Posted by sdb on August 11, 2006, at 16:18:00
Maybe of interest:
Double-Blind, Controlled, Crossover Trial of Inositol Versus Fluvoxamine for the Treatment of Panic Disorder
[Brief Reports]Palatnik, Alex MD*; Frolov, Katerina MD*; Fux, Mendel MD*; Benjamin, Jonathan MD†
*Ministry of Health Mental Health Center, Faculty of Health Sciences, and †Department of Psychiatry, Soroka Medical Center of the Kupat Holim Sick Fund, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheba, Israel
Received January 31, 2000; accepted after revision July 14, 2000.
Address requests for reprints to: Jonathan Benjamin, MD, Psychiatry Department, Barzilaí Medical Center, Histadrut Street, Ashkelon 78306, Israel. Address e-mail to: yonatan@bgumail.bgu.ac.il.
AbstractOnly 70% of patients respond to current treatments for panic disorder, and many discontinue drugs because of side effects. myo-Inositol, a natural isomer of glucose and a precursor for the second-messenger phosphatidyl-inositol system, has previously been found superior to placebo in the treatment of depression, panic disorder, and obsessive-compulsive disorder (OCD), but a direct comparison with an established drug has never been performed. A double-blind, controlled, random-order crossover study was undertaken to compare the effect of inositol with that of fluvoxamine in panic disorder. Twenty patients completed 1 month of inositol up to 18 g/day and 1 month of fluvoxamine up to 150 mg/day. Improvements on Hamilton Rating Scale for Anxiety scores, agoraphobia scores, and Clinical Global Impressions Scale scores were similar for both treatments. In the first month, inositol reduced the number of panic attacks per week (mean and SD) by 4.0 (2) compared with a reduction of 2.4 (2) with fluvoxamine (p = 0.049). Nausea and tiredness were more common with fluvoxamine (p = 0.02 and p = 0.01, respectively). Because inositol is a natural compound with few known side effects, it is attractive to patients who are ambivalent about taking psychiatric medication. Continuing reports of inositol’s efficacy in the treatment of depression, panic disorder, and OCD should stimulate replication studies.
PANIC DISORDER CONSISTS of recurring attacks of severe anxiety without apparent cause. The complications include agoraphobia (irrationally fearful avoidance of multiple situations such as crowds and travel), depression, alcohol abuse, and suicide. 1 Current standard treatments include antidepressants 2–5 and cognitive-behavioral therapy. 3,6–9 Although these treatments promise dramatic short-term improvement to approximately 70% of patients, there has lately been increasing and sobering recognition that the long-term prognosis of panic disorder is often one of chronic residual anxiety symptoms, depression, social and occupational morbidity, and increased use of health services. 10,11 Between 25% and 75% of patients discontinue drug treatment because of side effects, 12 and many of these quickly relapse. 13
These observations underscore the importance of the search for better treatments for panic disorder, or at least for equally efficacious treatments, that are less toxic and more acceptable, particularly in the long-term. A total of 12 to 18 grams per day of myo-inositol, a natural isomer of glucose and a precursor in the intracellular phosphatidyl-inositol second-messenger cycle, has demonstrated efficacy after 3 weeks in placebo-controlled trials in depression, 14 panic disorder, 15 and obsessive-compulsive disorder (OCD), 16 but not in schizophrenia, autism, or dementia. 17 Side effects in more than 100 subjects have mostly been limited to mild gastrointestinal discomfort. 17 In addition, the ubiquitous distribution of inositol in nature, including in the daily diet of humans, makes it attractive to patients who are ambivalent about taking psychiatric medication. Our previous study 15 showed the efficacy of inositol compared with placebo in panic disorder. The study presented here represents a more severe test, namely, the comparison of inositol with an established antidepressant, fluvoxamine. This is, to our knowledge, the first head-to-head comparison of inositol with an established drug.
Continuing demonstrations of inositol’s efficacy against panic disorder promise to widen the scope of investigation into the pathophysiology of panic. Hitherto, theories of the disorder, with few exceptions, have limited their attentions to abnormalities of cell-surface receptor systems, 18 in particular the serotonin (5-HT) 19 and noradrenaline 20 systems. Inositol’s therapeutic profile seems similar to that of antidepressant drugs, in particular 5-HT reuptake inhibitors (SSRIs), because of its efficacy in treating OCD. Key 5-HT receptor subtypes are linked to the phosphatidyl-inositol second-messenger system. 21 However, because the putative site of action of inositol is inside the cell membrane, whereas that of SSRIs is outside it, inositol may represent a novel therapeutic agent in psychiatric disorders.
Methods
SubjectsPatients seen in our anxiety disorders clinic who had DSM-IV panic disorder, with or without agoraphobia, who additionally satisfied the consensus recommendation 22 of a minimum of one panic attack per week over a period of 2 weeks, received a diagnosis using the Structured Clinical Interview for DSM-III-R 23 that was confirmed on clinical interview. The patients were aged between 18 and 65 years, and they underwent standard medical and psychiatric interviews and examinations to exclude significant concomitant medical and psychiatric illness and pregnancy. Apart from fluvoxamine and inositol, the only psychoactive medication allowed during the study and for 3 weeks preceding it was diazepam 5 mg as needed for anxiety. Fluoxetine was not allowed from 5 weeks before the study. Fluvoxamine was provided in the form of 100-mg tablets, and placebo tablets were identical in appearance to fluvoxamine tablets. Inositol was provided as powder, and placebo powder was glucose in the form of grape sugar for infant formula, of similar taste and texture to inositol powder.
DesignAll subjects began with 1 week (week 0) of single-blind placebo (one half of a placebo tablet and 12 g placebo powder); subjects with no panic attack during this week were eliminated from the study. 22 All continuing subjects were randomly assigned to begin 4 weeks of double-blind fluvoxamine and placebo powder or 4 weeks of double-blind inositol powder and placebo tablets. Dosages were one half tablet in the first week, one tablet in the second week, and 1.5 tablets in the third and fourth weeks (i.e., 150 mg of fluvoxamine in active tablets) and 12 g of powder in the first week and 18 g powder in the second through fourth weeks. This was followed by 1 week (week 5) of single-blind placebo washout (one half of a placebo tablet and 12 g of placebo powder), and then treatments were reversed. The study was approved by the institutional Helsinki ethics committee, and all subjects gave signed informed consent.
AssessmentAssessments were performed at the end of weeks 0, 3, 4, 5, 6, 8, and 9. As in our previous study, 15 assessments included the summation of entries on a daily panic diary, the Hamilton Rating Scale for Anxiety (HAM-A), 24 the Hamilton Rating Scale for Depression (HAM-D), 25 the Marks-Matthews Fear Questionnaire (for assessment of agoraphobia), 26 the Clinical Global Impression Scale (CGI), 27 and a side effects checklist.
AnalysisResults were analyzed using an analysis of variance by using order of treatment as a between-groups variable and change on outcome measures in the two treatment phases (mean of weeks 3 and 4 minus week 0, mean of weeks 8 and 9 minus mean of weeks 5 and 6) as repeated measures (within-group variables).
ResultsTwenty-five patients were recruited. Four patients were eliminated from the study because they had no panic attacks during the run-in week of single-blind placebo or because of incomplete compliance. One patient left the area after a month of fluvoxamine treatment; his data were used for the first-month, parallel-groups analysis, but not for the 2-month crossover analysis. Twenty subjects completed the protocol, and their results were used in all analyses.
Description of sampleMean (SD) age was 39.2 (11) years. Nine of the 21 subjects were men. Eleven subjects were randomly assigned to receive inositol first, and 10 were randomly assigned to receive fluvoxamine first. At baseline, the number of panic attacks per week was 6.5 (4): 7.2 (4) in those beginning with inositol and 5.8 (4) in those beginning with fluvoxamine (F [1,19] = 0.1 [not significant]). HAM-A scores were 16.4 (7): 15.5 (8) in those beginning with inositol and 10.7 (7) in those beginning with fluvoxamine (F [1,19] = 2.2 [not significant]). HAM-D scores were 4.2 (2), and this measure did not change significantly during the study. HAM-D scores were therefore not analyzed further. Phobia scores (range, 1–8) were 1.4 (1), and only three patients had moderate or higher agoraphobia. Phobia scores in those beginning with inositol were 1.4 (2) and, in those beginning with fluvoxamine, 1.5 (1) (F [1,19] = 0.1 [not significant]). CGI scores (range, 0–7: 0 = not ill, 7 = most severely ill patient ever encountered) were 4.0 (1): 4.0 (1) in those beginning with inositol and 4.1 (1) in those beginning with fluvoxamine (F [1,19] = 0.1 [not significant]).
Time and order effectsThere were significant effects of time in the study (regardless of treatment) for change in number of panic attacks and for change in CGI scores; mean number of panic attacks per week dropped 3.3 (2) in the first month, compared with 0.7 (2) in the second month (F [1,19] = 10.0, p = 0.005). Mean CGI scores dropped 1.5 (1) in the first month, compared with 0.6 (1) in the second month (F [1,19] = 8.0, p = 0.01). Changes on HAM-A and phobia scores did not differ between the two treatment phases. There were no effects of order of treatment.
Parallel-groups analysisBecause of the time effects, before proceeding to further analyze the effects of the two treatments across the 9 weeks of the crossover study (see below), we performed a parallel-groups analysis of improvement during the first month only, with 11 subjects in the inositol group and 10 subjects in the fluvoxamine group. Inositol was marginally more effective than fluvoxamine at reducing the number of panic attacks per week from baseline to the end of the first month: from 7.2 (4) to 3.1 (3), compared with change with fluvoxamine from 5.8 (4) to 3.4 (4) (F [1,19] = 4.4, p = 0.049). Eight of 11 patients responded to inositol with a 50% or greater reduction in panic frequency, and 6 of 10 patients responded similarly to fluvoxamine (Fisher exact test, p = 0.66). The two treatments were equally effective at reducing HAM-A, phobia, and CGI scores: for HAM-A, a reduction from 15.5 (8) to 11.0 (10) with inositol compared with 17.3 (7) to 9.8 (5) with fluvoxamine (F [1,19] = 1.0, not significant); for phobia scores, a reduction from 1.4 (2) to 1.0 (1) with inositol and from 1.5 (1) to 1.2 (1) with fluvoxamine (F [1,19] = 0.0, not significant); and for CGI scores, a reduction from 4.0 (1) to 2.6 (1) with inositol and from 4.1(1) to 2.6 (1) with fluvoxamine (F [1,19] = 0.1, not significant).
Crossover studyTable 1 shows F and p values for the effects of order of treatment, type of treatment, and interactions between them on the four outcome measures. There were no differences on HAM-A and phobia scores between improvement with inositol and with fluvoxamine or between these effects in those who began with one or the other treatment. There were no main effects of order of treatment or of drug on change in frequency of panic attacks or in CGI score, but there were significant interactions between these factors on these two measures. For those beginning with inositol, frequency of panic attacks declined by 4.0 (2) with inositol and by a further 1.0 (2) after switching to fluvoxamine; for those beginning with fluvoxamine, frequency of panic attacks declined by only 2.4 (2) with fluvoxamine and by a further 1.1 (2) after switching to inositol. Six patients (three in each treatment group) were free of panic attacks by the end of the first phase, as were seven (four taking inositol and three taking fluvoxamine) at the end of the second phase. CGI scores improved by 1.4 (1) with inositol in those beginning by taking inositol and then by an additional 0.6 with fluvoxamine. In those beginning with fluvoxamine, CGI scores improved by 1.6 (1) with fluvoxamine and then by an additional 0.6 (1) with inositol. Patients used a mean of 1.5 (3) diazepam tablets as needed per week during the last 2 weeks they received inositol, and they used 1.8 (2) tablets during the last 2 weeks of fluvoxamine (F [1,10] = 0.4, not significant).
Graphic
[Help with image viewing]
[Email Jumpstart To Image] Table 1. ANOVA (F ratios and significance levels;df = 1,18) of changes in four outcome measures on inositol and fluvoxamine treatment during a crossover study of panic disorder (N = 20) aa ANOVA, analysis of variance; HAM-A, Hamilton Rating Scale for Anxiety; NS, not significant.
Side effectsThe following side effects were reported by three or more subjects: nausea, tiredness, headache, and dizziness. Sixteen subjects complained of nausea during fluvoxamine treatment, and eight complained of these during inositol treatment ([chi] 2 with the Yates correction = 5.1, 1 df, p = 0.02; Fisher exact test, two-tailed p = 0.02). Nine subjects complained of tiredness during fluvoxamine treatment, compared with one during inositol treatment ([chi] 2 with the Yates correction = 6.5, 1 df, p = 0.01; Fisher exact test, two-tailed p = 0.01). Differences between frequency of headache and dizziness with the two treatments were not significant.
DiscussionThe principal finding of this study is that inositol and fluvoxamine were approximately equally effective in the treatment of panic disorder. Inositol was superior at reducing the number of panic attacks:p = 0.049 in the parallel-groups analysis and 0.004 in the interaction in the crossover analysis. Fluvoxamine seemed superior to inositol at reducing CGI scores in the crossover analysis (p = 0.012), but the size of the difference was small (1.6 vs. 1.4). The absence of additional significant differences between inositol and fluvoxamine was not caused by lack of power. A computer simulation of the parallel-groups analysis for the first month, with similar effects in 63 subjects, still showed superiority of inositol at reducing panic attacks (F [1,61] = 14.2, p = 0.0004) and no difference in the remaining measures (for HAM-A, F [1,61] = 3.4, not significant; for phobia, F [1,61] = 0.0, not significant; for CGI, F [1,61] = 0.4, not significant).
LimitationsTime and order effects complicate many crossover trials. 28 We interpret the time effect seen here, i.e., the superiority of the first month of treatment, as caused either by a ceiling effect or a placebo effect (which was stronger initially). Nevertheless, crossover trials continue to attract investigators and subjects—the former because they promise double the number of subjects in each treatment phase and a more powerful test (the same subject is compared while receiving two treatments), and the latter because randomization denies neither treatment, so there is no chance of missing a potentially superior treatment (or of receiving only placebo). The crossover analysis and the parallel-groups analysis of the first month suggest similar conclusions in this study.
The study would have been strengthened by the addition of a placebo arm. This is the only way to directly estimate the effects ascribed to the active treatments. A three-way crossover study would be more complicated, however, and the risk of attrition during its course must be greater. Higher doses and a longer treatment period might have revealed a greater effect of fluvoxamine. However, we were concerned that they might also compromise the double-blind condition. Some previous positive studies of fluvoxamine 3,8 used the same dose, duration of treatment, or both of these, as this one. Finally, most of our subjects had panic disorder without agoraphobia; there may be less difference in response to active drug versus placebo in this diagnosis than in panic disorder with agoraphobia. 29,30
ReplicationThere is little incentive for drug companies to support research on a nonpatentable compound. However, the number of published positive reports of trials with inositol (see reviews 17,31) should encourage academic investigators to perform replication studies. Inositol seems as effective (not more effective) as other treatments for depression, panic disorder, and OCD and is more acceptable to patients. The challenge to replicate this and previous reports and explore their implications is both humanistic and scientific.
AcknowledgmentR.H. Belmaker suggested this study, supplied the inositol and glucose, and constructively criticized a draft of the manuscript.
References1. Kaplan H, Sadock B, Grebb J. Synopsis of psychiatry. 7th ed. Baltimore: Williams & Wilkins, 1994. [Context Link]
2. Anderson I, Tomenson B. The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol 1994; 8: 238–49. Bibliographic Links [Context Link]
3. Black D, Wesner R, Bowers W, et al. A comparison of fluvoxamine, cognitive therapy, and placebo in the treatment of panic disorder. Arch Gen Psychiatry 1993; 50: 44–50. Bibliographic Links [Context Link]
4. Greist J, Jefferson J, Kobak K, et al. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 1995; 52: 53–60. Bibliographic Links [Context Link]
5. Mavissakalian M, Perel J. Imipramine treatment of panic disorder with agoraphobia: dose ranging and plasma level-response relationships. Am J Psychiatry 1995; 152: 673–82. Bibliographic Links [Context Link]
6. Barlow D. Cognitive-behavioral therapy for panic disorder: current status. J Clin Psychiatry 1997;58[suppl 2]:32–6. [Context Link]
7. Marks I. Treatment of panic disorder. Am J Psychiatry 1999; 156: 1129–30. Bibliographic Links [Context Link]
8. Sharp D, Power K, Simpson R, et al. Fluvoxamine, placebo, and cognitive behaviour therapy used alone and in combination in the treatment of panic disorder and agoraphobia. J Anxiety Disord 1996; 10: 219–42. Bibliographic Links [Context Link]
9. Shear M, Weiner K. Psychotherapy for panic disorder. J Clin Psychiatry 1997;58[suppl 2]:38–43. [Context Link]
10. Albus M, Scheibe G. Outcome of panic disorder with or without concomitant depression: a 2-year prospective follow-up study. Am J Psychiatry 1993; 150: 1878–80. Bibliographic Links [Context Link]
11. Breier A, Charney D, Heninger G. Agoraphobia with panic attacks: development, diagnostic stability, and course of illness. Arch Gen Psychiatry 1986; 43: 1029–36. Bibliographic Links [Context Link]
12. Pollack M, Otto M. Long-term course and outcome of panic disorder. J Clin Psychiatry 1997;58[suppl 2]:57–60. [Context Link]
13. Marks I. Fears, phobias and rituals. New York: Oxford University Press, 1987. [Context Link]
14. Levine J, Barak Y, Gonzalves M, et al. Double blind controlled trial of inositol treatment of depression. Am J Psychiatry 1995; 152: 792–4. Bibliographic Links [Context Link]
15. Benjamin J, Levine J, Fux M, et al. Double-blind, placebo-controlled, crossover study of inositol treatment for panic disorder. Am J Psychiatry 1995; 152: 1084–6. Bibliographic Links [Context Link]
16. Fux M, Levine J, Aviv A, et al. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 1996; 153: 1219–21. Bibliographic Links [Context Link]
17. Levine J. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 1997; 7: 147–55. Bibliographic Links [Context Link]
18. Nutt D, Lawson C. Panic attacks: a neurochemical overview of models and mechanisms. Br J Psychiatry 1992; 160: 165–78. Bibliographic Links [Context Link]
19. Coplan J, Gorman J, Klein D. Serotonin-related function in panic disorder: a critical overview. Neuropsychopharmacology 1992; 6: 189–200. Bibliographic Links [Context Link]
20. Charney D, Woods S, Price L, et al. Noradrenergic dysregulation in panic disorder. In: Ballenger J, ed. Neurobiology of panic disorder. New York: Wiley-Liss, 1990:91–105. [Context Link]
21. Rahman S, Neuman R. Myo-inositol reduces serotonin (5-HT 2 ) receptor induced homologous and heterologous desensitization. Brain Res 1993; 631: 349–51. Bibliographic Links [Context Link]
22. Shear M, Maser J. Standardized assessment for panic disorder research. A conference report. Arch Gen Psychiatry 1994; 51: 346–54. Bibliographic Links [Context Link]
23. Spitzer R, Williams J, Gibbon M, et al. Structured Clinical Interview for DSM-III-R (SCID, version 1.0). Washington, DC: American Psychiatric Press, 1990. [Context Link]
24. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol 1959; 32: 50–5. Bibliographic Links [Context Link]
25. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967; 6: 278–96. Bibliographic Links [Context Link]
26. Marks I, Matthews A. Brief standard self-rating for phobic patients. Behav Res Ther 1979; 17: 263–7. Bibliographic Links [Context Link]
27. Guy W. ECDEU assessment manual for psychopharmacology. Washington, DC: U.S. Department of Health, Education and Welfare, 1976. [Context Link]
28. Hills M, Armitage P. The two-period cross-over clinical trial. Br J Clin Pharmacol 1979; 8: 7–20. Bibliographic Links [Context Link]
29. Pollack M, Otto M, Sachs G, et al. Anxiety psychopathology predictive of outcome in patients with panic disorder and depression treated with imipramine, alprazolam and placebo. J Affect Dis 1994; 30: 273–81. Bibliographic Links [Context Link]
30. Slaap B, van Vliet I, Westenberg H, et al. Phobic symptoms as predictors of nonresponse to drug therapy in panic disorder patients (a preliminary report). J Affect Dis 1995; 33: 31–8. Bibliographic Links [Context Link]
31. Kofman O, Belmaker R. Biochemical, behavioral and clinical studies of the role of inositol in lithium treatment and depression. Biol Psychiatry 1993; 34: 839–52. Bibliographic Links [Context Link]
poster:sdb
thread:675673
URL: http://www.dr-bob.org/babble/alter/20060704/msgs/675673.html