The Effect of Clozapine on Self-reported Duration of Sleep and Its Interaction With 23 Other Medications: A 5-Year Naturalistic Study.

BACKGROUND: Sedation is a common and incapacitating clozapine adverse effect, but the factors associated with sedation and its pharmacological management remain poorly studied. METHODS: We conducted a retrospective cohort study based on deidentified electronic clinical records of clozapine-treated patients from the secondary mental health care provider for Cambridgeshire and Peterborough, United Kingdom. We first evaluated cross-sectionally the influence of clozapine dose, clozapine, and norclozapine plasma levels on self-reported hours slept, as a proxy for sedation, using bivariate correlation and then the longitudinal effect of changes in clozapine dose and other 23 medications using linear mixed effect models. We followed 241 clozapine-treated patients for 56 months on average, with 2237 face-to-face assessments in total. RESULTS: Patients slept for a mean of 9.35 h/d, with 46% reporting 10 h/d or more. Cross-sectionally, sleep duration did not correlate with clozapine dose (r = 0.14, P = 0.106), but with clozapine plasma levels (r = 0.38, P < 0.0001) and norclozapine plasma levels (r = 0.25, P = 0.005). Longitudinally, the final mixed-effects model revealed 4 pharmacological variables that had a significant impact on hours slept: clozapine, risperidone augmentation, and atenolol were associated with increased sleep, whereas aripiprazole augmentation was associated with decreased sleep. We found that 20 other psychotropic medications measured were not associated with changes in sleep when added to clozapine. Excess sleep is a clozapine level-dependent adverse effect. CONCLUSIONS: The impact of different augmentation strategies might help clinicians decide on the most adequate strategy, albeit further studies should confirm our results.

PROTECT: Relational safety based suicide prevention training frameworks.

Preventing suicide is a global priority, and staff training is a core prevention strategy. However, frontline pressures make translating training into better care and better outcomes difficult. The aim of the paper was to highlight challenges in suicide risk assessment and management and introduce training frameworks to assist with mindful practice so professionals can strike a balance between risk and recovery. We combined the scientific literature with contemporary practice from two successful initiatives from Cambridgeshire, UK: 333 - a recovery-oriented model of inpatient/community crisis care and PROMISE - a programme to reduce coercion in care by enhancing patient experience. The resulting PROTECT (PROactive deTECTion) frameworks operationalize ongoing practice of relational safety in these programmes. PROTECT is a combination of novel concepts and adaptations of well-established therapeutic approaches. It has four training frameworks: AWARE for reflection on clinical decisions; DESPAIR for assessment; ASPIRE for management; and NOTES for documentation. PROTECT aims to improve self-awareness of mental shortcuts and risk-taking thresholds and increase rigour through time-efficient cross-checks. The training frameworks should support a relational approach to self-harm/suicide risk detection, mitigation, and documentation, making care safer and person-centred. The goal is to enthuse practitioners with recovery-oriented practice that draws on the strengths of the person in distress and their natural circle of support. It will provide the confidence to engage in participatory approaches to seek out unique individualized solutions to the overwhelming psychological pain of suicidal distress. Future collaborative research with people with lived and carer experience is needed for fine-tuning.

The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people.

In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer's disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects 'cold' cognition, but also improves 'hot' cognition, such as emotion recognition and task-related motivation. The lifestyle use of 'smart drugs' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish.

Evidence for the differential co-localization of neurokinin-1 receptors with 5-HT receptor subtypes in rat forebrain.

Studies suggest that like selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors, antagonists at neurokinin-1 receptors (NK(1)Rs) may have antidepressant and anxiolytic properties. NK(1)Rs are present in 5-HT innervated forebrain regions which may provide a common point of interaction between these two transmitter systems. This study aimed to investigate for cellular co-localization between NK(1)Rs and 5-HT receptor subtypes in mood-related brain regions in the rat forebrain. With experiments using fluorescence immunocytochemistry, double-labelling methods demonstrated a high degree of co-localization between NK(1)Rs and 5-HT(1A) receptors in most regions examined. Co-localization was highest in the medial septum (88% NK(1)R expressing cells were 5-HT(1A) receptor-positive) and hippocampal regions (e.g. dentate gyrus, 65%), followed by the lateral/basolateral amygdala (35%) and medial prefrontal cortex (31%). In contrast, co-localization between NK(1)Rs and 5-HT(2A) receptors was infrequent (< 8%) in most areas examined except for the hippocampus (e.g. CA3, 43%). Overall co-localization between NK(1)Rs and 5-HT(1A) receptors was much greater than that between NK(1)Rs and 5-HT(2A) receptors. Thus, these experiments demonstrate a high degree of co-localization between NK(1)Rs and 5-HT(1A) receptors in cortical and limbic regions of the rat forebrain. These findings suggest a novel site of interaction between NK(1)R antagonists and the 5-HT system.

Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients.

OBJECTIVE: Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients. METHOD: Nineteen acutely depressed patients were randomized to receive Epo (40,000 IU) or saline intravenously in a double-blind, parallel-group design. On day 3, we assessed neuronal responses to fearful and happy faces using functional magnetic resonance imaging and measured facial expression recognition after the scan. RESULTS: Epo reduced neural response to fearful vs. happy faces in the amygdala and hippocampus, and to fearful faces vs. baseline in superior temporal and occipitoparietal regions 3 days after administration in acutely depressed patients. This was accompanied by a specific reduction in the recognition of fear in Epo-treated patients after the scan similar to the effects on face recognition seen with antidepressant drug treatment. CONCLUSIONS: The present findings are similar to the effects of conventional antidepressants in acutely depressed patients and opposite to hypervigilance to negative facial expressions in depression. This highlights a potential antidepressant mechanism and warrants further investigation of Epo as a new candidate compound for treatment of depression.

Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study.

INTRODUCTION: Erythropoietin (Epo) has neurotrophic effects and may be a novel therapeutic agent in the treatment of depression. We have found antidepressant-like effects of Epo on emotional processing and mood in healthy volunteers. OBJECTIVE: The current study aimed to explore the effects of Epo on the neural processing of emotional information in depressed patients. MATERIALS AND METHODS: Seventeen patients with acute major depressive disorder were randomised to receive Epo (40,000 IU) or saline iv in a double-blind, parallel-group design. On day 3, we assessed neural responses to positive, negative and neutral pictures during fMRI followed by picture recall after the scan. Mood and blood parameters were assessed at baseline and on day 3. RESULTS: Epo reduced neural response to negative vs. positive pictures 3 days post-administration in a network of areas including the hippocampus, ventromedial prefrontal and parietal cortex. After the scan, Epo-treated patients showed improved memory compared with those that were given placebo. The effects occurred in the absence of changes in mood or haematological parameters, suggesting that they originated from direct neurobiological actions of Epo. CONCLUSIONS: These findings are similar to the effects of conventional antidepressants and opposite to the negative biases in depression. The central effects of Epo therefore deserve further investigation as a potential antidepressant mechanism.

Neurokinin-1 receptor antagonists as novel antidepressants: trials and tribulations.

Based upon animal experiments and early clinical trials, neurokinin-1 receptor antagonists showed promise as novel antidepressants. Subsequently, however, more extensive clinical trials did not reveal evidence of efficacy in depression. The development of novel antidepressants will require a better understanding of the neural basis of antidepressant action in humans.

Role of the brain in the control of erection.

In contrast to the spinal control of erection, relatively little is known about the brain control. In the present review, we have outlined the role of brain structures involved in penile erection and provided a synopsis on the brain circuit of erection. Findings from both animal and human studies are discussed. Evidence suggests that the most important structures are the frontal lobe, cingulate gyrus, amygdala, thalamus and hypothalamus. Within the brain circuit of erection, the thalamus serves as a gate-controller in which all relevant information is evaluated and further processed to higher and lower centres.

The supraspinal network in the control of erection.

Penile erection is a complex event controlled by vascular, hormonal and neuronal systems. The neuronal system involved in erection is often divided into spinal and supraspinal networks. It is generally accepted that the spinal system directly controls erection and that the supraspinal network modulates this control mechanism through different ascending and descending pathways. In contrast to the spinal control of erection, relatively little is known about the supraspinal network. In the present review, the authors outline the supraspinal network involved in the control of penile erection. Firstly, the brain regions reported to be involved in erection are described and the brain circuit of erection is outlined. Subsequently, the neuromediators involved in erection are summarised. Finally, these data are discussed in the light of therapeutic possibilities in the management of erectile dysfunction by targeting the supraspinal system.

Increased salivary cortisol after waking in depression.

RATIONALE: Cortisol hypersecretion is regarded as important in the pathophysiology of major depression. However, recent studies in community-based samples have been inconclusive. OBJECTIVE: To determine whether acutely depressed, medication-free subjects show an exaggerated release of cortisol in saliva in relation to awakening. METHODS: We studied the pattern of waking salivary cortisol in 20 unmedicated acutely depressed subjects and 40 healthy controls. RESULTS: In both groups, salivary cortisol increased rapidly after waking, peaking at 30 min. Overall, patients with acute depression secreted approximately 25% more cortisol than controls, though 60 min after waking, their cortisol levels were similar. CONCLUSIONS: Depressed patients in the community appear to have increased early morning cortisol secretion, but the demonstration of this effect requires control for time of waking.

Olanzapine increases slow wave sleep and sleep continuity in SSRI-resistant depressed patients.

OBJECTIVE: The atypical antipsychotic drug olanzapine has been employed as an augmentation treatment in depressed patients unresponsive to treatment with selective serotonin reuptake inhibitors (SSRIs). In healthy subjects, acute olanzapine administration increases sleep continuity and enhances slow wave sleep (SWS). The aim of the present study was to determine if the addition of olanzapine to SSRI treatment in depressed patients produced similar effects on sleep. METHOD: We measured the effect of open-label olanzapine addition (2.5 mg/day initially) on the polysomnograms of 12 patients referred from primary care sources who met DSM-IV criteria for major depressive disorder and who had had an unsatisfactory response to therapeutic doses of an SSRI. Patients were first enrolled in November 2001; final assessment occurred in November 2003. Sleep polysomnogram recordings were made on 3 occasions: before olanzapine addition, on the first night of olanzapine treatment, and after 3 weeks of olanzapine treatment. RESULTS: After the first night of olanzapine treatment and during the third week, subjects showed improvements in sleep efficiency (p < .001), subjective sleep quality (p < .05), and SWS (p < .01). Scores on the Hamilton Rating Scale for Depression fell significantly (p = .001), with the majority of the decrease being apparent after the first week of treatment. CONCLUSION: Olanzapine improves sleep continuity and increases SWS in patients receiving SSRI treatment. These effects are apparent after the first dose of olanzapine and are maintained for the next 3 weeks. The ability of olanzapine to increase SWS is probably attributable to 5-HT(2A/2C) receptor blockade, which has been identified as a relevant mechanism in the therapeutic effect of olanzapine in SSRI-resistant depressed patients.

Increase in concentration of waking salivary cortisol in recovered patients with depression.

OBJECTIVE: Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis with elevated plasma cortisol levels is characteristic of acute major depression. However, it is unclear whether HPA axis abnormalities are present in fully recovered patients. An increase in salivary cortisol levels after waking provides a simple, dynamic measure of HPA axis activity. The authors measured this increase in recovered depressed patients and in a healthy comparison group. METHOD: Salivary cortisol levels were measured upon waking and at 15-minute intervals for the next hour in 31 medication-free, recovered depressed patients and in 31 matched healthy comparison subjects. RESULTS: The increase in salivary cortisol levels that followed waking was significantly higher in the patients. CONCLUSIONS: Greater secretion of cortisol may be present in depressed subjects after clinical recovery and withdrawal of medication. This may put patients at risk of further episodes of depression as well as comorbid medical conditions, such as coronary heart disease.

Risperidone augmentation decreases rapid eye movement sleep and decreases wake in treatment-resistant depressed patients.

BACKGROUND: The atypical antipsychotic agent risperidone has beneficial effects on mood in patients with schizophrenia. This study aimed to assess whether risperidone produced typical antidepressant-like effects in the polysomnogram of healthy subjects and in depressed patients unresponsive to antidepressant medication. METHOD: We measured the effect of a single dose of risperidone (1 mg) on the polysomnogram of 8 healthy volunteers in a placebo-controlled, double-blind, crossover design. We also measured the effects of open-label risperidone treatment (0.5-1.0 mg daily) on the polysomnogram of 8 patients meeting DSM-IV criteria for major depressive disorder who had received therapeutic doses of an antidepressant with an unsatisfactory response. Sleep was recorded at baseline and following 2 weeks of risperidone addition. RESULTS: In the healthy volunteers, risperidone significantly decreased rapid eye movement (REM) sleep (p =.04). After 2 weeks of risperidone treatment, depressed patients had significantly less wake (p =.02) and REM sleep (p =.02). Scores on depression rating scales for the depressed patients showed a significant decline (p <.05). CONCLUSION: Risperidone administration decreases REM sleep in both healthy volunteers and medication-resistant depressed patients, an action characteristic of conventional antidepressant medication. In depressed patients, risperidone also decreased wake. The utility of risperidone as an augmentation agent in depressed patients merits controlled study.

Cortisol modulation of 5-HT-mediated growth hormone release in recovered depressed patients.

BACKGROUND: Recent formulations of the pathophysiology of major depression suggest that stress-induced cortisol secretion may lower brain serotonin (5-HT) function, thereby precipitating depressive symptomatology. This implies that people who develop depression after stressful life events may be particularly vulnerable to the effect of cortisol on brain 5-HT activity. We therefore assessed the effect of a single dose of hydrocortisone on 5-HT-mediated growth hormone (GH) release in healthy volunteers and euthymic subjects recovered from at least two episodes of major depression. METHODS: Eleven recovered depressed patients and 20 healthy controls received intravenous tryptophan (TRP) 10.5 h after placebo and hydrocortisone (50 mg orally) in a double-blind, cross-over design. Plasma GH levels were sampled for 90 min after TRP infusion. RESULTS: The GH response to TRP was significantly lower in the recovered depressed patients than controls after hydrocortisone. LIMITATIONS: The number of recovered depressed subjects studied was small and the effect of hydrocortisone on TRP-induced GH release was different to that observed in a previous study. CONCLUSIONS: These findings are consistent with other evidence suggesting abnormal regulation of 5-HT neurotransmission in people vulnerable to recurrent depression.