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GABApentin Treatment Response in Selective Serotonin Reuptake Inhibitor (SSRI)-Refractory Panic Disorder

Principal author and correspondence:
Dr. Simon Chiu, MD, PHD, FRCP (C), Consultant Psychiatrist, Regional Mental Health Care, St. Thomas , Ontario N5P 3V9 Canada. ; Associate Prof. , Department of Psychiatry, University of Western Ontario, London, Ontario, Canada.
Telephone: 1-519-631-8510 ext. 49655
Fax: 1-519-631-2512
e-mail: schiu3207@rogers.com (personal e-mail)

Abstract:

In a naturalistic open-label 12-week study, the action of GABApentin, a putative alpha2delta Voltage Dependent Calcium Channel (VDCC) modulator, as adjunctive therapy in SSRI-refractory panic disorder was investigated at the outpatient setting. GABApentin, at the mean daily oral dosage of 1400 gm, when combined with optimal dosages of SSRI, demonstrated statistically significant ( p < 0.001) effects in reducing panic and anxiety symptoms as measured with PAS (Panic and Agoraphobic scale) and HAM-A scale in a sample of SSRI-resistant panic disorder patients ( n = 20). Side effects included headache, restlessness and sexual dysfunction. The dropout rate was 15%. The preliminary promising results merit further placebo-controlled studies to establish the efficacy of GABApentin in anxiety spectrum disorders.

Key words: GABApentin, Calcium channel , SSRI , Panic disorder

Introduction:

Panic Disorder has significant impact on excessive health service utilization in terms of excessive emergency visits and diagnostic tests, coupled with decline in productivity and high degree of psychiatric and substance use comorbidity ( 1 ). However, relatively little attention has been drawn to the issue of treatment-resistant panic disorder. In long-term follow up naturalistic studies, symptom persistence and recurrence occur at a rate ranging from 40% to 80% ( 2 ). Bandelow and Ruther (3) , in reviewing pharmacotherapy of panic disorder in relation to the issue of treatment resistance panic disorders, found positive evidence for alprazolam for the acute panic attacks. For maintenance treatment, positive evidence is found for both SSRI and tricyclic antidepressants. The risk factors predicting less favourable outcome include severe baseline symptoms of anxiety and agoraphobia, unemployment, co-morbid depression and personality disorders and other anxiety disorders.

Earlier pharmacological intervention focussed on the use of high potency benzodiazepines. Alprazolam while highly effective in controlling panic attacks, can result in interdose rebound anxiety and may lead to abuse and tolerance ( 4 ). The extended release formulation of alprazolam (alprazolam X-R) is comparable to the original oral divided dosage of alprazolam in its anti-panic efficacy and has the advantage of greater tolerability and safety ( 5). However, long-term therapy with alprazolam carries similar risks of withdrawal and dependence. The recent trend in the management of panic disorder has shifted gradually from benzodiazepines towards the use of anti-depressants ( 6). SSRI (Selective Serotonin Reuptake Inhibitor) has overshadowed the traditional tricyclic antidepressants as the mainstay pharmaco-therapy for panic disorder. However, the response rate towards SSRI in panic disorder is highly variable ranging from 36 to 86% (7 ). The issue of treatment resistance in panic disorder underlines the need to continuously search for more efficacious augmentation therapy to boost the SSRI response or combining SSRI or other medication with cognitive behavioural therapy, especially in tertiary care centre.

There has been recent interest in class of anti-epileptics in the treatment of panic disorder. Studies with anti-convulsants such as carbamazepine and valproate have been inconclusive ( 8 ). GABApentin, approved for the treatment of partial complex seizures , has a relatively unique pharmacological profile. GABApentin enhances the synthesis of GABA (gamma-amino-butyric acid), and modulates the release of the excitatory amino acid, glutamate at the synaptic terminal ( 9). The initial claim of GABApentin as a full agonist at GABA subtype b receptor has recently been disputed (10 ). The most appealing hypothesis of GABApentin mechanism of action is that GABApentin interacts with the alpha2delta voltage dependent calcium channel (VDCC) multiple subunit complexes heterogeneously expressed in the brain. The binding affinities of stereoselective analogues of GABApentin , including pregabaline, correlate with their structural activity relationship (SAR) in animal models of epilepsy ( 12 ). No data are available whether the SAR is also reflected in animal models of anxiety . In the rat hippocampus, GABApentin behaves similarly to the prototypal L-type calcium channel blocker, nimodipine. There is preliminary evidence suggesting that the signal transduction pathways mediating GABApentin action consist of activation of transcription factors like cyclic AMP response element (CREB), and protein kinase C. The recent discovery of the alpha2delta VDCC subunit has stimulated a great deal of interest as potential therapeutic targets for anxiety spectrum disorders, neuropathic pain, unipolar depression, bipolar disorder , addiction as well as in epilepsy.

In clinical studies of anxiety disorders, encouraging results are reported with GABApentin consistent with its anxiolytic properties. In social phobia, GABApentin was found to be superior than placebo ( 13 ) In epilepsy patients, GABApentin improves sense of well-being and mood disturbances ( 14 ) . A recent randomized placebo-controlled study found that GABApentin reduced panic symptoms in severe panic disorder ( 15 ). Treatment effect is more marked in females than males. It is highly likely that the severe panic disorder clients in Pande’s study (15) are non-responsive to SSRI therapy. Pregabalin, another VDCC modulator similar to GABApentin, has also been found more efficacious than placebo in a 4-week trial in generalized anxiety disorder ( 16). GABApentin and pregabalin distinguish from other anti-epileptic agents by virtue of the absence of drug-drug interactions and minimal severe side-effects. Dizzy spells and hypersomnolence are most commonly reported adverse events.

In the present study, we hypothesize that in moderately severe panic disorder, adjunct treatment of SSRI with GABApentin, the putative VDCC modulator, is capable of converting from SSRI-refractoriness to SSRI-responsive condition. Using naturalistic open-label design, we attempted to evaluate both the treatment responses and tolerability towards GABApentin in SSRI-refractory panic disorder

Methods

The design of our study was open-label naturalistic and prospective. Subjects with the DSM-IV (Diagnostic Statistical Manual IV-TR, 2002, American Psychiatric Association Washington, USA) diagnosis of Panic Disorder who have had at least two trials of optimal dosages of SSRI as described in previous RCT studies ( 3) and continued to score above 20 in Panic and Agoraphobia Scale (PAS) ( 17 ) were invited to enter the study after informed consent is given. The duration of SRRI treatment is at least 8 weeks. Outpatients who had concurrent mood disorders ( major depressive disorder, or bipolar affective disorder type 1 or type 2 ) , non-nicotine substance use or substance dependence or serious medical and endocrine disorders are excluded from the study. The subjects were required to have routine blood work and urine toxicological screen for substances of abuse prior to the start of the study.

The subjects were maintained on the same dosage of SSRI throughout the study period. At baseline, GABApentin was started at the flexible dosage titrated to the optimal clinical response, by the end of the 4 week. Psychiatric measures : PAS scale, HAM-A (Hamilton Anxiety Scale ) ( 18) HAM-D (Hamilton Depression Scale) ( 19) and CGI (Clinical Global Impression: improvement scale ) were administered at baseline, week 6 and week 12. The total duration of the study was 12 weeks. Side effects were monitored with treatment emergent adverse events.

Results

Twenty subjects attending psychiatric outpatient psychiatric services and satisfying the criteria of SSRI-refractory panic disorder entered the study. The gender ratio (male : female) was 8:12. All the subjects were of Caucasian descent with mean age of 35 years , with range from 5 years to 12 years with mean duration of DSM-IV panic disorder 8 +/- 2 years, 80% ( 16/20) had agoraphobia . Employment history showed that 80 % ( 16/20) were unemployed at time of study. Prior to the start of the study, routine medical screening and tests for urine toxicological screens were negative. Although none of the participants had any current history of substance abuse and dependence, all the of them had a current history of nicotine dependence; with 40 % ( 8 / 20 ) of the cohort had a co-morbid mood disorder: dysthymia. The subjects were evaluated for their competency to give consent to the combination medication treatment regimen. They were explained the off-label indications of GABApentin , the possible benefits and side effects and were fully aware of the naturalistic within-subject pre- and post-treatment design
Regarding the medication history, the subjects were continued with SSRI on the following dosages: fluoxetine ( 40%) mean dosage 30 mg po ; paroxetine ( 40% ) mean dosage 25 mg po and citaloprim (20%) mean dosage 37.5 mg po . They were maintained on the same dosage and GABApentin was titrated upwards to the optimal dosage, depending upon the subjects’ tolerability and response. By the end of the four weeks, GABApentin was maintained on the optimal dosage : the mean dosage was 1400 mg per day (range 600 mg to 2400 mg ) in divided dosage regimen of tid.

Three subjects dropped out from the study between week 4 and week 8 (dropout rate : 15 %) Non-compliance with the medication regimen and subjective complaints of the side effects were the main factors involved. Most of the side effects were noted during the initial 8 weeks of the study and included mild headache ( 10 %), subjective restlessness ( 10%) and sexual dysfunction ( 5%).

Table I

Outcome measures of GABApentin augmentation of SSRI-refractory panic disorder

	*Baseline	LOCF	% Change
# PAS score	25.0 +/- 2.6	11.9 +/- 1.4	-52.4
@ HAM- A	24.4 +/- 3.2	10.3 +/- 2.2	- 57.8
@# HAM- D	6. 0 +/- .85	5 .7 +/- 0.87	- 0.3

* values represent mean and standard deviation .
# ANOVA F = 194.2, p < 0.001
@ ANOVA F = 148.4 p < 0.001
@# ANOVA F = 0.73 p= 0.48 not significant

As shown in Table 1, the target symptoms of panic disorder as measured with the PAS score, improved over the course of the 12 week period. The total PAS score at baseline was comparable to the severe subset of panic disorder in an earlier study on GABApentin in panic disorder ( 15). The results were analysed using the last-observation carried forward method. The endpoint PAS score at week 12 was significantly reduced ( p < 0.001). as compared to the baseline value at week 0. The change in PAS score paralleled with the change in HAM-A change.

At week 12, the improvement in the anxiety symptoms as measured with HAM-A was statistically significant ( p < 0.001). No significant change was observed in the HAM-D score . Global functioning measure with the CGI-improvement score indicated that 30 % of the group were markedly improved , 50 % were moderately improved and 20 % were marginally improved.
There was no statistical difference when the results were analysed separately for the female and male subjects.

Discussion:

To the best of our knowledge, this is the first study of GABApentin adjunct therapy in SSRI-refractory panic disorder. GABApentin, when combined with SSRI, exhibits positive effects in SSRI-refractory panic disorder. Our results confirm an earlier randomized placebo-controlled study of GABApentin (15) in panic disorder. In the RCT study, drug-placebo difference was most pronounced among severely ill patients at baseline. Our study sample was comparable to the RCT study in terms of the baseline PAS score. Using the flexible dosage, the GABApentin dosage range in the present study falls between 600 mg and 2400 mg , comparable to the RCT study ( 15 ) with dosage range between 600 mg and 3600 mg po. In contrast to the RCT GABApentin monotherapy study, the current study shows the augmentation effect of GABApentin in SSRI-refractory panic disorder.
The favourable side effect profile of GABApentin (headache, subjective restlessness and sexual dysfunction ) in frequency and severity confirms earlier studies on the high degree of tolerability of GABApentin in the range of psychiatric disorders . The lack of significant drug-drug interaction most likely explains the low drop out rate ,with the combination GABApentin-SSRI treatment protocol. It is well known that subjects recruited for naturalistic studies are best characterized as treatment resistant, as evidenced by the chronicity of panic disorder and functional impairment of poor employment history.

The naturalistic study has methodological limitations. In interpreting the results, caution has to be exercised in view of the small sample size , the lack of a controlled group (SSRI-only group, placebo-control ) and the open-label conditions of the study . The study does not extend beyond the 12-week period. It is possible that the small sample size precludes us to detect any subtle gender differences in GABApentin augmentation response in panic disorder.
If the efficacy of GABApentin can be confirmed in future controlled clinical trials, using flexible or fixed dosage design, either as monotherapy or augmentation strategy, in panic disorder, GABApentin will be valuable addition to the pharmacological armamentarium in the treatment of refractory panic disorder. The results of the preliminary study raise the issue whether other VDCC modulators, such as pregabalin, will be equally efficacious in treatment resistant panic disorder and related anxiety disorders such as post-traumatic stress disorder ( 20). Since comorbid alcohol and substance dependence disorders are often associated with anxiety disorders, GABApentin offers promising lead for panic disorders with co-occurring substance use disorders. These considerations provide indirect evidence for the model of dysregulation of VDCC underlying the pathophysiology of the spectrum of anxiety disorders. The advent of specific imaging ligands for VDCC may validate the hypothesis.

Conflicting interests :

The author has nothing to declare. No financial support was received from any pharmaceutical companies.

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Submitted to Psychiatry-online Dec. 2004.

Published January 2005

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