutic promise for severe psychiatric disorders.

Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders.

BACKGROUND: The impact of anxiety disorders has not been well delineated in prospective studies of bipolar disorder. AIMS: To examine the association between anxiety and course of bipolar disorder, as defined by mood episodes, quality of life and role functioning. METHOD: A thousand thousand out-patients with bipolar disorder were followed prospectively for 1 year. RESULTS: A current comorbid anxiety disorder (present in 31.9% of participants) was associated with fewer days well, a lower likelihood of timely recovery from depression, risk of earlier relapse, lower quality of life and diminished role function over I year of prospective study. The negative impact was greater with multiple anxiety disorders. CONCLUSIONS: Anxiety disorders, including those present during relative euthymia, predicted a poorer bipolar course. The detrimental effects of anxiety were not simply a feature of mood state. Treatment studies targeting anxiety disorders will help to clarify the nature of the impact of anxiety on bipolar course.

Vagus nerve stimulation in depression.

Ever since the introduction of chemical and electrical convulsive treatment for psychiatric disorders in the 1930s and 1940s, biological techniques have been used extensively in the amelioration of a variety of psychiatric disorders. Techniques of recent vintage have included transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation (VNS). Since VNS attenuates seizures in animal models, the treatment was initially developed and approved by the FDA for treatment of drug-resistant partial-onset epilepsy. Additional data, including the known neuroanatomy of the vagus nerve, effects of VNS on monoamines and mood improvement in patients with epilepsy who were treated with VNS, provided a rationale for further investigation in patients with primary mood disorders. VNS has been administered acutely for 10 weeks to 60 patients with treatment-resistant depression. Longer-term follow-up data has been analysed for the first 30 patients. Response rates have been at least 30% in the acute study. Similar to findings in epilepsy and in contrast to the usual results of long-term medication trials, longer term data regarding symptomatic and functional outcomes of depressed patients receiving VNS continue to look promising. As opposed to electroconvulsive therapy, VNS is not associated with cognitive impairment. These results have led to approval of VNS for the treatment of resistant depression (unipolar or bipolar) in both Europe and Canada. Currently, a pivotal double-blind acute study is underway in the US.

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.

Switching antidepressants for treatment-resistant major depression.

A substantial proportion of patients suffering from major depression experience insufficient clinical response, despite appropriate treatment. Switching to a different monotherapy antidepressant medication is the preferred option for many patients and clinicians. The possible advantages of switching to a different monotherapy, as compared with adding a second agent (i.e., augmenting or combining), include reduced medication costs, fewer drug interactions, better adherence, and less patient burden over time. Response rates for switching, are based largely on open trials, which reveal a response rate of approximately 50%. These response rates are comparable to the response rates reported with augmentation or combination, again established largely by noncomparative open trials. This review article summarizes clinical considerations and available evidence regarding switching antidepressants in the treatment of major depression. Practical issues, such as when to consider switching and how to switch from one medication to another, are addressed.

Inhibitory effects of omega-3 fatty acids on protein kinase C activity in vitro.

Preliminary clinical data indicate that omega-3 fatty acids may be effective mood stabilizers for patients with bipolar disorder. Both lithium and valproic acid are known to inhibit protein kinase C (PKC) activity after subchronic administration in cell culture and in vivo. The current study was undertaken to determine the effects of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on protein kinase C phosphotransferase activity in vitro. Various concentrations of DHA, EPA, and arachidonic acid (AA) were incubated with the catalytic domain of protein kinase C beta from rat brain. Protein kinase C activity was measured by quantifying incorporation of (32)P-PO(4) into a synthetic peptide substrate. Both DHA and EPA, as well as the combination of DHA and EPA, inhibited PKC activity at concentrations as low as 10 micromol l(-1). In contrast, arachidonic acid had no effect on PKC activity. Thus, PKC represents a potential site of action of omega-3 fatty acids in their effects on the treatment of bipolar disorder.

The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression.

BACKGROUND: Chronic vagus nerve stimulation (VNS) is effective in the management of treatment-resistant epilepsy. Open-trial evidence suggests that VNS has clinically significant antidepressant effects in some individuals who experience treatment-resistant major depressive episodes. However, limited information regarding the effects of VNS on neurocognitive performance exists. OBJECTIVE: The primary aim of this study was to determine whether VNS leads to neurocognitive deterioration. METHOD: A neuropsychological battery was administered to 27 patients with treatment-resistant depression before and after 10 weeks of VNS. Thirteen neurocognitive tests sampled the domains of motor speed, psychomotor function, language, attention, memory, and executive function. RESULTS: No evidence of deterioration in any neurocognitive measure was detected. Relative to baseline, improvement in motor speed (finger tapping), psychomotor function (digit-symbol test), language (verbal fluency), and executive functions (logical reasoning, working memory, response inhibition, or impulsiveness) was found. For some measures, improved neurocognitive performance correlated with the extent of reduction in depressive symptoms, but VNS output current was not related to changes in cognitive performance. CONCLUSIONS: Vagus nerve stimulation in treatment-resistant depression may result in enhanced neurocognitive function, primarily among patients who show clinical improvement. Controlled investigation is needed to rule out the contribution of practice effects.

Protein kinase inhibition by omega-3 fatty acids.

Recent data suggest that omega-3 fatty acids may be effective in epilepsy, cardiovascular disorders, arthritis, and as mood stabilizers for bipolar disorder; however, the mechanism of action of these compounds is unknown. Based on earlier studies implicating omega-3 fatty acids as inhibitors of protein kinase C activity in intact cells, we hypothesized that omega-3 fatty acids may act through direct inhibition of second messenger-regulated kinases and sought to determine whether the omega-3 double bond might uniquely confer pharmacologic efficacy and potency for fatty acids of this type. In our studies we observed that omega-3 fatty acids inhibited the in vitro activities of cAMP-dependent protein kinase, protein kinase C, Ca(2+)/calmodulin-dependent protein kinase II, and the mitogen-activated protein kinase (MAPK). Our results with a series of long-chain fatty acid structural homologs suggest an important role for the omega-3 double bond in conferring inhibitory efficacy. To assess whether omega-3 fatty acids were capable of inhibiting protein kinases in living neurons, we evaluated their effect on signal transduction pathways in the hippocampus. We found that omega-3 fatty acids could prevent serotonin receptor-induced MAPK activation in hippocampal slice preparations. In addition, we evaluated the effect of omega-3 fatty acids on hippocampal long-term potentiation, a form of synaptic plasticity known to be dependent on protein kinase activation. We observed that omega-3 fatty acids blocked long-term potentiation induction without inhibiting basal synaptic transmission. Overall, our results from both in vitro and live cell preparations suggest that inhibition of second messenger-regulated protein kinases is one locus of action of omega-3 fatty acids.

Augmentation of standard depression therapy.

OBJECTIVE: This article reviews treatment options (eg, augmentation) for depressed patients with suboptimal clinical responses to an antidepressant. BACKGROUND: Approximately one third of patients treated with antidepressants exhibit suboptimal or delayed clinical response to these medications. In such cases, alternative options include switching to another antidepressant or adding a second antidepressant. Augmentation strategies include addition of lithium carbonate, atypical antipsychotics, psychostimulants, thyroid hormone (triiodothyronine), pindolol, or buspirone. CONCLUSIONS: In approximately half of all antidepressant-resistant cases of major depressive disorder, controlled clinical trials have indicated that augmentation with lithium or thyroid hormone is effective. Other reports suggest that central nervous system stimulants may augment antidepressant activity, but their use is constrained by possible abuse potential. Pindolol therapy has been shown to accelerate clinical response in some but not all studies. Finally, the favorable safety and tolerability profile of buspirone, together with its desirable anxiolytic effects, render it a sound therapeutic option in antidepressant augmentation.

Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.

BACKGROUND: Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS: Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS: In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS: These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Vagus nerve stimulation: a new tool for brain research and therapy.

Biological psychiatry has a long history of using somatic therapies to treat neuropsychiatric illnesses and to understand brain function. These methods have included neurosurgery, electroconvulsive therapy, and, most recently, transcranial magnetic stimulation. Fourteen years ago researchers discovered that intermittent electrical stimulation of the vagus nerve produces inhibition of neural processes, which can alter brain electrical activity and terminate seizures in dogs. Since then, approximately 6000 people worldwide have received vagus nerve stimulation for treatment-resistant epilepsy. We review the neurobiology and anatomy of the vagus nerve and provide an overview of the vagus nerve stimulation technique. We also describe the safety and potential utility of vagus nerve stimulation as a neuroscience research tool and as a putative treatment for psychiatric conditions. Vagus nerve stimulation appears to be a promising new somatic intervention that may improve our understanding of brain function and has promise in the treatment of neuropsychiatric disorders.

Vagus nerve stimulation. A potential therapy for resistant depression?

VNS builds on a long history of investigating the relationship of autonomic signals to limbic and cortical function and is one of the newest methods to physically alter brain function. VNS is a clinically useful anticonvulsant therapy in treatment resistant patients with epilepsy, and pilot data suggest that it has potential as an antidepressant therapy. The known anatomic projections of the vagus nerve suggest that VNS also might have other neuropsychiatric applications. Additional research is needed to clarify the mechanisms of action of VNS and the potential clinical utility of this intriguing new somatic portal into the CNS.

Omega-3 fatty acids and bipolar disorder: a review.

The important role of the omega-3 fatty acids in the pathophysiology and treatment of bipolar disorder is now supported by a substantial body of indirect and direct evidence. This paper will describe the clinical and pharmacological features of bipolar disorder, review the available data regarding omega-3 fatty acids in bipolar disorder and provide recommendations for future research.

CSF thyrotropin-releasing hormone gender difference: implications for neurobiology and treatment of depression.

In light of the postulated role of thyrotropin-releasing hormone (TRH) as an endogenous anti-depressant, 56 refractory mood-disordered patients and 34 healthy adult control subjects underwent lumbar puncture for cerebrospinal fluid (CSF) TRH analysis. By two-way analysis of variance, there was no difference between CSF TRH in patients (as a group or by diagnostic subtype) and control subjects (n = 90, F = 0.91, df = 2.84, P = 0.41). There was, however, a CSF TRH gender difference (females, 2.95 pg/ml; males, 3.98 pg/ml; n = 90, F = 4.11, df = 1.84, P < 0.05). A post hoc t-test revealed the greatest gender difference in the bipolar group (t = 2.52, P < 0.02). There was no significant difference in CSF TRH in "ill" vs. "well" state (n = 20, P = 0.41). The role of elevated levels of CSF TRH in affectively ill men--or the role of decreased levels of CSF TRH in affectively ill women--remains to be investigated but could be of pathophysiological relevance.