Search

Objectives: Serum or plasma levels of C-reactive protein (CRP) and highsensitivity CRP (hsCRP) are widely used clinical markers of inflammation in other branches of medicine, whereas its clinical use in psychiatry has been limited to research studies. We aimed to assess the possibility of using CRP/hsCRP in psychiatric practice. This is a review and evaluation of various lines of evidence supporting the concept of CRP as a biomarker for psychiatric disorders in certain conditions. Methods: We searched the literature for studies which assessed CRP/hsCRP levels in various psychiatric disorders. Results: The accumulating evidence from large studies and meta-analyses allows us to understand the role of CRP in major psychiatric disorders and increase our understanding of specific symptoms and subtypes of disorders. CRP may be considered a “psychiatric biomarker” which can alert clinicians about neuroinflammation, adverse effects of medications, cardiometabolic status, comorbidities, and may also predict clinical outcomes and guide optimal treatment selection. Conclusion: Although the underlying pathophysiological role of CRP and hsCRP is still elusive and the association between CRP and psychiatric disorders is inconsistent, CRP holds promise to become a psychiatric biomarker. WOS:000684418100001 34323645 Q2

Adjunctive inflammatory modulation improved remission rates in treatment-resistant bipolar depression (TRBDD), but reliable biomarkers must be established to characterize the biosignature of TRBDD and the mechanisms underlying treatment response. In this molecular profiling study, we describe TRBDD and treatment response from the standpoint of interleukin-1 Beta (IL-1β) and KYN/TRP.47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg-40 mg daily dose range) + celecoxib (CBX) (200 mg twice daily), or ESC (10 mg-40 mg daily dose range) + placebo (PBO) (twice daily). Plasma cytokine levels were measured in both treatment arms at baseline and week 8, and in a healthy control (HC) group of subjects (N = 43) once. A linear mixed model (LMM) was applied to evaluate whether clinical outcome is related to CBX and changes to biomarkers throughout treatment. A binary logistic regression model was formulated from this series to predict both the primary outcome of treatment response to CBX, and the secondary outcome of diagnosis of TRBDD using age, BMI, gender, and IL-1β at baseline.Patients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT = 3, and 15.300 times more likely to remit (p 0.001) with NNT = 2, compared with ESC + PBO patients. Patient BMI (p = 0.003), baseline IL-1β (p = 0.004), and baseline KYN/TRP (p = 0.001) were most predictive of TRBDD diagnosis. By Week 8, responders showed a downtrend in IL-1β compared to non-responders in the ESC + CBX treatment arm. However, there was no statistical difference in the IL-1β or KYN/TRP change after treatment between placebo and ESC + CBX group responders/non-responders (p = 0.239, and p = 0.146, respectively). While baseline IL-1β was elevated in TRBDD compared to HC (p 0.001), there was no difference in IL-1β between treatment responders at Week 8 compared to HC (p = 0.067).Elevated IL-1β and low KYN/TRP at baseline are components of the TRBDD molecular signature. CBX but not baseline IL-1β or KYN/TRP predict treatment response. Change in IL-1β and KYN/TRP did not predict treatment response.

Objective The goal of this study was to reduce treatment resistance and enhance antidepressant response in patients with treatment-resistant bipolar depression (TRBDD) by modulating inflammatory activation. Methods Forty-seven TRBDD patients completed a randomized, double-blind, placebo (PBO)-controlled two-arm study using celecoxib (CBX), a cyclooxygenase 2 (COX-2) inhibitor, in combination with escitalopram (ESC). The Hamilton Depression (17-Item) and the Hamilton Anxiety Rating Scales were used to quantify symptom severity. Self-rating instruments included BDI, BAI and QLES-Q questioner. An adverse events inventory was used, and the possibility of bleeding diathesis was monitored. Complete blood count (CBC), prothrombin time (PT), and activated partial thromboplastin time (APTT) were determined. Comparison of mood scores between the CBX and PBO groups were conducted using a mixed ANOVA and an Independent Sample Student t-test. Results The CBX adjunctive treatment produced significantly more responders and remitters than the PBO arm. Compared to the PBO group (n = 20), the CBX group (n = 27) experienced lower depression severity through the entire course of the study, showing significant decrease in depression and anxiety scores as early as week 1. Except for initial mild nausea, no adverse events were reported and study medications were well tolerated. Conclusions Modulation of the inflammatory response through targeted inhibition of the enzyme COX-2 by means of CBX reduces TRBDD and augments and accelerates treatment response in an efficacious and safe manner. Future studies should replicate these findings and additionally investigate whether prolonged administration of CBX is required to maintain remission by adding a discontinuation phase to the study design. Trial Registration Clinicaltrials.gov ID: NCT01479829.

Esketamine is a novel treatment for treatment resistant depression (TRD) and was approved by the FDA in early 2019. It antagonizes the NMDA receptor providing rapid improvement in symptoms with a complex mechanism of action primarily mediated through glutamatergic activation. Significant barriers exist to widespread use of esketamine including durability of response, particularly in the maintenance phase. Since it must be administered in combination with an oral antidepressant, investigating appropriate treatments to be given concomitantly may further improve outcomes and response duration. Specifically, due to dysfunction in dopaminergic pathways in many patients with MDD and TRD, addition of a prodopaminergic agent, such as bupropion, may provide additional benefit and durability of response. Historically, the addition of a dopaminergic agent to traditional treatment (e.g., SSRI, SNRI) has been shown to improve response in TRD. While we have anecdotal evidence to support adjunctive dopaminergic enhancement of esketamine response, robust data are limited. There are case reports that exhibit efficacy with the use of a MAO-I in combination with ketamine supporting at least in part a dopaminergic component. Additionally, there is mechanistic rationale for the use of dopaminergic agents with a NMDA antagonist. This includes co-localization of NMDA and dopamine receptors as well as increased glutamatergic signaling due to dopamine-induced phosphorylation of AMPAR. Recently, AXS-05, an oral combination of dextromethorphan and bupropion, has shown promise in both MDD and TRD clinical trials highlighting the potential validity of this mechanism. This paper describes how dopaminergic enhancement may increase efficacy and durability of response with esketamine, encouraging further research into this treatment option.

Aim. To determine the efficacy and safety of vitamin D3 supplementation in reducing depressive symptoms in women with type 2 diabetes (T2D), depression, and low vitamin D. Methods. In this double-blind randomized active comparator-controlled trial, women with significant depressive symptoms as assessed by the Center for Epidemiologic Studies Depression (CES-D) scale received weekly oral vitamin D3 supplementation (50,000 IU) or an active comparator (5,000 IU) for 6 months. Assessments of vitamin D, 25-hydroxyvitamin D [25 (OH) D], and depression were measured at baseline, 3 months, and 6 months. Results. A total of 129 women were randomized, from which 119 completed the study (57 in lower dose and 62 in higher dose). Participants had an average 25 (OH) D and HbA1c of 20.8 ng/mL and 7.8%, respectively, at baseline. They were diverse (48% Black) and had a mean age of 50 and T2D for about 8 years. Upon completion of vitamin D3 supplementation, serum 25 (OH) D levels increased with 50,000 IU (+34 ng/mL) and 5,000 IU (+10 ng/mL). There was no difference in CES-D scores by treatment dose. Overall, depressive symptoms significantly improved over time with an average CES-D decline of 12.98 points (95% CI: −15.04 to −10.93; p < 0.001 ). Among women with moderate baseline depressive symptoms, those receiving the lower dose had nominally lower depression scores at follow-up than those in the higher dose cohort. Among women with severe baseline depressive symptoms, the improvement in follow-up depression scores was the same regardless of dose. Conclusions. There was no difference in the dosing effect of vitamin D3 supplementation for the treatment of depressive symptoms in women with T2D who present with significant symptoms and low vitamin D. Regardless of the dose, participants’ mood improved over time. Further study of vitamin D to target depressive symptoms in comorbid populations is needed.

Purpose of review Up until the latter part of the previous century, the monoamine theory guided our understanding of psychiatric disorders, notably depressive illness in its various phenotypic manifestations. The purpose of this review is to provide an overview of newer theories that allow a deeper understanding of brain dysfunction and neuropsychiatric disease entities such as depressive illness. One such key theory is the theory of inflammation as a result of stress-induced immune system activation. Recent findings Stress activates the hypothalamic-pituitary-adrenal axis and the sympathetic branch of the autonomic nervous system [sympathetic branch (SNS)] with a concomitant reduction in vagal tone. This homeostatic imbalance makes a simultaneous dual contribution to the resulting proinflammatory state of depression. SNS stimulation results in upregulation of proinflammatory signaling, whereas diminution in parasympathetic tone affects the body's immune response. The resulting proinflammatory status has been closely associated with multiple organ dysfunction and comorbid conditions. Summary The advent of innovative theories about the pathophysiology of psychiatric disorders has ushered in a new era on the basis of the role of the immune system and inflammation in mediating depression in its multifaceted manifestations. Extensive studies have confirmed the proinflammatory status in depression and causal relationships with neurotransmitter dysregulation. Equally importantly the role the autonomic nervous system plays in this complex and multifactorial interplay of body systems is being increasingly elucidated.

Coronavirus may have a negative impact not only on physical, but also on mental wellbeing. Despite the different approaches of countries to stop the spread of the virus and different infection rates, the dynamically developing pandemic has already affected the entire world. The consequences of the coronavirus for our mental health can be divided into those related to strategies for the prevention of infection, like isolation, quarantine, limitation of social contacts, and remote work, and those related to the direct impact of infection on our nervous system. This review aims to highlight the global effects of the Coronavirus Disease 2019 (COVID-19) pandemic on public mental health following social restrictions, to identify how infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have direct neurophysiological effects and to compare the impact on public mental health between the USA, Australia, and Poland with Taiwan and Thailand.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

Objectives: Major depressive disorder (MDD) and depression in bipolar disorder (BD) are often difficult to distinguish from each other. Autonomic nervous system (ANS) dysregulation is associated wi...

Background Neuroinflammation plays a role in the pathophysiology of Bipolar Disorder Depression (BDD) and altered levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1, aka CCL2) have been reported. This study reports specifically on MCP-1 levels, as a potential marker of BDD and/or treatment response in patients receiving combination treatment with the cyclooxygenase-2 inhibitor, celecoxib (CBX). Methods In this randomized, 10-week, double-blind, two-arm, placebo-controlled study, 47 patients with treatment resistant BDD received either escitalopram (ESC) + CBX, or ESC + placebo (PBO). Plasma MCP-1 levels were measured at 3 time points in the BDD subjects, and in a healthy control (HC) group. Depression severity was quantified using the Hamilton Depression Scale (HAMD-17). Results The CBX group had significantly lower HAMD-17 scores vs. PBO at week 4 (P = 0.026) and week 8 (P = 0.002). MCP-1 levels were not significantly different in BDD vs. HC subjects at baseline (P = 0.588), nor in CBX vs. PBO groups at week 8 (P = 0.929). Week 8 HAMD-17 scores and MCP-1 levels were significantly negatively correlated in treatment non-responders to CBX or PBO (P = 0.050). Non-responders had significantly lower MCP-1 levels vs. responders at weeks 4 (P = 0.049) and 8 (P = 0.014). MCP-1 was positively correlated with pro-inflammatory analytes in the PBO group and with anti-inflammatory analytes in the CBX group. Conclusions Combination treatment reduced treatment resistance and augmented antidepressant response. Baseline plasma MCP-1 levels were not altered in BDD patients. Since non-responders had lower levels of MCP-1, elevated MCP-1 may indicate a better response to CBX + SSRI treatment.

Background Vascular Endothelial Growth Factor (VEGF) has been implicated in the neurotrophic model of depression. We explored the potential role of VEGF in the pathophysiology of bipolar depression and potential utility as a diagnostic or outcome predictive biomarker. Methods In a double-blind study, treatment-resistant bipolar depressed patients received Escitalopram and were randomized to receive add-on Celecoxib (26 participants) or Placebo (21 participants). There were 32 healthy controls. Plasma levels of VEGF were determined at three timepoints over eight weeks. Results Bipolar patients had significantly higher VEGF levels at baseline compared to healthy controls. Logistic regression analysis revealed that the AUC is 0.67 and the VEGF cut point is 8.21. At all timepoints, patients receiving Celecoxib had comparable VEGF levels to those receiving Placebo. VEGF levels did not change significantly over time. Baseline VEGF was a poor predictor of treatment response with an AUC of 0.53. Conclusions The increased VEGF in bipolar depression agrees with similar findings in major depressive disorder. A high VEGF level tended to accurately predict bipolar disorder, with apparent differential VEGF expression. Baseline VEGF did not predict treatment response, and levels did not change with treatment. Plasma VEGF may have diagnostic utility and guide personalized treatment.

The present case report describes a case of serotonin syndrome which developed post septal myectomy in a patient with hypertrophic cardiomyopathy. This case contributes to an emerging awareness of serotonin syndrome in the context of prescribed serotonergic agents, such as SSRIs, and triggered by the addition of fentanyl and methylene blue, particularly in conjunction cardiological procedures. Clinicians should be aware of such interactions which increase the emergence of the serotonin syndrome and the appropriate management of comorbid delirium post-serotonin syndrome.

A pro-inflammatory state and a dysregulation in the tryptophan/kynurenine pathway have been documented in depression. This study examined whether treatment with the SSRI, escitalopram (ESC), could suppress inflammation and favorably shift metabolites of the kynurenine pathway in patients with major depressive disorder (MDD) within the utilized treatment period. Twenty seven healthy control subjects were included for comparison. Thirty patients were enrolled after completing baseline assessments. They received a 12-week ESC monotherapy. Twenty subjects were completers. Clinical assessments were carried out at each visit using the HAM-D, HAM-A, CGI and BDI rating scales. Blood samples were collected at each assessment and stored until analyzed. Cytokines were analyzed with Randox multiplex assay and tryptophan and kynurenine metabolites were analyzed using HPLC/GCMS. Baseline plasma concentrations of hsCRP, TNF alpha IL6 and MCP-1 were significantly higher in patients compared to healthy controls. IL10 trended toward an increase. Baseline plasma IL1 beta correlated significantly with IL1 alpha, and IL4. Patients showed significant improvement in all outcome measures with a high remission rate. Significant correlations were obtained between specific symptoms and certain biomarkers at baseline but these correlations must be viewed as very preliminary. During ESC treatment concentrations of inflammatory biomarkers did not change except for TNF alpha that trended lower. Metabolites and ratios of the tryptophan/kynurenine pathway showed reductions of the neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, 3-hydroxykynurenine/kynurenine, quinolinic acid/tryptophan, kynurenic acid/quinolinic acid and quinolinic acid/3-hydroxylcynurenine. The results indicate that ESC may exert its antidepressant effect in part through inhibition of synthesis of certain neurotoxic kynurenine metabolites and possibly also through reduction of the inflammatory response, although there was no concordance in the time course of changes between antidepressant efficacy and reversal of the pro-inflammatory status.

Despite intense research efforts undertaken by investigators throughout the world over the past half century to identify a specific biomarker for major depressive disorder (MDD), none have so far met the rigorous test of specificity, reliability and reproducibility. Vascular Endothelial Growth Factor (VEGF) has been implicated in the neurotrophic model of depression and several studies have assessed VEGF levels in depressed patients. The results have been discrepant largely due to design and assay differences among studies. The aim of this study was to assess plasma VEGF levels in a cohort of MDD subjects prior to treatment with psychotropic medication and compare them to those of healthy control (HC) subjects. Prospective study participants underwent extensive medical and psychiatric assessments before they were enrolled. Plasma concentrations of VEGF were measured by the technique marketed by Randox Technologies. The mean baseline VEGF for the healthy and depressed groups was 5.91 pg/ml (SD: 3.04) and 10.51 pg/ml (SD: 9.04), respectively, and this difference was statistically significant (p = 0.001). We detected a very low univariate relationship between VEGF and demographic and clinical variables. Using the Optimal Data Analysis a cut score of 6.64 pg/ml for baseline plasma VEGF distinguished depressed from healthy subjects with a 63% overall accuracy. We conclude these results support a role of plasma VEGF as a useful biomarker of depression that can be measured with a routine blood draw at the point of service. The specificity of this potential biomarker must be confirmed in studies that include other psychiatric disease entities.

Immune system activation and neuroinflammation appear to play a key role in the pathophysiology and treatment of bipolar depression (BDD). This study is the first to analyze blood levels of the pro-inflammatory biomarker C-reactive protein (CRP) in bipolar disorder patients treated with the cyclooxygenase-2 inhibitor, celecoxib (CBX). In this double-blind study, 47 consenting patients with BDD were randomized to receive either escitalopram (10 mg twice/day) + CBX (200 mg twice/day), or escitalopram (10 mg twice/day) + placebo (twice/day). Plasma CRP levels were measured in both patient groups at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. Symptoms were rated using the 17-item Hamilton Depression Scale (HAMD-17). The CBX group had significantly lower HAMD-17 scores vs. placebo at week 4 (P = 0.026) and week 8 (P = 0.002). Therefore, SSRI + CBX is more effective than SSRI + placebo in reversing treatment resistance and augmenting antidepressant response in BDD. Baseline CRP levels were significantly increased amongst BDD patients versus HC subjects, indicating that CRP may be a useful biomarker for BDD (P = 0.044). No significant differences in CRP levels were measured between CBX and placebo groups at baseline (P = 0.156), but by week 8 CRP was significantly decreased in the CBX group vs. placebo (P = 0.003). This indicates reduced inflammation in CBX-treated patients, and that CRP may be a useful biomarker for monitoring treatment response in BDD patients during SSRI + CBX combination treatment. CRP and IL-6 levels were positively correlated in the CBX group, and CRP levels were positively correlated with BMI.

The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti-inflammatory properties (i.e., ω-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body-mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression.

Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.

Morbidity and mortality of cardiovascular disease (CVD) is exceedingly high worldwide. Depressive illness is a serious psychiatric illness that afflicts a significant portion of the world population. Epidemiological studies have confirmed the high co-morbidity between these two disease entities. The co-morbidity is bidirectional and the mechanisms responsible for it are complex and multifaceted. In addition to genetic, biological systems, psychosocial, and behavioral factors that are involved include the central and autonomic nervous systems, the neuroendocrine, immune, and the vascular and hematologic systems. Specific pathophysiologic factors across these systems include homeostatic imbalance between the sympathetic and the parasympathetic systems with loss of heart rate variability (HRV) in depression, sympathoadrenal activation, hypothalamic-pituitary-adrenal (HPA) axis activation, immune system dysregulation resulting in a pro-inflammatory status, platelet activation, and endothelial dysfunction. These abnormalities have been demonstrated in most individuals diagnosed with major depressive disorder (MDD), bipolar disorder (BPD), and probably in other psychiatric disorders. A likely common instigator underlying the co-morbidity between cardiovascular pathology and depression is mental stress. Chronic stress shifts the homeostatic balance in the autonomic nervous system with sustained sympathetic overdrive and diminished vagal tone. Diminished vagal tone contributes to a pro-inflammatory status with associated sequelae. Stress hormones and certain pro-inflammatory substances released by macrophages and microglia upregulate the rate-limiting enzymes in the metabolic pathway of tryptophan (TRP). This enzymatic upregulation stimulates the kynurenine (KYN) pathway resulting in the formation of neurotoxic metabolites. Inflammation occurs in cardiac, cardiovascular, and cerebrovascular pathology independent of the presence or absence of depression. Inflammation is closely associated with endothelial dysfunction, a preamble to atherosclerosis and atherothrombosis. Endothelial dysfunction has been detected in depression and may prove to be a trait marker for this illness. Thus understanding vascular biology in conjunction with psychiatric co-morbidity will be of critical importance. Antidepressant drug therapy is of definite benefit to patients with medical and psychiatric co-morbidity and may reverse the pro-inflammatory status associated with depression. There is, however, an urgent need to develop novel pharmacotherapeutic approaches to benefit a much larger proportion of patients suffering from these disease entities.

The aim of the study was to evaluate baseline plasma VEGF levels as a potential predictor of response to antidepressant pharmacotherapy. The study also sought to determine whether baseline plasma VEGF would be useful in predicting treatment outcome when two pharmacodynamically diverse agents with established antidepressant efficacy, escitalopram and quetiapine, were administered monotherapeutically to MDD patients.Two groups of qualifying MDD subjects were enrolled. One group was treated with escitalopram and the other with quetiapine. Plasma concentrations of VEGF were measured using Randox Technologies at baseline, and at weeks 8 and 12 of treatment.We stratified the MDD patients into those who remitted and those who failed to respond. Mean baseline VEGF for the remitters and non-responders was 9.61 and 5.40 pg/ml, respectively (P 0.0005). Using optimal data analysis a cut score of 7.49 pg/ml for baseline plasma VEGF distinguished remitters from non-responders with a 63% overall accuracy. The remission rate was comparable for both drugs (73 and 81% for quetiapine and escitalopram, respectively). VEGF levels did not significantly change following antidepressant treatment with either escitalopram or quetiapine when measured at 8 and 12 weeks; this result held true for both remitters and non-responders.Our results suggest that VEGF may predict response to antidepressant treatment and may ultimately prove to be a potential biomarker that can be measured with a routine blood draw at the point of service.

Major depressive disorder (MDD), a highly prevalent psychiatric condition, is encountered in 1 of every 10 to 20 patients seen in the primary care setting. While awareness of MDD has increased, timely and accurate diagnosis and adequate treatment remain formidable challenges. Treatment options for patients with MDD should be individualized according to each patient's clinical and medication history, pharmacologic tolerability profile, and personal preferences, to maximize long-term adherence. The most robust and consistently maintained positive outcomes occur in patients who are administered effective treatment with recommended antidepressant pharmacotherapy, psychotherapy, or a combination of these treatment modalities. This manuscript reviews the epidemiology, biologic and clinical features, diagnosis, and treatment of patients with MDD. A focus is placed on guidelines and strategies that target the achievement of MDD symptom remission. The article also includes details on individualizing treatment selection and novel and emerging therapies. Primary care physicians must be prepared to adjust, substitute, or augment antidepressant treatments to optimize patient response and enhance the chances of achieving remission. Considerations that strongly influence long-term patient adherence, including tolerability and cost, are also reviewed.

Previous studies have shown that imidazoline receptors (IR-1) are increased in platelets and frontal cortex of depressed patients, and this up-regulation is normalized (down-regulated) after antidepressant drug treatments. It has been hypothesized that IR-1 up-regulation during the depressive episode may be a state marker for depressive symptomatology. The goal of the present study was to address the state versus trait question.Twelve healthy subjects (six males and six females) met stringent inclusion and exclusion criteria for physical and mental health. They received desipramine for 6 weeks in order to simulate the length of time and dosing used previously to obtain an IR-1 down-regulation and a therapeutic response in depressed patients. Outcome and safety measures included clinical, psychological, and cardiovascular assessments obtained throughout the study. Plasma concentrations of desipramine were measured throughout the 6 weeks of treatment and again after 2 weeks following tapered discontinuation of desipramine. Platelet receptors were assessed by Western blotting and radioligand binding assays.Healthy subjects taking desipramine experienced mild dysphoric effects but there were no adverse events. The binding of 8 nM p-[(125)I]clonidine to IR-1 and alpha(2)-adrenoceptors in healthy subjects did not change during desipramine treatment. The immunodensity of the 33 kDa band associated with IR-1 gradually increased to a maximum, by week-6, of 26% higher than baseline (p0.01 compared to baseline). Two weeks after desipramine discontinuation, there was a decline in alpha(2)-adrenoceptor binding and 33 kDa band's immunodensity (p = 0.04).The findings support the hypothesis that platelet IR-1 binding sites are a marker of mood state rather than of antidepressant-induced pharmacological regulation. By comparison, platelet alpha(2)-adrenoceptors appear to be regulated by desipramine as a pharmacological effect independent of mood state.

High levels of pro-inflammatory biomarkers have been reported in depression. In the present study, five pro-inflammatory biomarkers were measured in the blood of patients with major depressive disorder (MDD). Biomarker levels were compared to age- and sex-matched healthy subjects. Patients with MDD had significantly higher baseline levels of tumour necrosis factor-alpha (TNFalpha, P=0.04), interleukin-1beta (IL1beta, P=0.03), and monocyte chemotactic protein-1 (MCP-1; P=0.02) compared to controls. There were no differences between groups in levels of cell determinant-40 ligand (CD40L) and C-reactive protein (CRP). A subset of the MDD patients consented to undergo treatment with venlafaxine (an SNRI: at lower doses a selective serotonin reuptake inhibitor; at higher doses also a norepinephrine reuptake inhibitor) for 8 weeks. By week 8, all treatment completers had responded therapeutically. However, levels of TNFalpha, IL1beta, and MCP-1 remained elevated. A concave quadratic equation described the associations between plasma venlafaxine concentrations and IL1beta (P=0.03), TNFalpha (P=0.09), and MCP-1 (P=0.02), suggesting that these biomarkers may have become selectively lowered in the serotonergic dose range of venlafaxine. This is the first report of venlafaxine's possible effect on pro-inflammatory biomarkers.

Agmatine is an endogenous neuromodulator that, based on animal studies, has the potential for new drug development. As an endogenous aminoguanidine compound (1-amino-4-guanidinobutane), it is structurally unique compared with other monoamines. Agmatine was long thought to be synthesised only in lower life forms, until its biosynthetic pathway (decarboxylation of arginine) was described in the mammalian brain in 1994. Human arginine decarboxylase has been cloned and shown to have 48% identity to ornithine decarboxylase. In neurons of the brain and spinal cord, agmatine is packaged into synaptic vesicles and released upon neuronal depolarisation. Other evidence of a neuromodulation role for agmatine is the presence of a specific cellular uptake mechanism and a specific metabolic enzyme (agmatinase; which forms putrescine).Initially, agmatine was conceptualised as an endogenous clonidine-displacing substance of imidazoline receptors; however, it has now been established to have affinity for several transmembrane receptors, such as alpha(2)-adrenergic, imidazoline I(1) and glutamatergic NMDA receptors. In addition to activity at these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase and downregulates inducible nitric oxide synthase. Endogenous agmatine is induced in response to stress and/or inflammation. Stressful conditions that induce agmatine include hypoxic-ischaemia and cold-restraint stress of ulcerogenic proportion. Induction of agmatine in the brain seems to occur in astrocytes, although neurons also synthesise agmatine. The effects of injected agmatine in animals include anticonvulsant-, antineurotoxic- and antidepressant-like actions. Intraperitoneal or intracerebroventricular injections of agmatine rapidly elicit antidepressant-like behavioural changes in the rodent forced swim test and tail suspension test. Intraperitoneal injections of agmatine into rats and mice also elicit acute anxiolytic-like behavioural changes in the elevated plus-maze stress test. In an animal model of acute stress disorder, intraperitoneal agmatine injections diminish contextual fear learning. Furthermore, intraperitoneal injections of agmatine reduce alcohol and opioid dependence by diminishing behaviour in a rat conditioned place preference paradigm. Based on these findings, agmatine appears to be an endogenous neuromodulator of mental stress. The possible roles and/or beneficial effects of agmatine in stress-related disorders, such as depression, anxiety and post-traumatic stress disorder, merit further investigation.

Aims: Testosterone synthesis in chronic alcoholics is affected by a variety of mechanisms. Little is known about the reversibility of these changes upon abstinence and available data on circulating hormone levels are incomplete and inconsistent. Methods: Serum concentrations of free testosterone, total testosterone, and luteinizing hormone (LH) were determined in 18 male non-cirrhotic chronic alcoholics on days 2, 22, 82 and 127 of strictly controlled abstinence, as well as in a group of 20 healthy age-matched controls. Results: Higher total testosterone concentrations were found in alcoholics on the second day of abstinence, as compared to controls (7.1 ± 1.9 vs 5.6 ± 1.4 ng/ml) and throughout the whole observation period. Correspondingly, free testosterone concentrations were increased over control levels on day 2 (40.0 ± 12.1 vs 29.7 ± 8.1 pg/ml) and stayed elevated in the presence of augmented concentrations of LH (4.5 U/l (range 1.6-9.5 U/l) vs 2.0 U/l (range 0.8-8.1 U/l)) for up to 127 days of strictly controlled abstinence. Conclusions: Sustained increases in serum free and total testosterone levels in the presence of inadequately raised LH concentrations point towards persisting disturbances of the hypothalamic-pituitary-gonadal axis in male alcoholics upon cessation of drinking.

The binding of an agonist, p-[125I]iodoclonidine, and an antagonist, [3H]yohimbine, to alpha 2-adrenoceptors was measured autoradiographically in the locus coeruleus from 10 pairs of antidepressant-free victims of suicide and age-matched controls. Agonist binding to alpha 2-adrenoceptors was significantly greater in the locus coeruleus from victims of suicide compared with control subjects. In contrast, antagonist binding to alpha 2-adrenoceptors in the locus coeruleus did not differ significantly between control and suicide subjects. HPLC analysis of norepinephrine in tissue sections of the locus coeruleus did not reveal any differences between control subjects and suicide victims, suggesting that differences in agonist binding are not a result of differences in retention of the endogenous agonist norepinephrine in tissue sections. The increase in agonist binding to alpha 2-adrenoceptors in the locus coeruleus of victims of suicide links an altered expression of the high-affinity state of autoinhibitory alpha 2-adrenoceptors with suicide.

Type 2 diabetes (T2D) patients are twice as likely to experience depressive symptoms than people without T2D, resulting in greater economic burden, worse clinical outcomes, and reduced quality of life. Several overlapping pathophysiological processes including hypothalamic-pituitary-adrenal axis hyperactivity, sympathetic nervous system activation, and elevated pro-inflammatory biomarkers are recognized as playing a role between T2D and depressive symptoms. However, other neurobiological mechanisms that may help to further link these comorbidities have not been extensively reviewed. Reduced neuroplasticity in brain regions sensitive to stress (e.g., hippocampus) may be associated with T2D and depressive symptoms. T2D patients demonstrate reduced neuroplasticity including morphological/volumetric abnormalities and subsequent neurocognitive deficits, similar to those reported by patients with depressive symptoms. This review aims to summarize recent studies on morphological/volumetric abnormalities in T2D and correlated neurocognitive deficits. Modifying factors that contribute to reduced neuroplasticity will also be discussed. Integrating reduced neuroplasticity with other biological correlates of T2D and depressive symptoms could enhance future therapeutic interventions and further disentangle the bidirectional associations between these comorbidities.

Background: Bipolar disorder (BPD) is a mental illness in which depression and mania typically alternate, and both phases can present with psychotic features. The symptomatology of BPD, therefore, resembles major depressive disorder (MDD) and schizophrenia (SCHZ), posing diagnostic dilemmas. Distinct alterations in cellular architecture of the dorsolateral prefrontal cortex distinguish SCHZ and MDD, whereas the cellular neuropathology of BPD has not been studied. Methods: Dorsolateral prefrontal area 9 was analyzed using a three-dimensional morphometric method in postmortem brains from 10 BPD patients and 11 matched nonpsychiatric control subjects. Results: Area 9 in BPD was characterized by reduced neuronal density in layer III (16%–22%) and reduced pyramidal cell density in layers III and V (17%–30%). A 19% reduction in glial density was found in sublayer IIIc coupled with enlargement and changes in shape of glial nuclei spanning multiple layers. Conclusions: The morphologic signature of BPD, i.e., decreased neuronal and glial density in association with glial hypertrophy, is distinct from previously described elevations in neuronal density in SCHZ, instead resembling the reductions in cell density found in MDD. Thus, the neuropathologic distinctions between BPD and SCHZ are indicative of separate mental illnesses, each with a unique morphologic disturbance of specific neural circuits.

Increased platelet activation has been suggested as a possible reason for the increased vulnerability of depressed patients to ischemic heart disease (IHD). Translocation of P-selectin, an integral alpha-granule membrane protein, to the platelet surface is a measure of platelet activation. Herein, western blots of platelet plasma membranes containing P-selectin were quantified in patients with major depression (n=19; mean age=39 +/- 2 years) and healthy comparison subjects (n=17; mean age=36 +/- 2 years). None evidenced clinical signs of IHD, and only two patients had a lifestyle IHD risk factor (smoking). Blood was obtained from all 19 depressed patients before treatment, and 15 returned after 6-8 weeks of open-label bupropion treatment. Bupropion was chosen as the antidepressant because it did not elevate plasma norepinephrine or serotonin, endogenous agonists that can induce platelet degranulation. Western blotting revealed more P-selectin immunoreactivity (75 kD band) in depressed patients compared to healthy controls (P=0.003). After bupropion treatment, P-selectin remained high in depressed patients. beta3-Integrin, a reference plasma membrane protein that does not translocate during activation, was of equivalent density in depressed patients and healthy control subjects, and was unchanged after treatment with bupropion. P-Selectin failed to correlate with severity of illness based on the Hamilton Depression scale, or with the post-treatment plasma concentration of bupropion. The results suggest an elevation in P-selectin on platelet plasma membranes might be a trait marker for depression.

A substantial number of studies have demonstrated increased imidazoline receptors (I1 binding sites) on platelets of depressed patients and downregulation following antidepressant treatments. Herein, imidazoline receptor binding protein (IRBP) antiserum was used to quantify imidazoline receptors on platelets of depressed patients before and after treatment with the atypical aminoketone antidepressant, bupropion. Western blots revealed an increase in IRBP-immunodensity (p = 0.01, two-tailed) in a 33 kDa protein band in untreated depressed patients (n = 21) as compared with controls (n = 17). This band has been positively correlated with I1 binding sites on platelets. Following 6 weeks' treatment with bupropion, IRBP-immunodensity was downregulated in depressed patients (p = 0.03, paired t-test); predominantly in responders (p = 0.005). Patients non-responsive to bupropion (n = 5) were significantly different from responders (p = 0.05) by exhibiting no elevation in IRBP-immunodensity at pre-treatment and no downregulation of the 33 kDa band after treatment. IRBP-immunodensity was negatively correlated (r = -0.79, p = 0.01) with plasma concentrations of bupropion and its metabolites at week-4 of BUP treatment. Thus, a 33-kDa IRBP on platelet plasma membranes is elevated in depression and normalized in responders to bupropion.

A comparison is presented between plasma catecholamine concentrations and platelet [125I]-p-iodoclonidine binding sites in 16 healthy women. Blood samples were obtained at six regularly spaced intervals over two consecutive menstrual cycles from healthy women with regular menstrual periods. Although no cycle-related changes were observed per se, there were significant correlations between the platelet binding sites and plasma norepinephrine and epinephrine concentrations. The densities of platelet alpha 2-adrenoceptors were negatively correlated in an exponential fashion (r2 = 0.694, P = 0.009) with plasma epinephrine concentrations, implying agonist-induced downregulation. On the other hand, platelet I1-imidazoline binding sites were positively correlated with plasma concentrations of norepinephrine in a linear fashion (r2 = 0.326, P = 0.021). This is the first indication that I1 binding sites might be upregulated by a physiological factor. Furthermore, the data suggest that elevations in plasma norepinephrine might explain reports of upregulated I1 binding sites in depressed patients.

Decarboxylated arginine, agmatine, is a neurotransmitter candidate for imidazoline receptors. A method is described to measure agmatine in rat brain and human plasma by isocratic high-performance liquid chromatography (HPLC) with fluorescence detection and o-phthalaldehyde derivatization. Quantitation is based on the method of additions of internal agmatine spikes. This assay has sensitivity in the low picomole range and a detection limit of 100 fmol. The correlation coefficient for the agmatine standard curve was 0.999+/-0.001 S.D., and intra- and inter-assay C.V.s were less than 8%. The accuracy of our isocratic method compared favorably with a gradient HPLC protocol, originally developed for bacterial agmatine, which we modified for use with tissues. Agmatine concentrations in rat brain were proportioned similarly to the regional distribution of imidazoline-1 receptors. These methods can be used as reliable research tools in various biological samples.

Morbidity and mortality of cardiovascular disease is exceedingly high worldwide. Depressive illness afflicts a significant portion of the population worldwide. Epidemiological studies have confirmed the high co-morbidity between these two entities and the co-morbidity is bidirectional. Systems that contribute to this co-morbidity include the central and autonomic nervous systems, the neuroendocrine, immune, vascular and hematologic systems. Specific pathophysiologic factors include imbalance between the sympathetic and the parasympathetic systems, sympathoadrenal activation, hypothalamic-pituitary-adrenal axis activation, immune system dysregulation with release of pro-inflammatory cytokines and chemokines, platelet activation and hypercoaguability. Inflammation occurs in cardiac and cardiovascular pathology independent of the presence or absence of depression and in depression. Inflammation is closely associated with endothelial dysfunction which is a preamble to atherosclerosis and atherothrombosis. A likely common instigator underlying this co-morbidity is mental stress leading to sustained sympathetic overdrive and diminished vagal tone. Diminished vagal tone contributes to a pro-inflammatory status which affects neurotransmitter regulation, specifically serotonergic transmission. Stress hormones and certain pro-inflammatory substances released by macrophages and microglia upregulate the rate-limiting enzymes in the metabolic pathway of tryptophan. This results in a shunt in tryprophan metabolism away from serotonin formation and down the kynurenine pathway with resulting formation of neurotoxic metabolites.

Vascular Endothelial Growth Factor (VEGF), initially identified as an angiogenic mitogen, is believed to play a role in hippocampal neurogenesis and response to stress. It exerts neuroprotective effects and influences synaptic transmission. The possible role of VEGF in depression has been hypothesized in the context of the neurotrophic model of depression, which postulates that stress can lead to decreased level of neurotrophins. Since VEGF has emerged as a potential component in the pathophysiology of stress and stress-related disorders, animal and clinical studies have attempted to delineate its precise role. In this review article we provide a synopsis of basic studies that are of direct relevance to the clinical findings in depression and antidepressant drug action. We have classified the studies on the basis of higher, lower or no different levels of VEGF as compared to control subjects. It became evident that there is conflicting data regarding VEGF levels in depressed patients. The fact that no definitive trend is apparent in the published data is likely attributable to differences in study designs. However, promising leads have emerged in our effort to understand and clarify this wide variation in results. Further study could establish the potential use of VEGF as a biomarker to aid in making a correct diagnosis and a successful treatment plan. Delineating the relationship of VEGF and depression ultimately has the potential to shed light on the still elusive neural mechanisms underlying the pathophysiology of depression and the mechanisms by which antidepressants exert their effects.

Summary Previous studies have indicated that there may be a dysregulation of α 2 -adrenoceptors and imidazoline receptors in depression. This study compares the effects of chronic antidepressant treatment with a serotonin reuptake inhibitor (fluoxetine) versus a noradrenaline reuptake inhibitor (desipramine) on the binding parameters of the platelet imidazoline binding site (subtype I 1 ) and of the platelet α 2 -adrenoceptor in depressed patients. After 6 weeks of treatment with either antidepressant, platelet I 1 binding sites became normalized (i.e. downregulated). A negative correlation was obtained between plasma epinephrine concentrations and platelet α 2 -adrenoceptor B max values within the samples, but no correlation was obtained between any plasma catecholamine and a platelet I 1 binding parameter. An additional finding was the increased affinity of α 2 -adrenoceptors for p 125 I-clonidine in untreated depressed patients compared to healthy subjects. Because of the density of platelet I 1 binding sites was downregulated by both of the antidepressants, we postulate that a decrease in platelet I 1 binding site density may be related to an improved state from depression that these antidepressants produce.

Plasma concentrations of total (free plus conjugated) 3-methoxy-4-hydroxyphynylglycol (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 acorphase were roughly twice as large in the patients compared to healthy subjecs. 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.

Circadian rhythm abnormalities have been described mostly with respect to manic-depressive illness; little information is available concerning circadian rhythms and schizophrenia or their influence on neuroleptic drugs. We showed previously that the MESOR of dopamine is higher in schizophrenic patients than in healthy subjects and that women who are drug-free schizophrenic have lower prolactin MESORs and lower amplitudes than healthy women. We now report the data of a cosinor analysis of tryptophan, serotonin, melatonin, and pituitary hormones in the blood of 34 healthy subjects, 90 drug-free schizophrenics, and 25 neuroleptic-treated schizophrenic patients. This data indicated a significant phase advance of serum tryptophan, prolactin, and melatonin concentrations, a trend toward a phase advance in serotonin. Thyroid stimulating hormone (TSH), and growth hormone concentrations, and decreases in the TSH MESORs among patients compared to healthy subjects. These results suggest that circadian changes, such as phase advances and alterations in MESOR, are not only present in depression but also in schizophrenia. Although neuroleptic treatment raised the prolactin MESOR and amplitude, it did not elicit any change in circadian rhythmicity among the other parameters.

An association between dysphoric premenstrual syndromes (PMS) and a lifetime history of major depressive disorders has previously been documented. Other studies have demonstrated an increase in the binding of radiolabeled imidazoline compounds to platelets of depressed patients. Clonidine and related imidazoline compounds interact with α 2 adrenoceptors to inhibit neuronal noradrenergic activity and in higher concentrations, they stimulate noradrenergic activity through their interaction with imidazoline receptors. Here we report increased 3 H para-aminoclonidine binding to high affinity α 2 adrenoceptor sites as well as to noradrenergic imidazoline binding sites in platelets of women with dysphoric PMS. This higher binding was most pronounced during the late-luteal-symptomatic phase of the menstrual cycle and, to a lesser degree, during the non-symptomatic mid-follicular phase. Binding to the imidazoline site distinguished women with dysphoric PMS from women with no such symptoms, was highly positively correlated with the severity of symptoms, and was negatively correlated with plasma levels of progesterone. These findings suggest that platelet imidazoline binding sites might be a biological marker for dysphoric states in PMS or for the vulnerability to develop them. These findings also point to a possible biological link between dysphoric PMS and major depressive disorders.

Circadian rhythm abnormalities have been described in various psychiatric disorders, but they have not received much attention in studies of schizophrenia and schizophreniform psychosis. The present study used the cosine model to determine the circadian patterns of amino acids, dopamine, and prolactin concentrations, which were analyzed over a 24-hour period in serum of healthy subjects, drug-free schizophrenic patients, and neuroleptic-treated schizophrenic patients. The mesor (the daily mean) of phenylalanine was lower in drug-free schizophrenic women than in healthy women. The mesors of the ratio of phenylalanine or tyrosine to competing amino acids were similar in healthy subjects and patients. The ratio of phenylalanine/competing amino acids showed a phase advance (i.e., earlier onset of the time of highest concentration) in drug-free patients compared with healthy subjects. Schizophrenic patients displayed a higher dopamine mesor than healthy subjects. Female drug-free schizophrenic patients had lower prolactin mesors and lower amplitudes (i.e., half of the total predictable change in rhythm) than healthy women. Compared with healthy subjects, schizophrenic patients showed a phase advance of circadian prolactin concentrations. Neuroleptics raised the prolactin mesor and amplitudes but did not elicit any phase change in amino acids, dopamine, or prolactin. These data confirm the indirect pharmacologic evidence of increased dopaminergic activity in schizophrenic patients that relates to dopamine's precursors and to the neuroendocrine regulation of prolactin.

Characterization of the binding of [ 3 H] p -aminoclonidine ([ 3 h]PAC) to purified plasma membranes from human platelets has revealed multiple binding sites. [ 3 h]PAC identified site-1 in the picomolar affinity range (site-1 K D estimates ranged from 13 to 94 pM). Site-1 displayed a rank order of competition by various compounds for [ 3 H]PAC, indicative of an α 2 -adrenoceptor, and was sensitive to 0.1 mM GTP. [ 3 H]PAC also identified a second site with nanomolar affinity (site-2 K D estimates ranged from 0.7 to 1.7nM). In the presence of 0.1 mM GTP, site-2 was not diminished significantly. Also in contrast to site-1, site-2 displayed low affinity for yohimbine (YOH), (−)-epinephrine and (−)-norepinephrine (NE). Therefore, site-2 could not be an active α 2 -adrenoceptor; instead it had properties similar to a previously reported imidazoline-preferring binding site. A third site (site-3) bound [ 3 h]PAC with a K D for site-3 of 26.6 ± 10.0 nM (SD). Site-3 had a rank order of competition by various compounds for 5nM [ 3 H]yohimbine ([ 3 H]YOH) binding which was indicative of an α 2 -adrenoceptor. (−)-NE competed for 5 nM [ 3 H]YOH binding at two sites: site-1 K i = 32 pM, site-3 K i = 239 nM. Treatment with 0.1 mM GTP completely removed site-1 and transferred the competitive binding of (−)-NE to low affinity ( K i = 437 nM). Thus, site-3 appears to be a free α 2 -adrenoceptor. B max estimates for untreated membranes, derived from simultaneous multi-experiment curve-fitting analyses, were site-1 = 36 ± 29 fmol/mg plasma membrane protein, site-2 = 95 ± 34 fmol/mg and site-3 = 154 ± 35 fmol/mg. We are the first to report a site for [ 3 H]PAC binding on platelets (site-2) with properties uncharacteristic of an adrenoceptor. This observation appears to be due to our use of purified plasma membrane and low ionic strength buffer. These studies relate to reports of increased binding of [ 3 H]PAC to platelets from depressed patients.

Membrane fluidity and adrenergic receptor binding were studied in platelets of depressed patients before and during treatment with desmethyl-imipramine to investigate the relationship between the α 2 -adrenergic receptor and its membrane environment in depression. Most samples came from a previous study in which we observed higher 3 H-para-aminoclonidine ( 3 H-PAC) binding in platelets from depressed patients compared to healthy subjects. Fluidity was measured by steady state diphenylhexatriene (DPH) anisotropy in both purified plasma membranes and in intracellular membrane preparations from platelets. No differences were observed in DPH membrane fluidity, per se, indicating that fluidity changes probably do not underlie either the increased α 2 -adrenergic receptor binding in depression or the normalization of binding during treatment. However, lower intra cellular membrane fluidity was correlated with higher binding to 3 H-PAC site-1 in healthy subjects, but not in depressed patients. Thus, during depression there may be a disruption in the normal relationship between the adrenergic receptor and its membrane environment.

The binding characteristics of [3H]proprionyl-neuropeptide Y ([3H]proprionyl-NPY) were studied in frontal cortical membranes prepared from rat and human postmortem tissue. The specific binding of NPY decreased as the magnesium concentration increased from 1.05 to 10 mM. The binding was also influenced by the concentration of GTP in the buffer medium, with a resulting 45% decrease in NPY binding in the presence of 10(-6) M GTP. Using equilibrium binding studies, [3H]proprionyl-NPY was found to bind in both tissues with high affinity to a single class of receptors with a similar KD (0.035 nM). However, kinetic experiments in both tissues provided evidence for two components of [3H]proprionyl-NPY binding which may be related to receptor states. Competition binding experiments showed that peptide YY (PYY) was equal to NPY in its ability to displace [3H]proprionyl-NPY, whereas rat and human pancreatic polypeptide were without effect up to a concentration of 10(-6) M. This suggests that, whereas PYY and NPY may compete for the same receptor(s), the pancreatic polypeptides probably act on a separate population of receptors.

The role of stress was examined in a sample of 68 endogenously depressed patients. Antecedent and concurrent life events and long-term difficulties, operationalized by different subcategories and scoring options, were related to depression severity, treatment response versus nonresponse, and maintenance versus relapse. Results showed an association between initial depression and various categories of subjective stress; a reduction in subjective (but not objective) event-related stress coincident with remission; positive relationships between life events and response and maintenance and between difficulties and relapse; and a higher event profile among unipolar depressive patients. Results are discussed in terms of the positive prognostic value of reactivity in endogenous depression, as well as the interactive relationship between continuing depression and long-term difficulties.

Pharmacological characterization is described for a human imidazoline binding site (I-site) labeled by [(3)H]clonidine using standard autoradiographic method. Under conditions that mask alpha(2)-adrenergic sites, only a single high affinity site was observed in human caudate and blood platelet sections. Affinity constants (K(i)) were highly correlated between the two tissues (r = 0.90, P = 0.0003). This site is dissimilar to classical I(1) and I(2) sites, even though both tissues possess abundant I(1) and I(2) sites by filtration binding methods. It is suggested that the isotonic buffer conditions inherent to the procedure alter drug affinities to the classical I(1) site.

The cardiovascular relevance of imidazoline receptors (IR) has received tremendous attention since their discovery in 1984. However, evidence also has accumulated for the relevance of IR and an endogenous ligand, agmatine, to psychiatric disease. Emphasis has been placed on altered levels of the I(1)-imidazoline site on human platelets and in human postmortem brain tissue from depressed patients. Attempts at exploring the molecular nature of the I(1) protein have led to the cloning of a protein, IRAS. Based on transfection studies, IRAS seems to be involved in neuronal plasticity events. The I(2) site also appears linked to psychiatric research since some of these sites are localized to a specific domain on monoamine oxidases. Different peptides have been identified by means of an imidazoline-receptor-binding-protein (IRBP) antiserum, and these peptides, some of which appear to be fragments derived from IRAS, undergo changes in platelets and brain commensurate with altered mood states of the subject, notably depressive symptomatology. The search for an endogenous ligand for imidazoline receptor(s) also has led to agmatine, a decarboxylated derivative of arginine. Research on agmatine has mushroomed over the past several years and its measurement in the blood and brain has opened new research opportunities. This novel neurotransmitter interacts with a variety of receptors and has been implicated in mediation of stress responses, analgesia, drug addiction and withdrawal, convulsions, and neuroprotection. Given that IR and agmatine appear involved in a multitude of neurophysiologic and pathologic functions, the potential for new drug development is intriguing.

Clonidine is a well established antihypertensive agent that is also used effectively to treat a variety of psychiatric disorders. Clonidine is a prototypic imidazoline compound that acts as an alpha(2)-adrenergic agonist but possesses nearly equivalent affinity for non-adrenergic imidazoline binding sites (I-sites). Receptor autoradiography of [(3)H]-clonidine binding presented herein compares densities of alpha(2)-adrenoceptors and I-sites (under a noradrenergic-mask) in Brodmann's area 47 of the left orbitofrontal cortex (OFC) and in six amygdaloid nuclei of subjects with major depression (n=12) vs. controls with no psychiatric history (n=11). Postmortem diagnoses were made from psychiatric interviews with next-of-kin. [(3)H]-Clonidine binding to alpha(2)-adrenoceptors in each of six OFC layers was lower, although not reaching statistical significance in any one layer by multivariate analysis, in depressives vs. control subjects. Binding to I-sites was conversely higher in depressives compared to control OFC layers, but did not reach statistical significance alone. However, the ratios of alpha(2)-adrenoceptor : I-sites in all six layers of OFC of depressed subjects were nearly half that of control subjects (P

An elevation of I1 (imidazoline-1)-binding sites on platelets may be a state marker for depression. Herein, platelet I1 sites were compared in two groups of unipolar depressed patients given different regimens of bupropion treatment: Regimen 1 (n = 13 titrated up to 300 mg/d by week 4 and held constant until week 6); Regimen 2 (n = 15 titrated up to 300 mg/d by week 2, to 450 mg/d by week 6, and held constant until week 8). Platelet I1 sites were quantified by p-[125I]iodoclonidine binding (0.5-15 nM) and displaced by moxonidine under a saturating concentration of norepinephrine to mask alpha2-adrenoceptors. I1 B max values were confirmed to be high at pretreatment in depressed patients (n = 28) compared to healthy control subjects (n = 18; p = 0.02). Highest B max values at pretreatment were found in patients who responded worst to treatment. More than two-thirds of patients recovered from depression (69 and 80% in Regimens 1 and 2, respectively) after treatment. Dose and/or time of exposure to bupropion were relevant variables since (1). only Regimen 2 led to platelet I1 down-regulation and (2). the extent of down-regulation correlated with plasma concentrations of bupropion. The data suggest a dissociation exists between I1 down-regulation and therapeutic response, or else platelet I1 down-regulation lags behind clinical antidepressant response before becoming measurable.

Background: A downregulation of I2-imidazoline binding sites has been reported in frontal cortices of depressed suicide victims, according to I2-radioligand binding and confirmed by Western blotting. We now report Western blots of imidazoline receptor proteins in hippocampi of subjects with and without depression at the time of death. Methods: Postmortem diagnoses were obtained from 17 cases of Axis I major depressive disorder and 17 cases without Axis I psychopathology. No psychotropic compounds were found in body fluids. Hippocampi were removed, sectioned, and assessed histologically. Throughout the analysis, each major depressive disorder sample was paired with a sample from a psychiatrically healthy subject based on equivalent life spans and postmortem delays. The antiserum was identical to that used in previous studies that reported a downregulation of cortical 29/30-kd imidazoline receptor–binding proteins in depression. Results: A triad of imidazoline receptor–binding protein bands (40–50 kd) was detected in the human hippocampus. Subjects with major depressive disorder had significantly less intensity in each imidazoline receptor–binding proteins band compared with control subjects (p = .01 for overall bands). Conclusions: The present results can be aligned with previous reports of downregulation of I2-radioligand binding sites in both cortices and platelets of depressed patients.

Clonidine is a partial agonist at brain alpha(2)-adrenoceptors (alpha(2)AR), but also has high affinity (K(D) = 51 nM) in homogenate binding assays for non-adrenergic imidazoline-binding sites (I-sites; imidazoline receptors). Herein, an autoradiographic comparison of [3H]-clonidine binding to I-sites and alpha(2)AR in sections of human brain is reported. For I-sites, the adrenergic component of 50 nM [3H]-clonidine binding was masked with either 60 microM norepinephrine (NE; alpha(2)AR agonist) or 12.5 microM methoxy-idazoxan (MIDX; selective alpha(2)AR antagonist), whereas the remaining non-adrenergic sites were studied by displacement with 20 microM cirazoline. Levels of [3H]-clonidine binding to alpha(2)AR and I-sites, determined in adjacent tissue sections, were positively correlated across 27 brain regions (p = 0.0003; r(2) = 0.385). The principal olivary nucleus and the rostral portion of the ventrolateral medulla had highest ratios of I-sites: alpha(2)AR (4:1). Quantitative transepts drawn across hippocampal images revealed alpha(2)AR enrichments in the CA-1 and inner molecular layers of the dentate gyrus-areas not enriched in I-sites. Competition curves were generated for I-sites in caudate sections using 10 ligands known to distinguish between I(1) and I(2) subtypes. The rank-order of affinities were cirazolineharmaneBDF6143idazoxan = tizanidine (affinities of agmatine, efaroxan, moxonidine, NE, and oxymetazoline were too low to be reliable). Only the endogenous I-site ligand, harmane, had a monophasic displacement curve at the non-adrenergic sites (Ki = 521 +/- 12 nM).1) the distribution of non-adrenergic [3H]-clonidine binding sites in human brain sections was correlated with, but distinct from alpha(2)AR; and 2) the affinities of these sites was distinct from alpha(1)AR, alpha(2)AR, I(1) or I(2) sites as previously defined in membrane binding assays. The properties of this non-adrenergic [3H]-clonidine binding site are consistent with I-sites previously labeled by [3H]-cirazoline in rat brain.

The precise role of testosterone in regulating mood, especially in alleviating depression, remains unclear although converging evidence indicates that androgens may exert antidepressant action. A model that may potentially assist in the clarification of androgen-mediated effects on mood is the study of cryptorchid men who may grow up with varying degrees of testosterone deficiency depending on the time in their life when cryptorchism is corrected. In this report, we describe a rare case of bilateral cryptorchism that did not come to the attention of the physician to implement effective substitution with testosterone until much later in adult life. The patient developed severe and suicidal depression which responded solely to testosterone. In addition, the patient experienced a delayed but accelerated puberty without any adverse events. These observations, although based on a single case, provide strong evidence that testosterone may exert powerful antidepressant action in the absence of concomitant antidepressant agents.