Ann Rich

Mechanisms of action of selective serotonin reuptake inhibitors in the treatment of psychiatric disorders.

Selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy in depression and anxiety disorders. This raises the question of how the single action of serotonin reuptake inhibition can improve several psychiatric conditions. In order to understand this apparent paradox it is necessary to consider where SSRIs act in the pathogenic process underlying depression or anxiety disorders. Tryptophan depletion has been used extensively in research into depression and has shown that, in patients receiving an SSRI whose depression is in remission, depleting serotonin leads to recurrence of the disorder. Similar results have been found for panic disorder. This suggests that increased levels of serotonin are necessary in the synapse for the SSRI to be effective in the treatment of depression and panic disorder. In obsessive compulsive disorder, depletion of serotonin in patients recovered on an SSRI does not cause relapse; receptor adaptation may be more important. Variations within the SSRI drug class, such as the selectivity ratios for serotonin versus noradrenaline uptake, elimination half-life, and affinity for the 5-HT2 receptor have been identified and may be important determinants of efficacy, side effects and clinical use.

Correlation of subjective and objective sleep measurements at different stages of the treatment of depression

Studies of the correlation of subjective and objective sleep measures in depressed patients have produced mixed results so far. Further, they were carried out in sleep laboratories and tended to obtain one-off assessments, thus not taking into account the effect of treatment. We investigated forty (40) patients over the course of 8-week treatment of depression with either paroxetine or nefazodone. We used home polysomnography at baseline, nights 3 and 10, and week 8 of treatment, with extensive assessments of subjective sleep, the morning after each sleep recording. The patients were able to judge accurately their total sleep time and sleep onset latency, both before and during treatment. However, they were inaccurate in estimating the number of times they woke up during the night. Sleep satisfaction correlated negatively with Stage 1 sleep at baseline. Sleep quality was represented by a combination of subjective parameters measuring the ease of initiation and maintenance of sleep, and it appeared to derive from slow wave sleep and sleep continuity as seen in polysomnography. The partial discrepancy between subjective and objective measures suggests that a cognitive element is combined with the biological element to produce the sleep problems reported by depressed patients.

Inhalation of 35% CO2 results in activation of the HPA axis in healthy volunteers

BACKGROUND The hypothalamo-pituitary-adrenal (HPA) axis is a major stress responsive system in humans. Although there are numerous ways of testing responsiveness of the HPA in experimental animals, this is much more difficult in man. Hypercapnea is a very stressful stimulus for humans and has been used as an anxiogenic probe in psychiatric patients. We have now investigated whether the simple challenge of a single 35% inhalation of CO(2) activates the neuroendocrine system as evidenced by changes in HPA activity, as well as cardiovascular and subjective responses, in healthy volunteers. METHODS Fourteen healthy male volunteers were recruited. They underwent single vital capacity inhalation of room air and 35% CO(2), in a single blind fashion. Neuroendocrine, cardiovascular and subjective fear measures were taken at regular intervals. RESULTS CO(2) inhalation produced significant activation of the HPA axis in all subjects, as measured with plasma cortisol. Heart rate was decreased and systolic blood pressure was significantly increased shortly after the inhalation of CO(2). The subjects reported short-lived symptoms of fear with the experimental gas. CONCLUSIONS Single vital capacity inhalation of 35% CO(2) activated the HPA axis in healthy volunteers. It also had a significant cardiovascular and psychological (anxiogenic) effect, as expected from previous published studies. The test is potentially useful in studying the responsivity of the HPA axis in health and disease.

Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine

The neurobiological basis of panic disorder has not been clearly established, although a role for serotonin (5-HT) has been postulated. It is clear that drugs which increase 5-HT neurotransmission are effective in treating the condition but how they do so remains a point of debate. The aim of this study was to determine if lowering brain serotonin activity using the technique of tryptophan depletion provoked a short-term relapse of panic symptoms in patients with panic disorder who had responded to drug treatment. Fourteen patients with panic disorder who had responded to treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine received a tryptophan-free amino acid drink on one occasion and a control drink on the other in a double-blind crossover design. In addition, they received an infusion of flumazenil (used as a pharmacological challenge) and placebo on each day. The tryptophan depleted drink produced an 87% reduction in plasma tryptophan concentration. Flumazenil produced a panic attack (defined by changes in the panic inventory) in seven out of 14 patients when tryptophan depleted and one out of 14 on the control day (p < 0.02). Three patients also experienced temporary depressive symptoms when tryptophan depleted, with no mood changes being seen on the control days. We conclude that rapid lowering of brain serotonin function can allow the precipitation of panic symptoms in response to flumazenil in panic disorder patients who have responded to treatment with an SSRI. This implies that in panic disorder increased 5-HT availability is important in maintaining the response to SSRIs.

Tryptophan depletion reverses the therapeutic effect of selective serotonin reuptake inhibitors in social anxiety disorder

BACKGROUND Tryptophan depletion studies have suggested that central serotonin (5-hydroxytryptamine, 5-HT) function mediates the therapeutic effect of selective serotonin reuptake inhibitors (SSRIs) in depression and panic disorder. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion, could reverse the therapeutic effect of the SSRIs in social anxiety disorder (SAD) patients. METHODS Fourteen patients with SAD who showed sustained clinical improvement with SSRI treatment underwent tryptophan depletion in a double-blind, placebo-controlled, crossover design, over 2 days 1 week apart. At the peak time of depletion, the participants also underwent three behavioral challenges: autobiographical script, verbal task, and neutral script. Psychological outcome was assessed with the Spielberger State Anxiety Inventory (STAI) Form Y-1 and visual analog scales (VAS) measuring anxiety, depression, and somatic symptoms. RESULTS Anxiety was significantly increased on the depletion day compared with the control day, both on the STAI Form Y-1 and composite VAS score. Furthermore, there was a significant depletion x time interaction, explained mainly by the anxiogenic effect of the autobiographical script. In contrast, the verbal and the neutral tasks failed to differentiate between depletion and placebo. CONCLUSIONS Tryptophan depletion induced significant increase of anxiety in treated SAD patients, which was more prominent during the recital of an autobiographical script. This finding supports the notion that SSRIs improve social anxiety by increasing 5-HT availability. The autobiographical script seems to be a more robust challenge test for SAD than the stressful verbal task.

The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability.

This study sought to assess the tolerability of intravenously administered psilocybin in healthy, hallucinogen-experienced volunteers in a mock-magnetic resonance imaging environment as a preliminary stage to a controlled investigation using functional magnetic resonance imaging to explore the effects of psilocybin on cerebral blood flow and activity. The present pilot study demonstrated that up to 2 mg of psilocybin delivered as a slow intravenous injection produces short-lived but typical drug effects that are psychologically and physiologically well tolerated. With appropriate care, this study supports the viability of functional magnetic resonance imaging work with psilocybin.

The use of sleep measures to compare a new 5HT1A agonist with buspirone in humans

The partial agonist buspirone has a REM (rapid eye movement) suppressing effect on human sleep probably via a 5HT1A receptor in the pontine area. Eptapirone is a new 5HT1A agonist with a greater intrinsic effect than buspirone. The objective of this study was to examine the effects of eptapirone on sleep architecture, particularly REM sleep, in normal volunteers and compare it with buspirone and placebo. This was a randomized, double-blind placebo-controlled four-way crossover study in 12 healthy volunteers. Volunteers were screened to ensure that they had normal overnight sleep EEG (electroencephalogram) and were extensive CYP 2D6 metabolizers. Sleep was recorded on pairs of nights on four occasions, with medication being taken before the second night. Treatments were eptapirone 1.5mg at 10 AM, eptapirone 1.5mg at 11 PM, buspirone 20mg at 11 PM and placebo. Standard measures of sleep were derived and compared among the four treatments using ANOVA. REM sleep was significantly suppressed supporting the proposition that activation of post-synaptic 5HT1A receptors reduces REM sleep. Sleep fragmentation increased by both drugs. REM sleep suppression was significantly greater with morning eptapirone than with buspirone. Wakefulness in sleep was significantly greatest after morning eptapirone. REM sleep effects were greatest after evening eptapirone, suggesting a greater effect on central serotonin receptors than that of buspirone.

The effects of single dose anxiolytic medication on the CO2 models of anxiety: differentiation of subjective and objective measures

This was a double blind, placebo-controlled, 4-way cross-over study in 12 healthy volunteer subjects of the acute effects of three drugs each of which are used in the clinic to treat some forms of anxiety: propranolol 40 mg, hydroxyzine 25 mg, flupentixol 0.5 mg and placebo. Each test session consisted of inhalation of air for 20 min, 10-min rest, inhalation of CO2 7.5% for 20 min, 10-min rest, followed by a single vital capacity inhalation of 35% CO2. The CO2 7.5% was administered at peak drug effect. Subjective effects were measured using Visual Analogue Scales (VAS), the Panic Symptom Inventory and the Generalised Anxiety Disorder Assessment inventory. Twelve subjects participated (eight men), with a mean age of 25.9 years. The expected subjective effects of CO2 were seen and these were significantly different from effects of peak air. However, there were no statistically significant differences between the drugs or between drugs and placebo, indeed there was a trend for some VAS anxiety Email: Jayne.Bailey@bristol.ac.uk scores to be higher than placebo in the drug groups. There were some significant differences in cardiovascular responses to CO2, with propranolol significantly decreasing heart rate and flupentixol increasing blood pressure when compared with placebo. The lack of subjective anxiolytic actions of the three drugs contrasts with our previous findings with acute benzodiazepines and chronic selective serotonin reuptake inhibitor administration. It may be that prolonged treatment with these agents would be required to show anxiolytic effects, although it may also be that their efficacy is insufficient to be demonstrated in this model. The lack of anxiolytic actions of propranolol, despite a significant reduction in heart rate, is a further support for a central action of CO2 to produce anxiety.

Effects of 7.5% CO2 challenge in generalized anxiety disorder.

We have previously developed a putative model of generalized anxiety disorder in healthy volunteers using a 20-minute 7.5% carbon dioxide (CO2) inhalation challenge. The aim of this study was to validate the 7.5% CO2 paradigm by assessing its effects in patients with generalized anxiety disorder in a test–retest design. Twelve medication-free generalized anxiety disorder patients attended our lab for two study days. On each study day placebo (compressed air) and 7.5% CO2 mixture were randomly administered over 20 min, at least 30 min apart, in a single blind, randomized, placebo-controlled cross-over design. Subjective ratings, cardiovascular measures and cortisol levels were collected throughout. CO2 challenge significantly increased ratings for anxiety and other subjective symptoms associated with generalized anxiety disorder, compared with air. It also significantly increased systolic blood pressure on day 2, indicating increased autonomic arousal. There was no change between the two test days in mean anxiety rating scores, and there also appeared to be a correlation for individual scores on a number of the subjective measures. In conclusion, 20 min of 7.5% CO2 gas inhalation increases anxiety responses in patients with generalized anxiety disorder, and this is reliable over time.

Crossover trial of pagoclone and placebo in patients with DSM-IV panic disorder

Pagoclone is a cyclopyrrolone that is believed to act as a partial agonist at the γ-aminobutyric acid (GABA) A/benzodiazepine (BDZ) receptor. In theory, such partial agonists should be anxiolytic but lack the adverse side-effects of sedation, tolerance and withdrawal associated with full GABA-A/BDZ agonists. The objective of the randomized double-blind crossover study was to assess whether pagoclone was an effective anti-panic agent and also to assess its side-effect profile. Patients recruited had a diagnosis of Panic Disorder (DSM-IV) with at least one panic attack per week. Following a 2-week screening period, patients entered a 6-week trial consisting of two 2-week treatment periods, each followed by a 1-week washout. Patients were randomly assigned to receive either pagoclone 0.1 mg t.d.s. or placebo on their first treatment period and the converse on their second. The primary measure was daily panic attack dairy. Fourteen patients completed the study, the mean number of panic attacks during screening was 5.8 ± 0.8 (SEM), this fell to 3.6 ± 0.5 during treatment with pagoclone (p = 0.05) and 4.3 ± 0.8 with placebo (p = 0.14). There was no significant difference on direct comparison of pagoclone with placebo or in any of the secondary measures (including Rickels withdrawal scale) or the adverse event profiles. The study provides preliminary evidence that pagoclone has anxiolytic properties in the absence of typical BDZ side-effects. This is consistent with its theoretical mode of action as a partial agonist at the GABAA/BDZ receptor.