John Potokar

Serotonin reuptake inhibitor withdrawal.

We studied reported withdrawal symptoms in a retrospective chart review of 352 patients treated in an outpatient clinic with the nonselective serotonin reuptake inhibitor clomipramine or with one of the selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine, paroxetine, or sertraline. In 171 patients who were supervised during medication tapering and discontinuation, the most common symptoms were dizziness, lethargy, paresthesia, nausea, vivid dreams, irritability, and lowered mood. When patients with at least one qualitatively new symptom were defined as cases, these symptoms occurred significantly more frequently in patients who had been treated either with one of the shorter half-life SSRIs, fluvoxamine or paroxetine (17.2%), or with clomipramine (30.8%), than in patients taking one of the SSRIs with longer half-life metabolites, sertraline or fluoxetine (1.5%). The rate was not significantly different between the different shorter half-life treatments. Cases treated with fluvoxamine or paroxetine had received a significantly longer period of treatment (median 28 weeks) than noncases (16 weeks), but there were no significant associations with age or with diagnostic grouping. There was a trend toward an association with male sex. The majority of cases occurred despite slowly tapered withdrawal. Symptoms persisted for up to 21 days (mean = 11.8 days) after onset. These symptoms were relieved within 24 hours by restarting the medication, but were not relieved by benzodiazepines or by moclobemide. A role has been suggested for serotonin in coordinating sensory and autonomic function with motor activity. We suggest that this may lead to useful hypotheses about the pathophysiology of withdrawal symptoms from serotonin reuptake inhibitors.

Serotonin 5-HT1A receptor binding in people with panic disorder: positron emission tomography study

BACKGROUND The importance of the neurotransmitter serotonin (5-HT) in the pathophysiology of anxiety is well known. A key role for postsynaptic 5-HT(1A) receptors has recently been suggested in studies of genetic knockout mice. AIMS To measure 5-HT(1A) receptor binding in patients with panic disorder in the untreated state and after recovery on treatment with selective serotonin reuptake inhibitors (SSRIs). METHOD Nine symptomatic untreated patients with panic disorder, seven patients recovered on SSRI medication and nineteen healthy volunteers underwent a single positron emission tomography (PET) scan using the 5-HT(1A) tracer [(11)C]WAY-100635. RESULTS In comparison with controls, both presynaptic and postsynaptic 5-HT(1A) receptor binding was reduced in untreated patients, with the most significant reductions being in the raphe, orbitofrontal cortex, temporal cortex and amygdala. In recovered patients presynaptic binding was reduced, but there was no significant reduction in postsynaptic binding. CONCLUSIONS Panic disorder is associated with reduced 5-HT(1A) receptor availability, which is also known to have a key role in depression.

Hospital admissions for self harm after discharge from psychiatric inpatient care: cohort study

Objective To determine the risk of non-fatal self harm in the 12 months after discharge from psychiatric inpatient care. Design Cohort study based on national hospital episode statistics. Setting England. Population Patients aged 16-64 years discharged from psychiatric inpatient care between 1 April 2004 and 31 March 2005 and followed up for one year. Results 75 401 people were discharged from psychiatric inpatient care over the study period, 4935 (6.5%) of whom were admitted at least once for self harm in the following 12 months. Risk of self harm was greatest in the four weeks after discharge; one third (32%, n=1578) of admissions for self harm occurred in this period. The strongest risk factor for self harm after discharge was admission for self harm in the previous 12 months (hazard ratio 4.9, 95% confidence interval 4.6 to 5.2). The risk of self harm was also higher in females, younger people, those with diagnoses of depression, personality disorders, and substance misuse, and those with short lengths of stay. Conclusion More than 6% of patients discharged from psychiatric inpatient care are readmitted for an episode of self harm within 12 months, with one third of these episodes occurring in the month after discharge. Self harm after discharge from hospital shares many of the features of suicide after discharge. Interventions should be developed to reduce risk in this period.

Adult night terrors and paroxetine

Although rare, night terrors are difficult to treat and a major management problem, especially when accompanied by sleepwalking or other automatic behaviours. Severe injury (sometimes death) during the period of confusion following the rise from bed has been reported, and more frequent attacks lead to serious disruption of sleep, which may impair subsequent daytime functioning and result in psychiatric comorbidity. Night terrors can thus cause severe disability, and effective therapy would be of benefit to patients and their families. There have been reports of treatment with benzodiazepines, imipramine, and longterm psychotherapy, but only benzodiazepines have shown any notable success. Selective serotonin reuptake inhibitors (SSRIs) have antipanic actions and there is some overlap in symptoms of nocturnal panic attacks and night terrors. We report a series of six patients with night terrors, referred for drug treatment because of distressing or dangerous accompanying behaviours, or sleep disruption. All six patients were assessed clinically and by home polysomnography (medilog). All responded to treatment with the SSRI paroxetine (table). In these patients paroxetine was effective in the treatment of longstanding and disabling night terrors and may be as effective as benzodiazepines, although formal comparison is necessary. Two of our patients were having terrors while on benzodiazepines, possibly because of the development of tolerance which does not occur with paroxetine. Other advantages of paroxetine over benzodiazepines is that it treats comorbid or secondary depression and is not a drug of abuse. We suggest that the terror-suppressing action of paroxetine is a direct effect of its ability to increase 5hydroxytryptamine (5-HT) concentrations in the brainstem by blocking reuptake. Terror-like behaviour in animals and man can be readily provoked by stimulation of the periaqueductal grey matter, and this behaviour in animals is suppressed by acute administration of SSRIs and direct-acting 5HT2c receptor agonists. 5HT2c agonists are in clinical development for the treatment of anxiety and depression and it would be interesting to test their efficacy in night terrors. The effects of paroxetine on sleep are known and probably do not contribute to its effect on night terrors. Further evidence that the therapeutic action of paroxetine may be direct rather than through a neuroadaptive mechanism (thought to underlie the antipanic action) comes from the patients who had relapse after stopping treatment. Night terrors recurred rapidly as plasma and brain concentrations of paroxetine fell, and restarting treatment quickly suppressed them again. In one patient the treatment effect seemed dose related. The two cases previously reported to have responded to imipramine also responded rapidly, suggesting a different mode of action to the antidepressant effect. Imipramine also has 5-HT-uptake blocking effects. We found paroxetine to be a safe and effective treatment for disabling night terrors in a small group of patients. The effectiveness of such a selective agent as paroxetine may also suggest a role for decreased central 5-HT function in the aetiology of night terrors.

A biological pathway linking inflammation and depression: activation of indoleamine 2,3-dioxygenase.

This article highlights the evidence linking depression to increased inflammatory drive and explores putative mechanisms for the association by reviewing both preclinical and clinical literature. The enzyme indoleamine 2,3-dioxygenase is induced by proinflammatory cytokines and may form a link between immune functioning and altered neurotransmission, which results in depression. Increased indoleamine 2,3-dioxygenase activity may cause both tryptophan depletion and increased neurotoxic metabolites of the kynurenine pathway, two alterations which have been hypothesized to cause depression. The tryptophan-kynurenine pathway is comprehensively described with a focus on the evidence linking metabolite alterations to depression. The use of immune-activated groups at high risk of depression have been used to explore these hypotheses; we focus on the studies involving chronic hepatitis C patients receiving interferon-alpha, an immune activating cytokine. Findings from this work have led to novel strategies for the future development of antidepressants including inhibition of indoleamine 2,3-dioxygenase, moderating the cytokines which activate it, or addressing other targets in the kynurenine pathway.

A validation of the 7.5% CO2 model of GAD using paroxetine and lorazepam in healthy volunteers

The inhalation of 7.5% carbon dioxide (CO2) in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al. 2005). As this state is similar to that of general anxiety rather than panic, we further validated this by examining the effects of anxiolytic medication. Two separate studies in healthy volunteers are described; study one is a double-blind, placebo-controlled study of a single dose of 2mg lorazepam and study two describes the effects of 21 days of treatment with paroxetine. Gas challenges were air and 7.5% CO2 inhaled for 20 minutes, delivered on day 0 (before treatment) and day 21 (after treatment) in the paroxetine study. Subjective effects were measured using visual analogue scales and questionnaires. When compared with placebo, lorazepam 2mg significantly reduced peak CO2-induced subjective fear, feelings of wanting to leave, tension and worry. In the paroxetine study, when compared with day 0, day 21 showed a significantly attenuated peak CO2-induced nervousness and a trend for reduced ratings of anxiety, fear, feel like leaving, tense and worried. In these studies we have shown that this CO2 model of anxiety is sensitive to lorazepam and to a lesser extent paroxetine. This gives support to its utility as an experimental model of general anxiety disorder in healthy volunteers.

Depleting Serotonin Enhances both Cardiovascular and Psychological Stress Reactivity in Recovered Patients with Anxiety Disorders

Abstract: Serotonin-promoting drugs show cardioprotective properties in patients with anxiety or depression, but it is not known if this is a direct effect of increasing serotonin. We aimed to characterize the effect of serotonin manipulation through acute tryptophan depletion on cardiovascular and psychological responses to stress challenge in recovered patients with anxiety disorders. In 27 recovered patients with anxiety disorders (panic disorder treated by selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy, social anxiety disorder treated by SSRIs), we performed a double-blind randomized crossover study. On 2 separate days, the subjects ingested an acute tryptophan-depleting (aTD) or nondepleting (nD) drink in random order and underwent a stress challenge at time of maximum depletion. Systolic blood pressure (P = 0.007; diff = 9.0 mm Hg; 95% confidence interval (CI), 2.6-15.3 mm Hg) and diastolic blood pressure (P = 0.032; diff = 5.7 mm Hg; 95% CI, 0.6-10.9 mm Hg) responses to stress were significantly greater under aTD than nD, as were the psychological responses to stress (for Spielberger state anxiety, difference in stress response between aTD and nD = 7.11; P = 0.025). Blood pressure responses to stress showed no correlation with psychological responses. The significant increases in acute stress sensitivity in both cardiovascular and psychological domains on serotonin depletion suggest that serotonin is involved in the control of both cardiovascular and psychological aspects of the acute stress response. The lack of correlation in the difference between aTD and nD conditions in cardiovascular and psychological responses suggests that serotonin may have distinct effects on these 2 domains, rather than the cardiovascular responses being merely a secondary consequence of psychological changes.

Increased sympathetic response to standing in panic disorder

Although autonomic function has been investigated in panic disorder (PD), previous studies have not used non-invasive beat by beat blood pressure (BP) monitoring to assess the rapid dynamics of BP during autonomic reflex tests. The hypothesis of the current study was that patients with PD would show increased cardiovascular sympathetic reactivity compared with healthy or anxious controls, as assessed by the initial overshoot of diastolic BP during the immediate response to standing. Patients with PD (n=56), social phobia (n=28) and healthy volunteers (n=56) were tested using finger photoplethysmography during an orthostatic challenge. Panic disorder patients showed an increased BP overshoot compared with both control groups. Moreover, in a preliminary assessment of selective serotonin reuptake inhibitor treatment effects, the BP overshoot was significantly reduced towards normal values. These findings are consistent with recent evidence for increased sympathetic baroreflex function in PD and may be relevant to the pathophysiology of the disorder.

Treatment of anxiety and depressive disorders in patients with cardiovascular disease.

What role do selective serotonin reuptake inhibitors have in treating psychiatric morbidity in patients with cardiovascular disease? This review discusses the safety and efficacy of various antidepressants in this group of patients and their potential for improving cardiovascular outcomes Anxiety and depressive disorders are common in the general population and are particularly prevalent in patients with cardiovascular disease (box 1).1–3 w1-w3 We reviewed evidence for a biological explanation for this association and for drug treatment and psychotherapy for psychiatric morbidity in patients with cardiovascular disease. We systematically searched Medline (1966 to August 2003 through Ovid) and Embase (1980 to October 2002) for all relevant English language articles. Firstly, we entered terms and text words including myocardial infarction, angina, hypertension, stroke, cerebrovascular, and poststroke. Secondly, we used the terms and text words “SSRIs”, “serotonin reuptake inhibitors”, and individual drug names. The searches were combined and relevant articles retrieved. The reference lists were searched for other potentially relevant articles. Much evidence links depression with coronary artery disease and hypertension; 16% of patients assessed seven days after myocardial infarction had symptoms consistent with a major depressive episode.1 w1 w2 Several studies have shown a link between anxiety disorders and coronary heart disease and between anxiety disorders and hypertension.2 Associations between psychiatric morbidity and cardiovascular disease could simply be attributed to patients being psychologically undermined after diagnosis but this does not explain prospective studies showing excess incidence of cardiovascular problems or poorer cardiovascular outcome in patients with depression and anxiety disorders. One study reported a 3.5-fold increase in mortality of depressed patients compared with non-depressed patients within six months of myocardial infarction.1 Depression has been associated with the development of cardiovascular complications in patients with hypertension, and several prospective studies have suggested a link between anxiety disorders and …

The 5-HT3 antagonist ondansetron reduces gastrointestinal side effects induced by a specific serotonin re-uptake inhibitor in man

The selective serotonin re-uptake inhibitors (SSRIs) are increasingly being used to treat depression and anxiety disorders. Gastrointestinal (GI) symptoms are the main side effects, probably resulting from the stimulation of central or peripheral 5-HT receptors. The present double-blind, placebo-controlled study was undertaken to see if the GI side effects of fluvoxamine could be attenuated by the co-administration of the 5-HT3 antagonist ondansetron. The results demonstrate that, in volunteers, a single 100 mg oral dose of fluvoxamine can produce GI symptoms. Co-administration of ondansetron significantly reduced peak nausea and GI side effects, compared with placebo.