piperidines and Panic-Disorder

In this Research Review, several recent clinical trials in panic disorder and social phobia are reviewed. First, two social phobia studies which used the monoamine oxidase type A inhibitors brofaromine and moclobemide are considered. Then, three panic disorder studies which used clonazepam, clomipramine or paroxetine, and citalopram are examined. These studies serve to strengthen the empirical research base regarding which treatments are useful in these disorders.

Topics: Antidepressive Agents, Tricyclic; Benzamides; Benzodiazepines; Citalopram; Clinical Trials as Topic; Clomipramine; Clonazepam; Dose-Response Relationship, Drug; Female; Humans; Male; Moclobemide; Monoamine Oxidase Inhibitors; Panic Disorder; Paroxetine; Piperidines; Recurrence; Selective Serotonin Reuptake Inhibitors; Social Behavior Disorders

The present study was designed to examine the efficacy and tolerability of the non-peptide neurokinin-3 (NK3) receptor antagonist SR142801 in outpatients suffering from panic disorder.. In a pilot study, 52 patients who were responders to a cholecystokinin tetrapeptide (CCK-4) challenge were randomized to four weeks of treatment with SR142801 (n = 36) or placebo (n = 16). Panic symptoms were assessed on weekly visits and a second CCK-4 challenge was performed at the end of the double-blind placebo controlled treatment period. Tolerability of SR142801 was generally good.. The proportion of patients who had at least one adverse event (AE) in the SR142801 group and the placebo group was similar (58.3 and 50 %, respectively). Independent of treatment group, patients' overall panic symptomatology was substantially improved at the end of the treatment.. With regard to efficacy of outcome, the compound was not significantly different from placebo. However, post-CCK-4 plasma prolactin concentrations showed a significant difference between placebo and SR142801.

Topics: Adolescent; Adult; Antipsychotic Agents; Double-Blind Method; Electrocardiography; Endpoint Determination; Female; Humans; Male; Middle Aged; Panic Disorder; Piperidines; Receptors, Neurokinin-3; Tetragastrin

Previous studies have shown that both selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs) are effective in the treatment of panic disorders (PD). In this study, the SSRI fluvoxamine (Fluv) was compared with the MAO-A-I brofaromine (Brof). Thirty patients with the diagnosis of PD with or without agoraphobia were treated with either Fluv or Brof (150 mg daily) in a double-blind design. After 12 weeks of treatment, 93% of the Brof group and 87% of the Fluv group considered themselves much or very much improved. Taking a reduction in the Hamilton Rating Scale for Anxiety score of 50% or more, 33% of the Fluv patients and 47% of the Brof patients were responders to treatment. After an increase in anxiety in the 1st week, which was more severe in Fluv-treated patients than for Brof, a clinically relevant decrease in anxiety symptoms and reduction in panic attacks and avoidance behavior was observed. There was no significant difference between the treatment groups. The most prominent side effects were middle-sleep disturbance (Brof), tiredness (Fluv), and nausea after taking the medication (Brof and Fluv). During a double-blind follow-up period of another 12 weeks, a further improvement was found in both treatment groups without significant differences between the two groups. The selective and reversible MAO-A-I brofaromine and the SSRI fluvoxamine are equally effective in the treatment of PD. Both compounds lead to a reduction in the number of panic attacks and a subsequent reduction in agoraphobic avoidance.

Topics: Adult; Anti-Anxiety Agents; Double-Blind Method; Female; Fluvoxamine; Headache; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Nausea; Panic Disorder; Piperidines; Selective Serotonin Reuptake Inhibitors

Little is known about biological predictors of treatment response in panic disorder (PD). In the present study heart rate, blood pressure, plasma cortisol and plasma MHPG were investigated at baseline in a sample of 44 PD patients as possible predictors for nonresponse to treatment. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment with brofaromine or fluvoxamine. Patients were considered nonresponders when they fulfilled two criteria: they did not show a 50% reduction of agoraphobic avoidance and they still experienced panic attacks at endpoint. The variables that differed significantly between the groups were used to predict nonresponse to drug therapy. Using this strict definition of nonresponse, 15 patients (32.6%) were considered nonresponders. These patients were characterised by a higher plasma MHPG concentration and a higher heart rate at baseline. These variables were subsequently used to predict nonresponse.

Topics: Adult; Biomarkers; Blood Pressure; Double-Blind Method; Female; Fluvoxamine; Heart Rate; Humans; Hydrocortisone; Male; Methoxyhydroxyphenylglycol; Middle Aged; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Selective Serotonin Reuptake Inhibitors; Treatment Failure

Factors that predict nonresponse to drug therapy (brofaromine or fluvoxamine) were investigated in a sample of 44 panic disorder patients. We used a strict definition of nonresponse to find patients who did not respond at all after 12 weeks of treatment. Using this definition, 15 patients (32.6%) were considered nonresponders. Nonresponders had a higher score on the Blood-Injury subscore of the Fear Questionnaire (FQ) and more often had high scores on several FQ subscores, indicative of comorbid phobic symptoms. These variables were subsequently used to predict nonresponse.

Topics: Adult; Agoraphobia; Double-Blind Method; Female; Fluvoxamine; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Panic; Panic Disorder; Personality Inventory; Phobic Disorders; Piperidines; Prognosis; Treatment Outcome

Topics: Adult; Agoraphobia; Humans; Male; Monoamine Oxidase Inhibitors; Panic Disorder; Phobic Disorders; Piperidines

There is considerable evidence that antidepressants, particularly serotonin uptake inhibitors, are effective in the treatment of panic disorder (PD). Monoamine oxidase inhibitors (MAOI) may also have beneficial effects in PD. In this study 30 patients with PD with or without agoraphobia (DSM-III-R) were treated with the selective and reversible MAO-A inhibitor brofaromine (150 mg daily) in a 12-week double-blind placebo controlled design. A clinical relevant improvement was found in more than 70% of the patients treated with brofaromine, whereas no significant improvement was observed on placebo. After an increase in anxiety in the first week, a clinically relevant improvement in anxiety symptoms was found, followed by a subsequent reduction in agoraphobic avoidance in patients treated with brofaromine. A similar improvement was observed on distress scores related to panic attacks, although there was no significant reduction in the number of panic attacks. The most prominent side-effects were middle sleep disturbance and nausea. No increase in blood pressure was observed. During a follow-up period of another 12 weeks a further improvement was found in patients treated with brofaromine.

Topics: Adult; Agoraphobia; Double-Blind Method; Fear; Female; Follow-Up Studies; Humans; Male; Middle Aged; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Psychiatric Status Rating Scales

Monoamine oxidase (MAO) inhibitors are known to be effective in panic disorder, but a high incidence of adverse reactions have limited their use. The new, selective, and reversible MAO-A inhibitors exemplified by brofaromine and moclobemide do not require dietary restrictions, have fewer drug interactions, and are better tolerated. This paper reports a randomized, double-blind, 8-week trial in which the efficacy and safety of brofaromine was compared to clomipramine in patients with panic disorder with or without agoraphobia. Both treatments achieved a significant and comparable reduction in the number of panic attacks, and were equally effective in all the parameters measured. Side effects were typical of the drug class. Further trials are required to evaluate this promising new treatment.

Topics: Agoraphobia; Clomipramine; Double-Blind Method; Humans; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Psychiatric Status Rating Scales

The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.. This study was designed to explore the specific pattern of distribution of the CB. A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB. The morphological procedures demonstrated distribution of labelled CB. These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB

Topics: Animals; Cannabidiol; Fear; Injections, Intraventricular; Male; N-Methylaspartate; Pain Measurement; Panic Disorder; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Ventromedial Hypothalamic Nucleus

Recurrent panic attacks, comprising emotional and cardiovascular aversive responses, are common features in panic disorder, a subtype of anxiety disorder. The underlying brain circuitry includes nuclei of the hypothalamus, such as the dorsomedial hypothalamus (DMH). The endocannabinoid system has been proposed to modulate several biological processes in the hypothalamus. Thus, we tested the hypothesis that hypothalamic endocannabinoid signalling controls aversive responses in an animal model of panic attacks. Local infusion of NMDA into the DMH of rats induced panic-like behaviour. This effect was prevented by local, but not intraperitoneal, injection of a 2-arachidonoylglycerol (2-AG) hydrolysis inhibitor (MAGL inhibitor, URB602). The anandamide hydrolysis inhibitor (FAAH inhibitor), URB597, was ineffective. The anti-aversive action of URB602 was reversed by CB

Topics: Animals; Arachidonic Acids; Benzamides; Biphenyl Compounds; Blood Pressure; Cannabinoids; Carbamates; Corticosterone; Dorsomedial Hypothalamic Nucleus; Endocannabinoids; Indoles; Male; Microinjections; N-Methylaspartate; Panic Disorder; Piperidines; Pyrazoles; Rats

The effects of cannabinoids in brain areas expressing cannabinoid receptors, such as hypothalamic nuclei, are not yet well known. Several studies have demonstrated the role of hypothalamic nuclei in the organisation of behavioural responses induced through innate fear and panic attacks. Panic-prone states are experimentally induced in laboratory animals through a reduction in the GABAergic activity. The aim of the present study was to examine panic-like elaborated defensive behaviour evoked by GABA

Topics: Animals; Arachidonic Acids; Bicuculline; Disease Models, Animal; Endocannabinoids; Escape Reaction; GABA-A Receptor Antagonists; Male; Panic Disorder; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, GABA-A; TRPV Cation Channels; Ventromedial Hypothalamic Nucleus

2-arachidonoylglycerol (2-AG) is an endogenous ligand of the cannabinoid CB1 receptor. This endocannabinoid and its hydrolyzing enzyme, monoacylglycerol lipase (MAGL), are present in encephalic regions related to psychiatric disorders, including the midbrain dorsolateral periaqueductal grey (dlPAG). The dlPAG is implicated in panic disorder and its stimulation results in defensive responses proposed as a model of panic attacks. The present work verified if facilitation of 2-AG signalling in the dlPAG counteracts panic-like responses induced by local chemical stimulation. Intra-dlPAG injection of 2-AG prevented panic-like response induced by the excitatory amino acid N-methyl-d-aspartate (NMDA). This effect was mimicked by the 2-AG hydrolysis inhibitor (MAGL preferring inhibitor) URB602. The anti-aversive effect of URB602 was reversed by the CB1 receptor antagonist, AM251. Additionally, a combination of sub-effective doses of 2-AG and URB602 also prevented NMDA-induced panic-like response. Finally, immunofluorescence assay showed a significant increase in c-Fos positive cells in the dlPAG after local administration of NMDA. This response was also prevented by URB602. These data support the hypothesis that 2-AG participates in anti-aversive mechanisms in the dlPAG and reinforce the proposal that facilitation of endocannabinoid signalling could be a putative target for developing additional treatments against panic and other anxiety-related disorders.

Topics: Animals; Arachidonic Acids; Biphenyl Compounds; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Fluorescent Antibody Technique; Glycerides; Male; N-Methylaspartate; Panic Disorder; Periaqueductal Gray; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1

Direct activation of the cannabinoid CB1 receptor in the dorsolateral periaqueductal gray (dlPAG) inhibits anxiety- and panic-related behaviours in experimental animals. It has remained unclear, however, whether the local endocannabinoid signalling is recruited as a protective mechanism against aversive stimuli.. The present study tested the hypothesis that the endocannabinoid system counteracts aversive responses in the dlPAG-stimulation model of panic attacks.. All drugs were infused into the dlPAG of rats. Local chemical stimulation with N-methyl-D-aspartate (NMDA, 1 nmol) was employed to induce panic-like behavioural and cardiovascular responses in freely moving and anaesthetized animals, respectively. The neuronal activity in the dlPAG was investigated by c-Fos immunohistochemistry.. The selective CB1 receptor agonist, ACEA (0.005-0.5 pmol), prevented the NMDA-induced panic-like escape responses. More interestingly, increasing the local levels of endogenous anandamide with a fatty acid amide hydrolase (FAAH) inhibitor, URB597 (0.3-3 nmol), prevented both the behavioural response and the increase in blood pressure induced by NMDA. The effect of URB597 (3 nmol) was reversed by the CB1 receptor antagonist, AM251 (0.1 nmol). Moreover, an otherwise ineffective and sub-threshold dose of NMDA (0.5 nmol) was able to induce a panic-like response if local CB1 receptors were previously blocked by AM251 (0.1 nmol). Finally, URB597 prevented the NMDA-induced neuronal activation of the dlPAG.. The endocannabinoid system in the dlPAG attenuates the behavioural, cellular and cardiovascular consequences of aversive stimuli. This process may be considered for the development of additional treatments against panic and other anxiety-related disorders.

Topics: Amidohydrolases; Animals; Anxiety; Arachidonic Acids; Behavior, Animal; Benzamides; Carbamates; Disease Models, Animal; Endocannabinoids; Enzyme Inhibitors; Male; N-Methylaspartate; Panic Disorder; Periaqueductal Gray; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1

Panic attacks, a major feature of panic disorder, can be modelled in rats by exposing animals to stimuli that induce escape reactions, such as the elevated T-maze or the activation of the dorsolateral periaqueductal grey. Since the cannabinoid CB1 receptor modulates various types of aversive responses, this study tested the hypothesis that enhancement of endocannabinoid signalling in the dorsolateral periaqueductal grey inhibits panic-like reactions in rats. Local injection of the CB1 agonist, arachidonoyl 2-Chloroethylamide (0.005-0.5 pmol), attenuated the escape response from the open arm of the elevated T-maze, a panicolytic effect. The anandamide hydrolysis inhibitor, URB597 (0.3-3 nmol), did not induce consistent results. In the test of dorsolateral periaqueductal grey stimulation with d,l-homocysteic acid, arachidonoyl 2-Chloroethylamide, at the lowest dose, attenuated the escape reaction. The highest dose of URB597 also inhibited this response, contrary to the result obtained in the elevated T-maze. This effect was reversed by the CB1 antagonist, AM251 (100 pmol). The present results confirm the anti-aversive property of direct CB1 receptor activation in the dorsolateral periaqueductal grey. The effect of the anandamide hydrolysis inhibitor, however, could be detected only in a model employing direct stimulation of this structure. Altogether, these results suggest that anandamide signalling is recruited only under certain types of aversive stimuli.

Topics: Animals; Arachidonic Acids; Benzamides; Carbamates; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Escape Reaction; Male; Maze Learning; Panic Disorder; Periaqueductal Gray; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Signal Transduction

Panic attacks are a hallmark in panic disorder (PAND). During the panic attack, a strong association with the surrounding context is established suggesting that the hippocampus may be critically involved in the pathophysiology of PAND, given its role in contextual processing. We previously showed that variation in the expression of the neurotrophin tyrosine kinase receptor type 3 (NTRK3) in both PAND patients and a transgenic mouse model (TgNTRK3) may have a role in PAND pathophysiology. Our study examines hippocampal function and activation of the brain fear network in TgNTRK3 mice. TgNTRK3 mice showed increased fear memories accompanied by impaired extinction, congruent with an altered activation pattern of the amygdala-hippocampus-medial prefrontal cortex fear circuit. Moreover, TgNTRK3 mice also showed an unbalanced excitation-to-inhibition ratio in the hippocampal cornu ammonis 3 (CA3)-CA1 subcircuit toward hyperexcitability. The resulting hippocampal hyperexcitability underlies the enhanced fear memories, as supported by the efficacy of tiagabine, a GABA reuptake inhibitor, to rescue fear response. The fearful phenotype appears to be the result of hippocampal hyperexcitability and aberrant fear circuit activation. We conclude that NTRK3 plays a role in PAND by regulating hippocampus-dependent fear memories.

Topics: Analysis of Variance; Animals; Bacterial Proteins; Conditioning, Classical; Disease Models, Animal; Disks Large Homolog 4 Protein; Excitatory Amino Acid Antagonists; Exploratory Behavior; Extinction, Psychological; Fear; GABA Agonists; Generalization, Psychological; Glutamate Decarboxylase; Guanylate Kinases; Hippocampus; Luminescent Proteins; Maze Learning; Membrane Proteins; Memory; Mice; Mice, Transgenic; Nipecotic Acids; Panic Disorder; Piperidines; Proto-Oncogene Proteins c-fos; Receptor, trkC; Tiagabine; Vesicular Glutamate Transport Proteins

Topics: Brain Mapping; Humans; Panic Disorder; Piperidines; Positron-Emission Tomography; Protein Binding; Receptors, Neurokinin-1; Tetrazoles

Positron emission tomography (PET) can localize and quantify neurokinin-1 (NK(1)) receptors in brain using the nonpeptide antagonist radioligand, [(18)F]SPA-RQ. We sought to determine if patients with panic disorder have altered density of NK(1) receptors in brain because of their history of recurrent panic attacks. We also sought to determine if a drug-induced panic attack releases substance P in brain, as measured by decreased binding of [(18)F]SPA-RQ.. Positron emission tomography scans with [(18)F]SPA-RQ were performed in 14 patients with panic disorder and 14 healthy subjects. Of these two groups, 7 patients and 10 healthy subjects were scanned twice, once at baseline and once after injection of doxapram, a drug that induces panic attacks.. NK(1) receptor binding in patients (n = 14) compared with that in healthy subjects (n = 14) was significantly decreased by 12% to 21% in all brain regions. Doxapram effectively produced panic attacks in 6 of 7 patients with panic disorder but only 2 of 10 healthy subjects. Doxapram caused no significant change of [(18)F]SPA-RQ binding in either patients or healthy subjects.. Although induction of a panic attack has no significant effect on [(18)F]SPA-RQ binding to NK(1) receptors, patients with panic disorder have widespread reduction of NK(1) receptor binding in brain.

Topics: Adult; Brain; Brain Mapping; Female; Humans; Male; Middle Aged; Panic Disorder; Piperidines; Positron-Emission Tomography; Protein Binding; Receptors, Neurokinin-1; Tetrazoles

The clinically tested reversible inhibitors of monoamine oxidase A (RIMAs) include brofaromine, moclobemide and toloxatone. Moclobemide has shown unequivocal antidepressant activity against serious depressive illness in 4 placebo-controlled double-blind trials. It has been compared with amitriptyline, imipramine, clomipramine, desipramine, maprotiline, fluoxetine, fluvoxamine, tranylcypromine, toloxatone, mianserin and amineptine in the treatment of depressive disorders. Meta-analysis showed convincing evidence of moclobemide efficacy, comparable with the most potent antidepressants available. The efficacy of moclobemide has been demonstrated in psychotic and non-psychotic depression, in depression with and without melancholia, in endogenous depression (both unipolar and bipolar), in retarded depression and in agitated depression. The efficacy of moclobemide, allied to the unusually benign side effect profile, has led to exploration of its use in other disorders. Two small studies have given encouraging results in the treatment of attention-deficit hyperactivity disorder. Large placebo-controlled studies have shown the activity of moclobemide in the depression that accompanies dementia (such as senile dementia of Alzheimer type). The results also suggested that, in this patient population, cognitive ability improved in parallel. Social phobia has also been shown to improve on treatment with either moclobemide or brofaromine. Clinical trials are in progress on the effect of moclobemide in chronic fatigue syndrome. Moreover, there are encouraging results with the use of brofaromine and moclobemide in panic disorder. Other disorders in which treatment with RIMA is of interest include agoraphobia, bulimia, borderline personality disorder, post-traumatic stress disorder, compulsive hair pulling (trichotillomania), dysmorphophobia, kleptomania as well as various anxiety syndromes.

Topics: Alzheimer Disease; Antidepressive Agents, Tricyclic; Attention Deficit Disorder with Hyperactivity; Benzamides; Humans; Moclobemide; Monoamine Oxidase Inhibitors; Oxazoles; Oxazolidinones; Panic Disorder; Phobic Disorders; Piperidines

The therapeutic efficacy of brofaromine--a new reversible and short acting MAO-A inhibitor--was evaluated in 14 inpatients with a panic disorder. In an open trial, the patients were treated with placebo during the first week and with 150 mg brofaromine per day during the following four weeks. In all patients a distinct improvement in both anxiety and depressive symptoms was observed under the active drug. Treatment outcome was the same in patients with and without a concomitant major depressive episode. No side-effects of any note were reported. Our findings suggest that the MAO-A inhibitor brofaromine is an effective drug in the treatment of anxiety disorders.

Topics: Adult; Agoraphobia; Female; Humans; Male; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Panic Disorder; Piperidines; Psychiatric Status Rating Scales