Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

Intensive behavioral therapy for agoraphobia.

BACKGROUND: We investigated the efficacy of an intensive 1-week behavioral therapy program focusing on agoraphobia for panic disorder patients with agoraphobia (PDA). DESIGN AND METHODS: The study design was a case-control study. Main outcome measure was the agoraphobia score of the Fear Questionnaire (FQ-AGO). The outcomes on the FQ-AGO of a 1-week intensive therapy (96 patients) and a twice-weekly therapy (98 patients) were compared. RESULTS: Agoraphobia improved significantly in both groups, 1 week and 3 months after therapy. Effect size for changes in the 1-week intensive therapy on the FQ-AGO was 0.75. LIMITATIONS: Limitations are use of antidepressants, no placebo group, and no long term follow-up. CONCLUSION: Behavioral therapy for agoraphobia can be shortened significantly if intensified without affecting therapy outcome, thus allowing patients a more rapid return to work and resumption of daily activities.

Therapygenetics: 5-HTTLPR genotype predicts the response to exposure therapy for agoraphobia.

This study was intended to assess the extent to which the low-expression allele of the serotonin transporter gene promoter predicts better response to exposure-based behavior therapy in patients with panic disorder with agoraphobia (PDA). Ninety-nine patients with PDA underwent a 1-week in vivo exposure-based behavior therapy program and provided saliva samples to extract genomic DNA and classify individuals according to four allelic forms (SA, SG, LA, LG) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in avoidance behavior in PDA following treatment. After controlling for pre-treatment avoidance behavior, the 5-HTTLPR low-expression genotypes showed a more favorable response to exposure therapy two weeks following treatment, compared to the other patients. This study suggests a genetic contribution to treatment outcome following behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PDA.

Brainstem response to hypercapnia: a symptom provocation study into the pathophysiology of panic disorder.

BACKGROUND: The biological basis of uncued panic attacks is not yet understood. An important theory concerning the nature and cause of panic disorder is the 'suffocation false alarm theory'. This alarm is supposed to be over-sensitive in panic disorder patients and can be triggered by CO2. No neurobiological substrate has been identified for such an alarm. The present study investigates differences in brain activation in panic patients, healthy individuals and experienced divers in response to CO2, representing three groups with descending sensitivity to CO2. METHOD: Brain activation was measured with functional magnetic resonance imaging. Subjects breathed through a mouthpiece delivering a continuous flow of 100% oxygen for two minutes, followed by a hypercapnic gas mixture (7% CO2) for the next two minutes. Statistical analysis was performed using SPM8. RESULTS: There was a significant main effect of group in response to the CO2. Patients show increased brainstem activation in response to hypercapnia compared to controls and divers. Subjective feelings of breathing discomfort were positively correlated with brain activation in the anterior insula in all groups. CONCLUSION: This is the first study showing that the behavioural response to CO2 that characterises panic disorder patients is likely due to increased neural sensitivity to CO2 at brainstem level.

On the psychotropic effects of carbon dioxide.

It has been well established that the inhalation of Carbon Dioxide (CO2) can induce in humans an emotion closely replicating spontaneous panic attacks, as defined by current psychiatry nosology. The purpose of this review is to provide a critical summary of the data regarding CO2's psychopharmacological properties and underlying mechanisms. The authors review the literature on the human and animal response for the exposure of exogenous CO2 focusing on five points of interest: 1) the early history of the use of CO2 as an anesthetic and therapeutic agent, 2) the subjective effects of breathing CO2 at different concentrations in humans, 3) the use of CO2 in experimental psychiatric research as an experimental model of panic, 4) the pharmacological modulation of CO2-induced responses, and 5) the putative neurobiological mechanisms underlying the affective state induced by CO2. The authors conclude with an evolutionary-inspired notion that CO2 might act as an agent of a primal emotion serving a homeostatic function, in the control of respiration and acid-base balance.

Effects of acute exercise on CO(2) -induced fear.

BACKGROUND: Acute exercise has shown to reduce the effects of experimental panic provocation in healthy volunteers and in patients with panic disorder. Recent evidence suggests that when larger amounts of CO(2) are inhaled, a large proportion of healthy subjects can also develop an affective response consistent with definitions of a panic attack. Our aim was to test whether exercise can show antipanic effects in healthy subjects when exposed to higher concentrations of CO(2). METHODS: Thirty-one healthy subjects, on four separate occasions in a randomized Latin square design, performed either moderate/hard or very-light exercise immediately followed by either a single or a double 35% CO(2)/65% O(2) inhalation. RESULTS: Compared to very-light exercise, when subjects performed moderate/hard exercise they reported a reduction in panic symptoms on the Panic Symptom List and the Visual Analogue Scale of Fear but no difference on the Visual Analogue Scale of Discomfort after a double CO(2) inhalation. After a single CO(2) inhalation, reductions were only seen on the Panic Symptom List. CONCLUSIONS: After intense exercise, subjects had less panic symptoms when exposed 35% CO(2), particularly after a double inhalation.

Effects of tryptophan depletion and tryptophan loading on the affective response to high-dose CO2 challenge in healthy volunteers.

RATIONALE: It has been reported that in panic disorder (PD), tryptophan depletion enhances the vulnerability to experimentally induced panic, while the administration of serotonin precursors blunts the response to challenges. OBJECTIVES: Using a high-dose carbon dioxide (CO(2)) challenge, we aimed to investigate the effects of acute tryptophan depletion (ATD) and acute tryptophan loading (ATL) on CO(2)-induced panic response in healthy volunteers. METHODS: Eighteen healthy volunteers participated in a randomized, double-blind placebo-controlled study. Each subject received ATD, ATL, and a balanced condition (BAL) in separate days, and a double-breath 35% CO(2) inhalation 4.5 h after treatment. Tryptophan (Trp) manipulations were obtained adding 0 g (ATD), 1.21 g (BAL), and 5.15 g (ATL) of l-tryptophan to a protein mixture lacking Trp. Assessments consisted of a visual analogue scale for affect (VAAS) and panic symptom list. A separate analysis on a sample of 55 subjects with a separate-group design has also been performed to study the relationship between plasma amino acid levels and subjective response to CO(2). RESULTS: CO(2)-induced subjective distress and breathlessness were significantly lower after ATD compared to BAL and ATL (p < 0.05). In the separate-group analysis, ΔVAAS scores were positively correlated to the ratio Trp:ΣLNAA after treatment (r = 0.39; p < 0.05). CONCLUSIONS: The present results are in line with preclinical data indicating a role for the serotonergic system in promoting the aversive respiratory sensations to hypercapnic stimuli (Richerson, Nat Rev Neurosci 5(6):449-461, 2004). The differences observed in our study, compared to previous findings in PD patients, might depend on an altered serotonergic modulatory function in patients compared to healthy subjects.

Genetic moderation of CO2-induced fear by 5-HTTLPR genotype.

Inhalation of an increased concentration of carbon dioxide (CO(2)) has been shown to induce a state of negative affect in healthy subjects that is closely related to the clinical phenomenon of panic. It has been suggested that the vulnerability to CO(2) is moderated by differences in serotonin (5-HT) activity, caused by a functional polymorphism in the promoter region of the 5-HT transporter (5-HTTLPR) gene. Our aim was to examine the relationship between bi- and tri-allelic 5-HTTLPR genotype and the affective response to different dosages of inhaled CO(2) in healthy volunteers. Ninety-six subjects performed a double inhalation of four mixtures containing, respectively, 0%, 9%, 17.5% and 35% CO(2), following a double-blind, cross-over, randomized design. Affective responses were measured with a visual analogue scale for fear and the Panic Symptom List. 5-HTTLPR genotype was expressed as LL, SL and SS. Subjects with the SL and SS genotype reported less fear than LL subjects. A significant interaction effect was found between genotype and CO(2) dosage: the SS genotype showed lower fear scores than the LL genotype, particularly in the 17.5% CO(2) dose condition. The present study suggests that the dose-dependent fear reaction to CO(2) is moderated by a polymorphism in the 5-HT transporter gene, particularly at intermediate CO(2) dosages. It also underscores the usefulness of the introduction of an intermediate phenotype related to panic to reveal an underlying genetic vulnerability otherwise staying elusive. These results are in line with current theories on the role of 5-HT in both panic and respiration.

REVIEW: Genome-wide findings in schizophrenia and the role of gene-environment interplay.

The recent advent of genome-wide mass-marker technology has resulted in renewed optimism to unravel the genetic architecture of psychotic disorders. Genome-wide association studies have identified a number of common polymorphisms robustly associated with schizophrenia, in ZNF804A, transcription factor 4, major histocompatibility complex, and neurogranin. In addition, copy number variants (CNVs) in 1q21.1, 2p16.3, 15q11.2, 15q13.3, 16p11.2, and 22q11.2 were convincingly implicated in schizophrenia risk. Furthermore, these studies have suggested considerable genetic overlap with bipolar disorder (particularly for common polymorphisms) and neurodevelopmental disorders such as autism (particularly for CNVs). The influence of these risk variants on relevant intermediate phenotypes needs further study. In addition, there is a need for etiological models of psychosis integrating genetic risk with environmental factors associated with the disorder, focusing specifically on environmental impact on gene expression (epigenetics) and convergence of genes and environment on common biological pathways bringing about larger effects than those of genes or environment in isolation (gene-environment interaction). Collaborative efforts that bring together expertise in statistics, genetics, epidemiology, experimental psychiatry, brain imaging, and clinical psychiatry will be required to succeed in this challenging task.

Tradução e adaptação transcultural do Questionário de Atividade Física Habitual / Translation and cross-cultural adaptation of the Habitual Physical Activity Questionnaire

CONTEXTO: Atualmente há na literatura um crescente interesse na interface entre exercício físico e transtornos psiquiátricos. Apesar disso, ainda há uma deficiência de instrumentos de autorrelato para medir os níveis de atividade física dos pacientes. OBJETIVO: A tradução, a aferição da equivalência semântica e uma aplicação piloto (n = 30), sem pretensão psicométrica, do Questionário de Atividade Física Habitual, visando sua utilização na população brasileira de diferentes níveis de escolaridade. MÉTODOS: O processo envolveu duas traduções e retrotraduções realizadas por avaliadores independentes, avaliação das versões seguida da elaboração de uma versão síntese e pré-teste comentado. RESULTADOS: A maioria dos participantes (91 por cento) não apresentou dificuldades de compreensão com o questionário. Para cada item do instrumento, apresentam-se os resultados das quatro etapas. Mais estudos são necessários para determinar a adequação para populações de baixa escolaridade. Os autores recomendam que sujeitos menos instruídos sejam supervisionados ao preencher o questionário. CONCLUSÕES: A utilização de duas versões de tradução e retrotradução, a discussão sobre a versão síntese e a interlocução com a população-alvo proporcionam maior segurança ao processo de equivalência semântica.

BACKGROUND: There has been a growing scientific interest on the interface between exercise and psychiatric disorders. However, there is a lack of self-report instruments to assess levels of physical activity adapted to Brazilian Portuguese. OBJECTIVE: To translate, assess the semantic equivalence of the Habitual Physical Activity Questionnaire and perform a non-psychometric pre-test with subjects (n = 30) from the Brazilian population, with different educational backgrounds. METHODS: The cross-cultural adaptation process consisted of two translations and back translations performed by two independent evaluators; an evaluation of the versions and the development of a synthetic version; and a commented pretest of the questionnaire. RESULTS: For each item of the instrument, the results of the four stages are reported. Most of the participants (91 percent) did not present any difficulties comprehending the items of the instrument. Further studies should be addressed to determine the adequacy of using this instrument in the less-educated population. We recommend that less instructed subjects be supervised while responding the questionnaire. DISCUSSION: The use of two translations versions, their critical appraisal and the assessment of the target population conceives more safety to the process of semantic equivalence.

Cigarette smoking and 35% CO(2) induced panic in panic disorder patients.

BACKGROUND: A disproportionately large number of persons with panic disorder (PD) smoke cigarettes compared to people in the general population and individuals with other anxiety disorders. Clinical and epidemiological data suggest that cigarette smoking increases the risk for the development and maintenance of PD. The carbon dioxide (CO(2)) challenge is well established as experimental model for panic. The present study seeks to examine whether cigarette smoking has an influence on laboratory elicited panic in PD patients. METHODS: In total 92 subjects (46 smokers and 46 non-smokers) with PD, according to the DSM-IV criteria, were compared. All subjects received a baseline clinical assessment and underwent a 35% CO(2) challenge. Response to the challenge was evaluated via the Panic Symptom List and the Visual Analogue Fear Scale. RESULTS: The two samples did not differ on baseline anxiety level. Smokers had a significantly higher increase in panic symptoms in response to the challenge compared to non-smokers (p=0.04). LIMITATIONS: This type of study does not provide information concerning the underlying mechanisms of the link between smoking and panic. Study limitations include lack of formal assessment of personality and of inter-rater reliability. CONCLUSIONS: The present findings are consistent with the idea that smoking facilitates panic in PD subjects. This may have clinical implications, as quitting smoking could become one of the relevant steps in the treatment of PD patients.

Effect of buspirone on the behavioral regulation of rats in low versus high anxiety conditions.

INTRODUCTION: Buspirone (CAS 33386-08-2) is reported to have anxiolytic effects in humans and is mostly described for mild anxiety. To further explore the effects of buspirone on different levels of anxiety, the effect of buspirone was evaluated in two different conditions of the open field which were distinguished as low and high anxiety (enclosed and exposed open field, respectively). MATERIALS AND METHODS: Twenty-eight albino Wistar rats (350-400 g) were tested in two different arena settings, an enclosed and an exposed open field. Fourteen animals were initially injected with 1 ml saline while the others (n = 14) received buspirone 3 mg/kg. RESULTS: The data showed clear differences in the two open-field settings, suggesting a higher anxiety level in the exposed open field. In addition, correlation analysis showed that the two anxiety tests measure different aspects of anxiety. Buspirone treatment reduced the behavioral activity in both the enclosed and exposed open-field, which is generally interpreted as an anxiogenic effect. However, buspirone increased the time in the center areas and decreased the frequencies in the outer regions. These behavioral changes are generally seen as an anxiolytic effect. Correlation analysis showed that buspirone treatment disrupted the relation between indices of anxiety. CONCLUSION: These results showed that in an open-field setting buspirone appears to have a dual effect. The reduced activity and increase in time spent in the center areas are indicative of both an anxiogenic and an anxiolytic effect, respectively. This was found in both open-field settings, suggesting that the effects of buspirone are independent of the anxiety level.

Acute exercise reduces the effects of a 35% CO2 challenge in patients with panic disorder.

BACKGROUND: Chronic exercise has been shown to have therapeutic effects in panic disorder (PD). The mechanism of these effects is unknown. Acute exercise reduces the effect of a panic challenge in healthy volunteers. Such an effect has not yet been demonstrated in PD patients. The present study aimed at exploring the antipanic effects of acute exercise on a 35% CO2 panic provocation in treatment-naïve PD patients to further elucidate the mechanisms of the beneficial effects of exercise on panic. METHODS: Eighteen PD patients performed either moderate/hard exercise or very-light exercise before a 35% CO2 challenge in a randomized, between-group design. The reactivity to CO2 was assessed with the Visual Analogue Anxiety Scale and the DSM-IV Panic Symptom List. RESULTS: Panic reactions to CO2 were smaller in patients that performed moderate/hard exercise in contrast to those that performed very-light exercise. Increments in both measurements and panic rates were consistently reduced by intense exercise. LIMITATIONS: Since this study focuses on the acute effects of exercise on CO2 sensitivity in patients with PD, the results of repetitive exercise sessions on the rate of spontaneous panic attacks and overall symptoms are warranted. The small sample size and other limitations are addressed. CONCLUSIONS: Exercise reduced the panicogenic effects of a CO2 challenge. In addition to its therapeutic potential, exercise may also be useful as a laboratory maneuver with heuristic value in experimental research into the mechanisms of antipanic treatment.