Don't panic. A guide to tryptophan depletion with disorder-specific anxiety provocation.

The 2002 paper "Does 5-HT restrain panic? A tryptophan depletion study in panic disorder patients recovered on paroxetine" by Bell and colleagues - reprinted in this issue of the Journal - reports on a study undertaken in the halcyon days of David Nutt's Psychopharmacology Unit at the University of Bristol, England. In this invited commentary authors of the original work discuss the impact of this paper on the field of acute tryptophan depletion research (especially in the field of clinical anxiety disorders) and the development of disorder-specific anxiogenic provocations over the past decade.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

Acute citalopram administration may disrupt contextual information processing in healthy males.

Selective serotonin reuptake inhibitors (SSRI) are the most commonly prescribed antidepressants. It has been suggested however that SSRI administration may affect response inhibition and contextual processing but the available evidence is minimal. Therefore, the purpose of this study was to identify the effect size of acute (within 24 hours) and chronic (28 days) administration of the highly selective SSRI, Citalopram, compared to placebo on response inhibition (measured by the Degraded Symbol Continuous Performance Task [DS-CPT]) and contextual processing (assessed using a Delayed Non-Matching to Sample Task [DNMS]) in healthy males (n=20) using a randomised double-blind design. We found no effect of Citalopram on participants' performance on the DS-CPT which suggests either that SSRIs do not affect response inhibition or that this measure is insensitive to any potential disinhibition effects of SSRI. Acute, but not chronic, Citalopram administration was associated with a measurable decrement in the DNMS suggestive of a negative impact of SSRI administration on contextual processing at least during treatment initiation. These findings provide a useful guide for designing future studies in clinical populations.

Threat and anxiety affect visual contrast perception.

Threat cues activate the visual cortex and are detected faster than neutral cues as evidenced by functional brain imaging during viewing of visual threat and neutral stimuli. The functional visual processes underlying these phenomena have not been determined. Pattern visual evoked potentials were elicited in a baseline and a verbal threat condition with two stimulus contrasts in subjects with high and low trait anxiety. Threat reduced the latency of the early P100 wave in the low but not the high anxious group. The reduction was greater with increasing stimulus contrasts. The dependence of the P100 latency on trait anxiety is reminiscent of the Yerkes-Dodson inverted U-shape curve, which relates anxiety to behavioural responses. These results show that threat affects perceptual processes and suggest that data based on the effects of threat in visual search studies should be reappraised to include acceleration of contrast perception.

Dopaminergic challenges in social anxiety disorder: evidence for dopamine D3 desensitisation following successful treatment with serotonergic antidepressants.

Serotonergic antidepressants (SSRIs) are first-line treatments for social anxiety disorder [SAnD], though there is evidence of dopaminergic system dysfunction. Twenty subjects with DSM-IV SAnD, untreated (n = 10) and SSRI-remitted DSM-IV SAnD (n = 10), were administered a single dose of 1) a dopamine agonist (pramipexole 0.5 mg) and 2) a dopamine antagonist (sulpiride 400 mg), followed by anxiogenic challenges (verbal tasks and autobiographical scripts) in a double-blind crossover design, the two test days being one week apart. Anxiety symptoms were measured by self-reported changes in Visual Analogue Scales, specific SAnD scales and anxiety questionnaires. Plasma levels of prolactin were obtained. Untreated SAnD subjects experienced significant increases in anxiety symptoms following behavioural challenges after either sulpiride or pramipexole. Following remission with SSRIs, the socially anxiogenic effect of behavioural provocation was significantly attenuated under pramipexole, whereas under sulpiride effects remained significantly elevated. There appears to be instability of the dopamine system under behavioural stress in social anxiety subjects that is only partly rectified by successful treatment with an SSRI, which may induce a desensitisation of postsynaptic dopamine D(3) receptors.

Twins discordant for schizophrenia: psychopathology of the non-schizophrenic co-twins.

OBJECTIVE: Patients with schizophrenia are more likely to suffer from mood and anxiety disorders compared with the general population. We explored the aetiology of this comorbidity using a twin study design. METHOD: We applied an additive genetic + unique environment (AE) random effects model in the analysis of 35 non-schizophrenic co-twins from pairs discordant for schizophrenia, and 131 control twins. RESULTS: Non-schizophrenic co-twins had significantly increased rates of depression (P = 0.006) and anxiety disorders (P = 0.021) compared with the control twins. CONCLUSION: Our results provide evidence for a familial association between schizophrenia and anxiety and depression. This could reflect common aetiological factors contributing to each of the disorders. Future studies should attempt to investigate the relative genetic and environmental contribution to the shared risk factors for schizophrenia, mood and anxiety disorders.

The role of serotonin in panic: evidence from tryptophan depletion studies.

There has been growing interest in the role of serotonin (5-hydroxytryptamine, 5-HT) in anxiety, including pathological states such as panic disorder. The technique of tryptophan depletion (TD), which causes an acute, temporary and reversible reduction in brain 5-HT levels, is a useful minimally invasive paradigm to aid the research of the role of 5-HT in various disorders. This review discusses the evidence supporting the hypothesis that 5-HT function is of importance in the neurobiology of panic disorder and considers in more detail how our understanding has been influenced by work using the technique of TD. Possible avenues for future research are also discussed.

Does the brain noradrenaline network mediate the effects of the CO2 challenge?

The inhalation of carbon dioxide (CO2) is commonly used in patients and volunteers as a means of producing anxiety or panic. It is generally believed that patients with panic disorder are more vulnerable to the effects of CO2 than patients with other anxiety disorders or healthy volunteers and there is speculation and debate as to the mechanism for this apparent sensitivity. Recent work from our group has shown that a single inhalation of 35% CO2 activates the hypothalamic-pituitary-adrenocortical (HPA) axis, increases blood pressure (BP) and increases subjective fear responses in healthy volunteers. Correlation analyses reveal a relationship between the changes in BP and the cortisol increase. These findings led us to postulate that a common mechanism may mediate these and the subjective responses to inhalation of CO2. We propose that the noradrenergic system, particularly the locus coeruleus (LC), but including the A1 and A2 cell groups, may be a key mediator of these responses. This article examines the evidence and discusses the results of studies from our laboratory in relation to a neuroanatomical model centring on the LC.

Randomised controlled study of sleep after nefazodone or paroxetine treatment in out-patients with depression.

BACKGROUND: Sleep effects of antidepressants are important clinically and for elucidating mechanism of action: selective serotonin reuptake inhibitors disturb sleep and 5-HT(2) receptor-blocking compounds may enhance sleep quality. AIMS: To compare the objective and subjective effects on sleep of paroxetine and nefazodone in patients with moderate to severe depression. METHOD: Forty patients with depression were randomised to take paroxetine 20-40 mg/day or nefazodone 400-600 mg/day for 8 weeks. Objective and subjective quality of sleep and depression measures were assessed throughout. RESULTS: Nefazodone significantly increased objective sleep efficiency and total sleep time, and improved subjective sleep on days 3 and 10. Paroxetine decreased sleep efficiency early in treatment and some sleep disruption remained at week 8. Paroxetine but not nefazodone produced marked suppression of rapid eye movement (REM) sleep. CONCLUSIONS: Nefazodone improves sleep in early treatment compared with paroxetine in patients with moderate to severe depression. These effects are seen within the first 2 weeks of treatment and diminish thereafter.

Brain function in social anxiety disorder.

What have these studies revealed about SAD? First, few studies have been performed so far, with even fewer replications. Most of the work has been exploratory in nature and follows the paradigms used in PD. This approach has been justifiably criticized. The use of psychological (naturalistic) challenges may be more appropriate in SP than chemical challenges. The paradigms of public speaking, autobiographical scripts, or similar behavioral challenges merit further use, exploration, and validation if symptoms resembling those of the condition proper are to be induced in experimental circumstances. However, some tentative conclusions can be drawn from the research performed so far. There is no enough evidence to support the presence of structural brain abnormality in SAD. Admittedly, such a finding would have been very unlikely. On the other hand, evidence of subtle functional abnormalities is accumulating. On the nosologic question, there appear to be differences from PD. While in some challenges (e.g., CO2 and pentagastrin) the two conditions differ only in degree, in others (e.g., lactate, caffeine, and flumazenil), the separation is clearer. Equally, there is a strong argument to differentiate the generalized from the specific form of social anxiety on the basis of substantial (albeit accidental) findings outlined earlier. More sophisticated neuroimaging techniques, directly comparing patients from both groups before and after pharmacologic or psychological treatment, should provide more conclusive evidence on this issue. What might also help future research is the integration of biological investigations with specific personality profiles. In one study, SAD patients scored low in novelty seeking, self-directedness and cooperativeness and high in harm avoidance. It has been hypothesized that such results indicate serotonergic and dopaminergic dysregulation, which is consistent with the findings described earlier. The best evidence for neurotransmitter abnormality so far is for altered dopamine function at the level of the basal ganglia, either pre- or postsynaptic, which may result in reduced basal ganglia function so that the normal fluidity of social motor functions (e.g., smiling, eye movements, and speech) are impaired, thus leading to the cognitive symptoms of social anxiety and the subsequent generation of avoidance behavior. Such patients should respond poorly to antipsychotics, and additional challenges with these drugs could be used to test this theory. Furthermore, more research needs to be done to elucidate the mechanism by which SSRIs work in SAD. Neuroanatomical models of social anxiety (Fig. 4) [see structure: Text], explaining the site of action of drugs and psychological treatments, have been proposed in recent years. Central to these models is the notion of an innate anxiety circuit, which could be tentatively identified with the behavioral inhibition system, the septohippocampal system. This area receives 5-HT, NE, and dopamine input and has connections with the cortex and limbic structures. The relevance of these models remains to be assessed in experiments that are specifically designed to test them.

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 gamma-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 GABA(A)/BDZ receptor.

Substance P antagonists: novel agents in the treatment of depression.

The field of neuropeptides has been expanding very rapidly in recent years. Apart from understanding their physiology and elucidating their functional role as putative neurotransmitters, research has focused on producing drugs that may treat a variety of illnesses in a novel way. Substance P antagonists occupy a central role in this area of intensive scientific activity. Substance P (SP), an undecapeptide, is abundant both in the periphery and in the CNS, where it is usually co-localised with one of the classical neurotransmitters, most commonly serotonin (5-HT). A role for SP is proposed in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. A recently published positive study of MK 869, in depression, a novel SP antagonist has generated excitement amongst psychopharmacologists. It is the first time that a drug, not directly related to monoamine transmitters, has showed efficacy in depression. Although MK 869 has been suspended from further development, a host of other compounds, with similar action and better pharmacological profile, are currently under development. In this review, the pharmacology of central SP and its receptors are discussed, together with the exploration of the prospects and implications for future treatments of depression.

The psychobiology of anxiolytic drugs. Part 1: Basic neurobiology.

The authors provide an overview of the current state of knowledge with regards to the neurobiological mechanisms involved in normal and pathological anxiety. A brief review of the classification and cognitive psychology of anxiety is followed by a more in-depth look at the neuroanatomical and neurochemical processes and their relevance to our understanding of the modes of action of anxiolytic drugs. The serotonergic, noradrenergic, and gamma-aminobutyric acidergic systems are reviewed. The numerous physiological and pharmacological methods of anxiety provocation and the increasing importance of functional neuroimaging are also examined. The review provides an overview of the biology and basic pharmacology of anxiolytic drugs, and compliments the more clinically oriented companion review.

The psychobiology of anxiolytic drug. Part 2: Pharmacological treatments of anxiety.

Benzodiazepines have been the mainstay of pharmacological treatment of anxiety over the last 4 decades. The problems associated with their use prompted the research for alternative agents that would be useful in anxiety conditions. Old classes of antidepressants, such as tricyclic antidepressants and monoamine oxidase inhibitors, showed effectiveness in some anxiety syndromes, even in areas where benzodiazepines were not very effective. Newer antidepressants, the selective serotonin-reuptake inhibitors, also appear very useful in some anxiety states, and their favourable side-effect profile has elevated them to first-line treatment tools in these conditions. However, the ideal anxiolytic does not exist. Research with other new compounds is very active, and some experimental drugs show promise for the future.

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.

The use of benzodiazepines in anxiety and other disorders.

Benzodiazepines have come under scrutiny and attack over recent years because of their abuse liability, withdrawal reactions and development of tolerance. Consequently, practitioners worldwide are discouraged from prescribing them. While some of these risks may have been exaggerated, benzodiazepines remain a useful therapeutic tool, alone or in combination, in a number of psychiatric and medical conditions. Withholding such treatment may be unjustified and detrimental to the patients' health. Further, benzodiazepines have helped researchers in their attempts to elucidate the neurobiological mechanisms underlying anxiety. This, in return, leads to the development of new effective anxiolytic treatments, with fewer problems compared to the traditional benzodiazepine compounds. Such new agents are already available or at the closing stages of clinical trials.