Cognitive style, alprazolam plasma levels, and treatment response in panic disorder
Uhlenhuth EH, Starcevic V, Qualls C, Antal EJ, Matuzas W, Javaid JI, et al.;
Commented by , 30 Nov 2007
Aim of the study
Does patient cognitive style predict improvement in panic disorder during alprazolam treatment?
Method
Twenty six patients (13 men) who met DSM-III-R criteria for panic disorder (with or without agoraphobia) contributed data to the analysis. Patients were treated with alprazolam for 8 weeks. Starting dose (1 mg/day) was increased by 1 mg/day each week for four weeks and was maintained at 1 mg four times per day for a further four weeks.
Anxiety-prone cognitive style was assessed using the Anxious Thoughts and Tendencies Questionnaire (AT&T) at baseline and at the end of the 8 weeks of treatment. Plasma alprazolam levels were taken 5-6 hours after the first morning dose of alprazolam at baseline, and at the end of weeks 1-4, 6 and 8.
Outcome measures included number of situational and spontaneous panic attacks (determined via patient diary), CGI severity and improvement, POMS and the Hamilton Anxiety and Depression Scales.
Results
As expected, mean plasma alprazolam levels increased with dose and reached a plateau after the 4th week. Sedation, dysphoria and disinhibition were noted and reflected in POMS scores; no significant effect of drug plasma levels was demonstrated.
AT&T scores decreased throughout the course of treatment, but the effect size was small.
Although the authors had anticipated that subjects with high AT&T scores would respond less well to increasing alprazolam plasma levels, the interaction between these two variables was significant on only one response variable – and this was dismissed as a chance finding.
In general, alprazolam reduced panic and anxiety but had no effect on depression – independent of AT&T score. High AT&T scorers tended to show more severe impairment on clinical measures.
Dr Hood's and Prof Nutt's comments
Combining psychological therapies such as CBT and medication therapies is frequently proposed as "Gold Standard" care for patients with anxiety disorders in general, and panic disorder in particular – however the evidence base in support of this combination is surprisingly scarce despite its intuitive appeal and frequency in clinical settings (ref. 1, ref. 2).
The ability to accurately predict which treatment or combinations of treatments will work for a given individual remains a Holy Grail of psychiatric practice.
This study finds that the benzodiazepine alprazolam and a measure of anxiety-prone cognitive style (AT&T) are independent predictors of response (additive), and thus combination therapy may provide additional benefit to some patients.
It follows that the choice of alprazolam as a treatment for panic patients should not rest upon the intensity of their baseline anxiety-prone cognitions, because patients with low and high AT&T scores improved equally. Side effect profile, dependence and discontinuation issues are often of primary concern when choosing a benzodiazepine anxiolytic in clinical settings, however (ref. 3).
Plasma levels did not seem to predict response, but as the authors' note almost all subjects achieved high levels of alprazolam suggesting a ceiling effect, thus lower doses could be considered in any replication study.
Indeed, investigation of low-dose psychiatric drugs may be a particularly interesting pursuit due to anecdotal reports of low-dose efficacy and tolerability (ref. 4) and the experience of many of our GP colleagues with low-dose tricyclics in depressive illnesses (ref. 5) in contrast to the findings of traditional dose-finding studies in panic disorder (ref. 6). Determining variations in ability to metabolise anxiolytics using genetic testing could be more useful than plasma levels in targeting the most effective medication dose.
This study reminds us of the expectation of predicting response to treatments based on prior theoretical positions is rarely confirmed in clinical trials and that drug treatments generally work independent of cognitive style, but where extreme cognitive styles exist attempts to modify them may be sensible.
References
1. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Baldwin DS, den Boer JA et al. Consensus statement on panic disorder from the International Consensus Group on Depression and Anxiety. Journal of Clinical Psychiatry 1998; 59 Suppl 8; 47-54
2. Work Group on Panic Disorder. Practice Guideline for the Treatment of Patients With Panic Disorder, 2nd Edition (forthcoming). American Psychiatric Association
3. Argyropoulos SV, Nutt DJ. The use of benzodiazepines in anxiety and other disorders. European Neuropsychopharmacology 1999; 9 Suppl 6; 407-412
4. Dimmitt SB. PAnIC Meeting (Personal Communication). 2007
5. Hood SD. Can low dose of tricyclics work? Pulse 2000; 60 (13); 120
6. Ballenger JC, Wheadon DE, Steiner M, Bushnell W, Gergel IP. Double-blind, fixed-dose, placebo-controlled study of paroxetine in the treatment of panic disorder. American Journal of Psychiatry 1998; 155 (1); 36-42