Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways.

The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed for three variants, TMEM132D rs7370927 (T allele: odds ratio (OR)=1.27, 95% confidence interval (CI): 1.15-1.40, P=2.49 × 10(-6)), rs11060369 (CC genotype: OR=0.65, 95% CI: 0.53-0.79, P=1.81 × 10(-5)) and COMT rs4680 (Val (G) allele: OR=1.27, 95% CI: 1.14-1.42, P=2.49 × 10(-5)) in studies with samples of European ancestry. Nominal associations that did not survive correction for multiple testing were observed for NPSR1 rs324891 (T allele: OR=1.22, 95% CI: 1.07-1.38, P=0.002), TPH1 rs1800532 (AA genotype: OR=1.46, 95% CI: 1.14-1.89, P=0.003) and HTR2A rs6313 (T allele: OR=1.19, 95% CI: 1.07-1.33, P=0.002) in studies with samples of European ancestry and for MAOA-uVNTR in female PD (low-active alleles: OR=1.21, 95% CI: 1.07-1.38, P=0.004). No significant associations were observed in the secondary analyses considering sex, agoraphobia co-morbidity and studies with samples of Asian ancestry. Although these findings highlight a few associations, PD likely involves genetic variation in a multitude of biological pathways that is diverse among populations. Future studies must incorporate larger sample sizes and genome-wide approaches to further quantify the observed genetic variation among populations and subphenotypes of PD.

A randomized trial of sertraline, self-administered cognitive behavior therapy, and their combination for panic disorder.

BACKGROUND: Self-administered cognitive behavior therapy (SCBT) has been shown to be an effective alternative to therapist-delivered treatment for panic disorder (PD). However, it is unknown whether combining SCBT and antidepressants can improve treatment. This trial evaluated the efficacy of SCBT and sertraline, alone or in combination, in PD. METHOD: Patients (n=251) were randomized to 12 weeks of either placebo drug, placebo drug plus SCBT, sertraline, or sertraline plus SCBT. Those who improved after 12 weeks of acute treatment received treatment for an additional 12 weeks. Outcome measures included core PD symptoms (panic attacks, anticipatory anxiety, agoraphobic avoidance), dysfunctional cognitions (fear of bodily sensations, agoraphobic cognitions), disability, and clinical global impression of severity and improvement. Efficacy data were analyzed using general and generalized linear mixed models. RESULTS: Primary analyses of trends over time revealed that sertraline/SCBT produced a significantly greater rate of decline in fear of bodily sensations compared to sertraline, placebo/SCBT and placebo. Trends in other outcomes were not significantly different over time. Secondary analyses of mean scores at week 12 revealed that sertraline/SCBT fared better on several outcomes than placebo, with improvement being maintained at the end of continuation treatment. Outcome did not differ between placebo and either sertraline monotherapy or placebo/SCBT. Moreover, few differences emerged between the active interventions. CONCLUSIONS: This trial suggests that sertraline combined with SCBT may be an effective treatment for PD. The study could not confirm the efficacy of sertraline monotherapy or SCBT without concomitant medication or therapist assistance in the treatment of PD.

Behavioral, neurochemical, anatomical and electrophysiological correlates of panic disorder: multiple transmitter interaction and neuropeptide colocalization.

Neurochemical accounts of panic disorder focus on peripheral indices of central transmitter activity, hormonal correlates and therapeutic efficacy. Anxiogenic agents augment norepinephrine activity, some anxiolytics increase serotonin neurotransmission while benzodiazepines and antidepressants influence catecholamine, indoleamine and gamma-aminobutyric acid turnover in infrahuman subjects. Reliable correlates of central transmitter activity in panic disorder are not in evidence. While animal models of anxiety may not mirror the symptom profile of panic, neurobiological accounts of panic disorder fail to consider extensive central colocalization of neurotransmitter and putative neurotransmitters. In effect, transmitter release in major ascending and descending transmitter systems is modulated by variable neuropeptide interfacing. The behavioral concomitants of psychological disturbance likely follow from variable neurochemical release induced by stimuli as well as conditioning and sensitization. The functional role of receptor sites associated with multiple neurochemical systems may vary and the sensitivity and/or density of receptor sites may be modified. Accordingly, the behavioral and neurochemical concomitants of acute and chronic pathology may be fundamentally different from one another. The present review argues that the symptoms of panic disorder and the etiology of the illness must be evaluated against a background of genetic, organismic and experiential factors. Such variables presumably underlie the diverse behavioral symptoms associated with panic disorder and variations in the therapeutic efficacy of pharmacological treatment.

Enhanced sensitivity to cholecystokinin tetrapeptide in panic disorder. Clinical and behavioral findings.

We studied the action of cholecystokinin tetrapeptide (CCK-4) in patients with panic disorder and normal controls. Subjects received, in random order, one injection of CCK-4 and one injection of placebo (saline) on two separate days in a double-blind crossover design. Two doses of CCK-4, 50 and 25 micrograms, were administered to two different samples of subjects. The panic rate with 50 micrograms of CCK-4 was 100% (12/12) for patients and 47% (7/15) for controls. The panic rate with 25 micrograms of CCK-4 was 91% (10/11) for patients and 17% (2/12) for controls. Nine percent of patients compared with 0% of controls panicked with placebo. These findings concur with previous reports of a panicogenic effect of CCK-4 and suggest that patients with panic disorder are more sensitive to the panicogenic effect of the peptide than are normal controls.

The panicogenic effects of cholecystokinin-tetrapeptide are antagonized by L-365,260, a central cholecystokinin receptor antagonist, in patients with panic disorder.

BACKGROUND: We investigated whether the selective brain cholecystokinin (CCKB) receptor antagonist, L-365,260, could antagonize the panicogenic effects of CCK-tetrapeptide (CCK-4) in patients with panic disorder. DESIGN: The study employed a double-blind, placebo-controlled, two-period crossover design. Patients (N = 29) received a single oral dose of L-365,260 (10 or 50 mg) or placebo 90 minutes prior to injection of CCK-4. After a 1-week washout period, patients received a different dose of L-365,260 or placebo according to a balanced incomplete block design. RESULTS: The 50-mg dose of L-365,260 was superior to placebo in reducing the number (P < .01) and sum intensity (P < .001) of symptoms induced with CCK-4. Panic attack frequency following CCK-4 injection was 88% for patients receiving placebo, 33% for those receiving the 10-mg dose, and 0% for those receiving the 50-mg dose. The difference between the effects of the 50-mg dose and placebo was statistically significant (P = .002). Increases in heart rate following CCK-4 injection were markedly reduced with both the 50-mg (P < .0001) and 10-mg (P < .01) doses compared with placebo. CONCLUSION: These data suggest that CCKB receptors are an important site of action of exogenous CCK-4. It will be important to determine in future studies the efficacy of CCKB receptor antagonists as antipanic agents.

A dose-ranging study of the behavioral and cardiovascular effects of CCK-tetrapeptide in panic disorder.

Recent animal studies have shown that pretreatment with centrally active cholecystokinin (CCK) antagonists blocks the anxiogenic effects of CCK-tetrapeptide (CCK-4). In order to determine whether pretreatment with these antagonists can block the anxiogenic effects of CCK-4 in patients with panic disorder, a suitable challenge dose of CCK-4 must be selected. Thus, we conducted a dose range study in which patients with panic disorder (n = 29) were challenged with CCK-4 (10, 15, 20, or 25 micrograms) or placebo on two separate occasions, in a balanced incomplete block design. Patients received in random order 10 micrograms (n = 12), 15 micrograms (n = 11), 20 micrograms (n = 12), or 25 micrograms (n = 12) of CCK-4 or placebo (n = 11). CCK-4 induced anxiety and panic responses in a dose-dependent fashion. The incidence of panic attacks following the CCK-4 challenge was 17% (10 micrograms), 64% (15 micrograms), 75% (20 micrograms), and 75% (25 micrograms). None of the patients panicked with placebo. Moreover, a strong linear relationship between CCK-4 and increases in heart rate and diastolic blood pressure was found. The findings of this study suggest that a dose of 20 micrograms of CCK-4 (ED75) might be suitable for efficacy studies of CCKB antagonists and other potential antipanic drugs in patients with panic disorder.

Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers.

A randomized, placebo-controlled, double-blind, three-way crossover design was used to evaluate the effectiveness of single oral 100 mg doses of CI-988, a cholecystokinin B (CCKB) antagonist, in attenuating panic symptoms induced by intravenous injection of cholecystokinin-tetrapeptide (CCK-4). Thirty healthy men received the following treatments on three separate occasions: placebo capsules/placebo, placebo capsules/CCK-4, or CI-988 capsules/CCK-4. There was no marked difference in the number, time to onset, or duration of panic symptoms between CI-988/CCK-4 and placebo/CCK-4. There was, however, a 14% difference in sum intensity scores between these treatments that was statistically significant (p = 0.039). The symptoms most affected by CI-988 were cold chills/hot flushes, chest pain/discomfort, and anxiety/fear/apprehension. Panic attack frequency also decreased following CI-988 treatment (8/30 vs. 16/30; p = 0.035). This decrease, amid otherwise modest effects, could be explained by a preferential effect of CI-988 on the subjective experience of anxiety/fear/apprehension. Possible reasons for the relatively modest effects of CI-988 on CCK-4-induced panic symptoms are discussed.

Effect of acute tryptophan depletion on behavioral, cardiovascular, and hormonal sensitivity to cholecystokinin-tetrapeptide challenge in healthy volunteers.

Recent data suggest that serotonergic (5-HT) mechanisms may mediate the anxiogenic effects of cholecystokinin (CCK)-related peptides. Accordingly, we investigated the effect of lowering plasma tryptophan to the elicitation of behavioral, cardiovascular, and hormonal changes in healthy volunteers challenged with the tetrapeptide CCK agonist, CCK-4. Forty men without personal or family history of psychiatric disorders were randomly assigned to either a tryptophan-free amino acid mixture, which decreases central 5-HT concentrations, or a control mixture. Five hours after administration of the amino acid mixture, all subjects received a single intravenous injection of CCK-4. The main finding of the study was that acute depletion of tryptophan failed to modify the panicogenic and cardiovascular effects of CCK-4, although it did enhance CCK-4-mediated increases in ACTH/cortisol and prolactin secretion. While these findings suggest that at least part of the neuroendocrine action of CCK-4 is mediated through the 5-HT system, the locus of the 5-HT-CCK interaction and the specific 5-HT receptor subtype involved remains to be determined.

The role of the beta-noradrenergic system in cholecystokinin-tetrapeptide-induced panic symptoms.

BACKGROUND: The authors determined whether effective beta-adrenergic blockade could attenuate the panicogenic effects of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. METHODS: Subjects were randomly assigned to either a propranolol (n = 14) or placebo (n = 16) infusion. Ten minutes after completion of the infusion subjects received a bolus injection of CCK-4 (50 micrograms). RESULTS: Acute pretreatment with propranolol was more effective than placebo in decreasing behavioral and cardiovascular sensitivity. CONCLUSIONS: These preliminary results suggest that the panicogenic effects of CCK-4 are mediated, in part, through the beta-adrenergic system.

Imipramine antagonism of the panicogenic effects of cholecystokinin tetrapeptide in panic disorder patients.

Eleven panic disorder patients who panicked in response to exogenous cholecystokinin tetrapeptide (CCK-4) were rechallenged after chronic treatment with imipramine. In the rechallenge the patients displayed a marked reduction in the number and intensity of panic symptoms, duration of symptoms, frequency of panic attacks, and cardiovascular responsiveness. This study demonstrates that imipramine can antagonize the panicogenic effects of CCK-4.

Anxiety sensitivity and response to cholecystokinin tetrapeptide in healthy volunteers.

The authors determined whether fear of anxiety symptoms mediates panicogenic responses to cholecystokinin tetrapeptide (CCK-4) in healthy subjects. Individuals with a preexisting high level of anxiety sensitivity (N = 10) experienced significantly more catastrophic cognitions and fear of somatic symptoms than did subjects with low (N = 9) or medium (N = 17) anxiety sensitivity, but they were not more susceptible to experiencing a panic attack. Thus, cognitive factors do not appear to be critical determinants of CCK-4-induced panic attacks.

Replication of action of cholecystokinin tetrapeptide in panic disorder: clinical and behavioral findings.

Eleven patients with panic disorder were challenged with cholecystokinin tetrapeptide (CCK-4) on two occasions. The effects of CCK-4 were consistent except symptom onset was more rapid with the second injection. Demonstrating that the effects of CCK-4 are reproducible in panic patients opens the doors for studies of the effects of drug treatment on CCK-4-induced panic.

Effects of cholecystokinin tetrapeptide on respiratory function in healthy volunteers.

OBJECTIVE: The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. METHOD: Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. RESULTS: Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures. CONCLUSIONS: These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

Effect of aging on cholecystokinin-induced panic.

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Sensitivity to CCK-4 in women with and without premenstrual dysphoric disorder (PMDD) during their follicular and luteal phases.

The authors determined whether women with premenstrual dysphoric disorder (PMDD) exhibit a heightened sensitivity to the panicogenic effects of CCK-4 administration and whether this enhanced sensitivity to CCK-4 would vary with the phase of the menstrual cycle at the time of CCK-4 injection. Twenty-one normal controls and 18 PMDD women were randomly assigned to receive the first and second CCK-4 injection during the follicular phase and the luteal phase or vice versa. PMDD women showed a greater anxiety and panic response to CCK-4. These preliminary results suggest that the CCK-B system may play a role in the pathophysiology of PMDD.

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects.

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Effects of flumazenil on cholecystokinin-tetrapeptide-induced panic symptoms in healthy volunteers.

The neuropeptide cholecystokinin-tetrapeptide (CCK-4) has potent anxiogenic action in human and animal subjects. On the basis of prior work which demonstrated that benzodiazepine (BZD) receptor agonists antagonized CCK-induced excitation of rat hippocampal neurons we studied whether BZD receptors mediated the anxiogenic effect of CCK-4. To examine this possibility we determined whether the BZD receptor antagonist flumazenil could antagonize the effects of CCK-4 (50 micrograms) in healthy volunteers. Thirty subjects (10 females; 20 males) were pretreated with flumazenil (2 mg in saline) or placebo (0.9% NaCl in water) 15 min prior to CCK-4 challenge in a randomized double-blind crossover design. Flumazenil had no impact on the behavioral and cardiovascular effects of CCK-4, suggesting that BZD receptors do not mediate the anxiogenic action of CCK-4. The influence of GABA and non-GABA-related mechanisms on response to CCK-4 remains to be considered.

Decrease in short-term memory function induced by CCK-4 in healthy volunteers.

The purpose of this study was to assess the effects of continuous intravenous infusion of the central cholecystokinin (CCK) receptor agonist, CCK-4, on short-term memory and psychomotor performance in healthy volunteers in a double-blind, placebo-controlled, parallel group study. Compared to placebo, CCK-4 (0.5 mg/h) significantly impaired performance on free-recall and recognition of words in the middle of the CCK-4 infusion, but did not affect psychomotor acuity. The results of this study indicate that CCK-4 may exert a negative influence on memory consolidation and retrieval.

Arginine-vasopressin and oxytocin response to cholecystokinin-tetrapeptide.

This study examined the effects of i.v. administration of cholecystokinin-tetrapeptide (CCK-4) on plasma release of arginine vasopressin (AVP) and oxytocin (OT) in women with premenstrual dysphoric disorder (PMDD) and control women, during both the follicular phase and the luteal phase of their menstrual cycle. Plasma AVP and OT concentrations increased following CCK-4 administration. AVP and OT response to CCK-4 was similar for PMDD and control women and unaffected by menstrual cycle phase. AVP and OT may play a role in the hypothalamo-pituitary adrenal (HPA) axis activity associated with the panic response induced by CCK-4.

Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany.

The T102C serotonin-2A (5-HT2A) receptor gene polymorphism has been studied extensively in a number of complex psychiatric conditions with mixed results. Recently a genetic association has been described between this polymorphism and panic disorder in a Japanese sample. To evaluate the impact of the T102C polymorphism in panic disorder we genotyped triad families (panic disorder patient and parents), and cases with controls in Canadian and German samples. No significant transmission disequilibrium was observed between the alleles of the T102C 5-HT2A receptor gene polymorphism and panic disorder, nor was a significant excess of either allele found in the case control analysis. Our data suggest thus that this polymorphism is unlikely to play a major role in the pathogenesis of panic disorder.