Copeptin, the C-terminal part of the hypothalamic arginine vaspopressin (AVP) precursor, closely mirrors the production of AVP and was proposed as an easily measured novel marker of the individual stress level in man. First data in male volunteers proposed copeptin as a potential endocrine surrogate marker of cholecystokinin-tetrapeptide (CCK-4)-induced panic. We tried to replicate these pilot data and to extend them to the other sex. 46 healthy human subjects (29 men, 17 women) were given an intravenous bolus of 50 mu g CCK-4. Basal and stimulated plasma copeptin was measured and panic symptoms were assessed using the Acute Panic Inventory (API). Basal copeptin was significantly lower in women vs. men, while men showed a significantly higher CCK-4-induced increase of copeptin. In contrast, female subjects displayed a signifcantly higher increase of API ratings by CCK-4. No significant correlations of panic symptoms and copeptin release induced by CCK-4 could be found, neither in man, nor in women, nor in the total sample. A sexual dimorphism in copeptin secretion and in panic response was demonstrated. Prior unexpected findings of copeptin release as an objective read-out of panic could not be replicated. The role of the vasopressinergic system in panic anxiety needs further study in panic patients and in healthy man, using also other panic provocation paradigms.

Background: Cardiovascular disorders (CVD) and major depressive disorder (MDD) are the most frequent diseases worldwide responsible for premature death and disability. Behavioral and immunological variables influence the pathophysiology of both disorders. We therefore determined frequency and severity of MDD in CVD and studied whether MDD without CVD or other somatic diseases influences classical and inflammatory biomarkers of cardiovascular risk. In addition, we investigated the influence of proinflammatory cytokines on antidepressant treatment outcome. Methods: In a case-control design, 310 adults (MDD patients without CVD, CVD patients, and cardiologically and psychiatrically healthy matched controls) were investigated. MDD patients were recruited after admission in a psychiatric university hospital. Primary outcome criteria were clinical depression ratings (HAM-D scale), vital signs, classical cardiovascular risk factors and inflammatory biomarkers which were compared between MDD patients and healthy controls. Results: We detected an enhanced cardiovascular risk in MDD. Untreated prehypertension and signs directing to a metabolic syndrome were detected in MDD. Significantly higher inflammatory biomarkers such as the high sensitivity C-reaktive protein (hsCRP) and proinflammatory acute phase cytokines interleukine-1β (IL-1β) and interleukine-6 (IL-6) underlined the higher cardiovascular risk in physically healthy MDD patients. Surprisingly, high inflammation markers before treatment were associated with better clinical outcome and faster remission. The rate of MDD in CVD patients was high. Conclusions: Patients suffering from MDD are at specific risk for CVD. Precise detection of cardiovascular risks in MDD beyond classical risk factors is warranted to allow effective prophylaxis and treatment of both conditions. Future studies of prophylactic interventions may help to provide a basis for prophylactic treatment of both MDD and CVD. In addition, the high risk for MDD in CVD patients was confirmed and underlines the requirement for clinical attention.

cholecystokinin-tetrapeptide (CCK-4) induces panic symptoms in healthy human subjects, which closely resemble spontaneously occurring panic attacks in patients and provides a safe, valid and reliable experimental model for the investigation of pathophysiological, neurobiological and pharmacological aspects of panic disorder. Benzodiazepines modulate γaminobutyric acid type A (GABAA) receptors throughout the brain. However, it is not fully understood which brain regions within anxiety related brain circuits are really responsible for their anxiolytic effects and how these regions interact. We therefore investigated whether the benzodiazepine alprazolam affects activity in distinct regions within anxiety related brain circuits in humans by means of functional magnetic resonance imaging (fMRI) and experimental induction of panic symptoms with CCK-4.

According to to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis inhibitor metyrapone and the glucocorticoid receptor antagonist mifepristone in depression has been demonstrated in some small, double-blind, placebo-controlled studies. However, three recently completed Phase Ill trials failed to significantly separate mifepristone from placebo in depression. Thus, it is unclear at present to what extent new, clinically effective antidepressant therapies can be developed based on the corticoid receptor hypothesis of depression.

Background: Benzodiazepines modulate gamma-aminobutyric acid type A (GABA(A)) receptors throughout the brain. However, it is not fully understood which brain regions within anxiety-related brain circuits are really responsible for their anxiolytic effects and how these regions interact.Methods: We investigated whether the benzodiazepine alprazolam affects activity in distinct brain regions within anxiety-related circuits during an experimental anxiety paradigm by means of functional magnetic resonance imaging (fMRI). Panic symptoms were elicited by a bolus injection of the neuropeptide cholecystokinin-tetrapeptide (CCK-4) in 16 healthy male subjects in a double-blind, placebo-controlled design. Functional brain activation patterns were determined before and during the CCK-4-challenge without pretreatment and after treatment with either placebo or 1 mg alprazolam.Results: The CCK-4 induced anxiety and elicited widely distributed activation patterns in anxiety-related brain circuits, especially in the rostral anterior cingulate cortex (rACC), which was attenuated after alprazolam treatment. In contrast to placebo, alprazolam abolished the activation of the rACC after challenge with CCK-4 (p < .005, corrected for multiple comparisons) and increased functional connectivity between the rACC and other anxiety-related brain regions such as amygdala and prefrontal cortex. Moreover, the reduction in the CCK-4 induced activation of the rACC correlated with the anxiolytic effect of alprazolam (r(p) = .52; p = .04).Conclusions: These findings put forward the rACC as a target for benzodiazepines and suggest that the CCK-4/fMRI paradigm might represent a human translational model for the investigation of anxiolytic drugs.

The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.

SynapseVolume 65, Issue 3 p. 257-259 Short Communication Variation in binding affinity of the novel anxiolytic XBD173 for the 18 kDa translocator protein in human brain David R.J. Owen, Corresponding Author David R.J. Owen d.owen@imperial.ac.uk Division of Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom D.R.J.O and A.J.M.L contributed equally to this work.Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorAndrew J.M. Lewis, Andrew J.M. Lewis Division of Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom D.R.J.O and A.J.M.L contributed equally to this work.Search for more papers by this authorRichard Reynolds, Richard Reynolds Wolfson Neuroscience Laboratories, Imperial College London, London, United KingdomSearch for more papers by this authorRainer Rupprecht, Rainer Rupprecht Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstrasse 7, Munich 80336, Germany Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2, Munich 80804, GermanySearch for more papers by this authorDaniela Eser, Daniela Eser Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstrasse 7, Munich 80336, GermanySearch for more papers by this authorMartin R. Wilkins, Martin R. Wilkins Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorIdriss Bennacef, Idriss Bennacef Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorDavid J. Nutt, David J. Nutt Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorChristine A. Parker, Christine A. Parker Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this author David R.J. Owen, Corresponding Author David R.J. Owen d.owen@imperial.ac.uk Division of Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom D.R.J.O and A.J.M.L contributed equally to this work.Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorAndrew J.M. Lewis, Andrew J.M. Lewis Division of Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom D.R.J.O and A.J.M.L contributed equally to this work.Search for more papers by this authorRichard Reynolds, Richard Reynolds Wolfson Neuroscience Laboratories, Imperial College London, London, United KingdomSearch for more papers by this authorRainer Rupprecht, Rainer Rupprecht Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstrasse 7, Munich 80336, Germany Max-Planck-Institute of Psychiatry, Kraepelinstrasse 2, Munich 80804, GermanySearch for more papers by this authorDaniela Eser, Daniela Eser Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Nussbaumstrasse 7, Munich 80336, GermanySearch for more papers by this authorMartin R. Wilkins, Martin R. Wilkins Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorIdriss Bennacef, Idriss Bennacef Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorDavid J. Nutt, David J. Nutt Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this authorChristine A. Parker, Christine A. Parker Division of Experimental Medicine, Imperial College London, London W12 0NN, United KingdomSearch for more papers by this author First published: 03 December 2010 https://doi.org/10.1002/syn.20884Citations: 33 Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume65, Issue3March 2011Pages 257-259 RelatedInformation

Objectives: The effectiveness of electroconvulsive therapy (ECT) in pharmacotherapy-resistant major depressive disorder and schizophrenia has been shown for all age groups. Nevertheless, age-specific adverse effects such as greater cognitive impairment and higher somatic risks due to medical comorbidities and concomitant medication may be limiting factors in geriatric patients.Methods: We retrospectively evaluated 4457 treatments in 380 patients to investigate the influence of age on ECT outcome, safety, and adverse effects. Clinical variables, treatment modalities, and neurophysiological parameters were analyzed. For modeling the influence of age on these variables of interest, linear and logistic regression models were performed.Results: The mean (SD) age of our patients was 51.2 (15) years; 30% were older than 60 years. Diagnoses were major depressive disorder in 74.4% and schizophrenia in 25.6%. We found a considerable clinical improvement in all age groups. A higher severity of disease at admission corresponded to a better clinical response. Analyzing treatment modalities of elderly patients older than 60 years, no significant differences in need and number of concomitant psychotropic medications were seen, but significant differences were seen in medical co-medication. Ictal and postictal neurophysiological parameters were only in part predictive for clinical outcome, but age had a significant influence on most of them. Transient cardiovascular adverse effects and cognitive disturbances were more frequent in the elderly. In most cases, there was no need for any specific treatment.Conclusions: Our data confirm previous studies indicating the good effectiveness of ECT irrespective of age. We also found an excellent tolerability profile in the elderly in our patient sample. There was no mortality, and only transient and no life-threatening adverse events occurred.

Background. Among the neuroactive steroids, 3 alpha,5 alpha-tetrahydrodeoxycorticosterone (3 alpha,5 alpha-THDOC) is at least in part produced in the adrenal gland and is therefore under the control of the hypothalamic-pituitary-adrenocortical (HPA) system. The antidepressant mirtazapine has been shown to attenuate HPA axis activity and to increase the concentrations of 3 alpha-reduced metabolites of progesterone in depressed patients. In the present study, the impact of mirtazapine on 3 alpha,5 alpha-THDOC levels was investigated in relation to clinical response in depressed patients. Method. A total of 23 drug-free inpatients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 08:00 h and were quantified for 3 alpha,5 alpha-THDOC levels. Results. 3 alpha,5 alpha-THDOC levels were not correlated with demographic and clinical parameters such as age and severity of depression. Moreover, 5-week treatment with mirtazapine did not influence the 3 alpha,5 alpha-THDOC in the depressed patients, neither in responders nor in non-responders. Conclusion. Putative increasing effects of mirtazapine on 3 alpha-reduced neuroactive steroids such as 3 alpha,5 alpha-THDOC which may be mediated via an impact on the neurosteroidogenic enzyme 3 alpha-hydroxysteroid dehydrogenase seem to be counterbalanced by the mirtazapine-induced inhibition of ACTH secretion which directly influences the 3 alpha,5 alpha-THDOC release of the adrenal cortex.

Zolpidem, a non-benzodiazepine hypnotic, acts selectively via the alpha(1)-subunit of GABA(A) receptors at therapeutic doses. It is therefore thought to lack both benzodiazepine properties such as anxiolysis, anticonvulsion, muscle relaxation, and side effects such as dependency. We report a case of severe dependency of zolpidem taken because of percieved myorelaxation in a patient with multiple sclerosis and paraspasticity. The observations in the patient described here suggest that zolpidem looses alpha 1-receptor selectivity at higher doses, thereby leading to the same risks and benefits such as benzodiazepines. This should be taken into account by doctors when prescribing higher doses. Zolpidem may improve symptoms of spasticity in high doses via affection of GABA alpha 2-receptor and alpha 3-receptor subunits.

RATIONALE:There is evidence that the anti-glycation enzyme glyoxalase-1 (GLO1) may play a role in anxiety-related behaviour. However, discordant findings between GLO1 expression and anxiety-related behaviour have been observed in animal models. Because no data are available on the relation between GLO1 mRNA expression and human anxiety so far, we investigated the expression of GLO1 mRNA in peripheral blood cells in relation to cholecystokinin-tetrapeptide (CCK-4) induced panic anxiety in healthy subjects as an established model of human anxiety in healthy volunteers. METHODS:Twenty-three healthy subjects underwent challenge with CCK-4. GLO1 mRNA expression was assessed by quantitative real-time polymerase chain reaction prior to CCK-4 injection. Baseline anxiety was assessed with the State-Trait-Anxiety-Inventory (STAI) and panic response was measured with the Panic Symptom Scale (PSS). RESULTS:CCK-4 elicited a marked anxiety response accompanied by a significant increase in heart rate. GLO1 mRNA expression did not correlate with state or trait anxiety nor with severity of CCK-4 induced anxiety. CONCLUSIONS:The lack of correlation between GLO1 mRNA expression and CCK-4 induced panic severity suggests that GLO1 is not involved into the acute panic response to CCK-4 in healthy volunteers. Therefore, further studies are needed to clarify the involvement of GLO1 in anxiety disorders at baseline and in anxiety challenge paradigms to resolve the apparent contradictions of preclinical studies concerning the relationship between GLO1 expression and anxiety.

Background: Electroconvulsive therapy (ECT) is still considered the most effective biological treatment strategy in psychiatric disorders. However, the clinical efficacy of ECT may be affected by stimulus variables and the concomitant use of psychopharmacological medication. Furthermore, most anaesthetics have anticonvulsant properties and therefore might additionally influence the efficacy of ECT. Method: In order to explore whether different anaesthetics might alter the effectiveness or safety of ECT we retrospectively analyzed 5482 ECT treatments in 455 patients. Anaesthetics were chosen according to clinical reasons and comprised thiopental, methohexital, propofol and etomidate. Results: Seizure duration was significantly affected by the anaesthetic medication with longest seizure activity during thiopental anaesthesia. In addition, postictal suppression, a further prospective parameter of ECT effectiveness, was significantly higher during propofol and thiopental anaesthesia. The clinical effectiveness was significantly better during propofol and thiopental anaesthesia. In contrast, the overall safety did not differ between the anaesthetic groups. Conclusion: Our study supports the hypothesis that inducting anaesthetic agents have a different impact on seizure duration, ictal and postictal electrophysiological indices and clinical efficacy of ECT. Compared to thiopental, which has been established as a standard anaesthetic during ECT, also the modern anaesthetic propofol is a suitable inducting agent.

Most antianxiety drugs (anxiolytics) work by modulating neurotransmitters in the brain. Benzodiazepines are fast and effective anxiolytic drugs; however, their long-term use is limited by the development of tolerance and withdrawal symptoms. Ligands of the translocator protein [18 kilodaltons (kD)] may promote the synthesis of endogenous neurosteroids, which also exert anxiolytic effects in animal models. Here, we found that the translocator protein (18 kD) ligand XBD173 enhanced gamma-aminobutyric acid-mediated neurotransmission and counteracted induced panic attacks in rodents in the absence of sedation and tolerance development. XBD173 also exerted antipanic activity in humans and, in contrast to benzodiazepines, did not cause sedation or withdrawal symptoms. Thus, translocator protein (18 kD) ligands are promising candidates for fast-acting anxiolytic drugs with less severe side effects than benzodiazepines.

There is evidence that gamma-amino-butyric acid type A (GABAA)-receptor modulating neuroactive steroids play a role in the pathophysiology of panic disorder. Antidepressant treatment has been suggested to stabilize the concentrations of neuroactive steroids. In this pilot study we investigated neuroactive steroid concentrations during GABAergic treatment, which might represent an alternative anxiolytic pharmacotherapeutic strategy. Neuroactive steroid concentrations were determined in 10 healthy subjects treated with tiagabine. To evaluate the anxiolytic effects of tiagabine a cholecystokinine-tetrapeptide (CCK-4) challenge was performed before and after treatment. Treatment with tiagabine led to a significant increase in 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-THDOC) from 0.49 to 1.42 nmol/l (Z = −2.80, p = .005), which was significantly correlated with a decrease of panic symptoms in the CCK-4 challenge. Thus, it might be hypothesized that the anxiolytic effects of GABAergic treatment might in part be mediated by their influence on 3α,5α-THDOC concentrations.

Background. The purpose of the present open-label study was to investigate the antidepressant efficacy of lithium and carbamazepine as augmentation strategies in unipolar depressed inpatients. Method. Forty-six patients suffering from unipolar depression (major depressive episode according to DSM-IV criteria) were pre-treated with mirtazapine for 2 weeks initially (week -2 to week 0). Thereafter, the patients received either continuation of mirtazapine monotherapy (n = 23), combination treatment with mirtazapine and lithium (n = 13), or combination therapy with mirtazapine and carbamazepine (n = 10) for further 3 weeks (week 0 to week 3). Severity of depression was estimated weekly using the 21-item version of the Hamilton Depression Rating Scale (21-HAMD). Response was defined by a reduction of at least 50% in the 21-HAMD sum score after 3 weeks of pharmacotherapy (week 0 3). Results. Additional administration of lithium, but not adjunctive carbamazepine significantly augmented the antidepressant efficacy of mirtazapine in the unipolar depressed patients. Moreover, carbamazepine but not lithium significantly lowered the serum concentrations of mirtazapine. Conclusion. Whereas the clinical importance of anticonvulsants in the treatment of bipolar disorder is not in doubt, the therapeutic efficacy of antiepileptic drugs such as carbamazepine is obviously limited in the pharmacotherapy of unipolar depression.

Clinical data on the efficacy of agomelatine In spite of recent progress in the pharmacotherapy of depression, there is still a high non-response rate to the first antidepressant treatment. Furthermore, the latency of several weeks until sufficient clinical improvement and the risk of side effects remain unresolved problems. Therefore, there is still further need for the development of new antidepressants. Preclinical studies suggested that agomelatine, a synthetic melatonergic MT1 and MT2 receptor agonist with 5-HT2C receptor antagonistic properties may represent a new approach in the treatment of depression. In clinical trials, including phase III studies, superior efficacy compared to placebo and at least equal efficacy compared to standard antidepressants was shown for agomelatine. The improvement of sleep-wake-rhythm, the tolerability in terms of sexual side effects, and the lack of withdrawal symptoms after abrupt discontinuation of treatment may represent important clinical benefits compared to established amidepressants. Therefore, agomelatine may represent a novel perspective in the treatment of depression.