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Imipramine in agoraphobia
Imipramine in Agoraphobia Matig MavissakaIian This article briefly and selectively reviews recent controlled trials of imipramine in agoraphobia. It is concluded that (1) imipramine enhances the effects of exposure treatments of agoraphobia probably due to facilitation of the process of habituation underlying repeated/prolonged exposure to phobic stimuli, (2) that imipramine doses in the range of 150 to 200 mg/d may be required for optimal pharmacological effects and (3) that the extent of imipramine’s clinical effects in the absence of exposure and the relationship between its antiphobic, antipanic, and antidepressant actions require further elucidation. Some possibilities for future research are also discussed.
A
LTHOUGH THERE EXISTS LITTLE DOUBT that imipramine (and phenelzine) is clinically useful in the treatment of agoraphobia, ’ practical questions such as dosing and theoretical questions pertaining to its mode of action remain. In this brief and selective review, three controversial areas will be discussed in light of the literature and recent findings from the author’s clinic. THEROLEOFEXPOSURE Table 1 summarizes recent controlled studies with imipramine where it can be seen that the majority of studies included exposure treatment either in the form of therapist assisted in vivo sessions, systematic instructions for self-directed in vivo exposure or support and encouragement to enter hitherto avoided situations.*-* With the exception of the study by Marks et al., 5 all have obtained superior results with imipramine compared to placebo demonstrating a facilitative interactive effect of the drug with exposure. However, the extent of imipramine’s effectiveness without concurrent exposure is not clear.7*9-11 In one of the studies’ where countertherapeutic instructions refraining patients from entering phobic situations were given, imipramine had no effect on phobias and panic. In contrast, three other studies9-l1 suggest that imipramine given without any instructions regarding exposure may be clinically effective in the treatment of panic disorder and agoraphobia. However, numbers in these studies were small and placebo control absent. Thus, the most confident conclusion one can draw from the literature is that imipramine enhances the effectiveness of exposure treatments. Furthermore, in our equally enhanced the effects of instructional and therapist study, * imipramine assisted treatment and this enhancement was not related to frequency or duration of self-directed exposure practices. Taken together with the negative results with counter-exposure instructions and the promising results without any instructions, the literature seems to suggest that some exposure may be needed for imipramine’s
From the Western Psychiatric Institute and Cfinic, Department of Psychiatry, School of Medicine, University of Pittsburgh. Address reprint requests to Matig Mavissakalian. M.D., Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara St. Pittsburgh, PA 15213. Supported by Grant No. MH40141 fmm the National Institute of Mental Health. @ 1986 by Grune & Stmtton, Inc. OOIO- 440X/86/2 704- 0017%03.00/O Comprehensive
Psychiafry, Vol. 27, No. 4 (July/August),
1986: pp 401-406
401
MATIG MAVISSAKALIAN
402
Table 1. Recent Studies With lmipramine in Agoraphobia
No Exposure Sheehan et al. (1980) Zitrin et al. (1980) Zitrin et al. (1983) Marks et al. (1983) Mavissakalian et al. (1983) Ballenger et al. (1984) Garakani et al. (1984) Telch et al. (1985) Munjack et al. (1985) Mavissakalian and Michelson (1986)
Informal/Instructional Exposure
Systematic Therapist-Assisted Exposure
+ + + _
_
?+ + ?+ ??i-
+ +
+
+, lmipramine effect. No imipramine effect. ?,’ No placebo control.
effects in agoraphobia and tentatively raises the possibility that the drug may render even unstructured or incidental exposures to phobic stimuli therapeutic. From a practical perspective, there is evidence to suggest that systematic programming of exposure may have additional benefits since, in our study,9 the combination of imipramine and exposure instructions was consistently superior on phobic, panic, and depression measures compared to imipramine alone. This mutual potentiation of exposure in vivo and imipramine provides strong empirical support for combining pharmacological and behavioral treatments in clinical practice. therapeutic
IMIPRAMINE
DOSE
The literature also displays considerable variation in imipramine dosage. Three studies 3*47which found significant imipramine effects had mean imipramine dosages approximating 200 mg/d which is considerably higher than the 158 mg/d average in the study by Mark’s et a1.5 which failed to find significant drug effects. In a study achieving a mean daily dosage of 126 mg, improvement was judged by Munjack et al.” to be somewhat less than previous reports using higher dosages. To complicate matters, several reports have suggested that even miniscule doses or plasma concentrations of imipramine-desipramine can be effective in alleviating agoraphobia and panic attacks. 12-14 Furthermore, Marks et al5 reported that neither imipramine dosage nor plasma concentrations correlated with improvement and response and Ballenger et al. 6 did not find clear differences between different levels of total tricyclic serum concentration although they noted a tendency for agoraphobics maintained in the lower range (100 to 150 ng/mL) to respond better clinically than those maintained at 200 to 250 ng/mL. With this confusing background, correlational and stratified dosage analyses were conducted in 31 patients treated with imipramine in our study and revealed a consistent positive relationship between dosage of imipramine and response. I5 Although this was not a prospectively designed study to assess dose-response relationships by the balanced and random assignment of patients to fixed imipra-
IMIPRAMINE
IN AGORAPHOBIA
403
mine dosages, and despite the exposure confound, the results provided empirical support to recommendations that optimal response in agoraphobia may require imipramine doses of 150 mg / d or greater. Indeed, recovery rates among the group of patients given imipramine doses in the range of 25 to 125 mg/d (mean: 66.7 mg/d) were no better than the one third obtained with placebo whereas three fourths of the patients given doses between 150 to 200 mgld (mean: 186.8 mgld) had recovered. Furthermore, there was a positive relationship between total plasma imipramine levels and improvement in agoraphobia in a subsample of 15 of these agoraphobic patients whose steady imipramine dose approximated a weight adjusted fixed protocol of 2.5 mg/kg/d. I6 These findings were interpreted as compelling evidence in favor of a specific pharmacological effect with imipramine in agoraphobia although, clearly, future placebo controlled dose-response studies without the concurrent exposure will be needed for a definitive characterization of imipramine’s effects in agoraphobia. ANTIPANIC, ANTIPHOBIC, OR ANTIDEPRESSANT ACTION? To date, reports that imipraminer7*r8 can block the panicogenic effect of lactate infusion in agoraphobic and panic disordered patients provide persuasive evidence in favor of its specific antipanic effect. Consistent with the view that imipramine’s major therapeutic effect in agoraphobia is in its suppression of panic attacks are findings that patients who have specific phobias without panic attacks do not respond or respond very poorly to the drug. 4 Since fear of panic is a central phenomenon in agoraphobia and since patients do not seem to distinguish between their experience of spontaneous attacks and panic provoked by phobic situations, it has been generally assumed that successful control of suppression of spontaneous panic attacks eliminates their potential to sensitize, reinforce, and maintain phobic anxiety and avoidance. A number of observations, however, have begun to challenge this general assumption and have suggested a specific antiphobic effect instead. Thus, in our study, significant imipramine effects were found on phobic and depressive measures but not on two separate panic indices. * Similarly, the significant dose and plasma level effects were limited to phobic and depressive measures. 15~16 The insignificant differences obtained on panic measures were not due to the lack of commensurate levels of improvement in panic with imipramine but rather due to the substantial improvement and response rates in panic with placebo and low drug dosages. This would suggest that improvement in panic was due to nonpharmacological factors, most probably to exposure treatment, which taken together with the findings by Telch et al.,’ calls into question the assumption that the specific effect of imipramine in agoraphobia is the blocking of “spontaneous” panic attacks. On the other hand, our findings that response in agoraphobia was dependent on dose, as well as the bioavailability of imipramine, presents compelling evidence for a specific antiphobic effect with this drug. More specifically, imipramine had a significant effect on the reduction of phobic anxiety experienced during an equivalent amount of in vivo exposure which, in turn, suggests that the drug enhanced the therapeutic process of habituation underlying exposure treatments. lg Indeed, that imipramine has a specific antiphobic effect in agoraphobia has also been shown by Ko et alzo who used exposure to phobic stimuli, rather than lactate infusion, as their challenge condition.
MATIG MAVISSAKALIAN
404
Last but not least, a major disagreement among researchers centers around the role of depression-dysphoria in mediating the therapeutic effects of imipramine in agoraphobia. Thus, although Marks et a1.5 contend that the absence of significant imipramine effects in their study was due to the relatively low pretreatment depression levels of their sample, other studies have not revealed significant correlations with pretreatment depression levels and improvement; nor do they suggest the opposite of what may be expected if the drug’s action was primarily antidepressant in nature, e.g., high depression scores correlating with poor outcome. 2-4 Although, effects on the Beck Depression in our study,* we found significant imipramine Inventory, it is unlikely that the action of imipramine was primarily antidepressant in nature, because patients with major depression were excluded and, as suggested by others, 2-4 higher initial depression levels were not predictive of better outcome. That depression, more appropriately conceived of as secondary dysphoria-demoralization associated with the disabling symptoms, curtailed work, and social activities of agoraphobics would improve in parallel with agoraphobia is hardly surprising. Nevertheless, controlled trials with imipramine in agoraphobics with and without major depressive disorder and utilizing the cut-off score of I 14 on the Hamilton Depression Scale*’ may be necessary to definitively study the relationship of antidepressant and antiphobic-panic effects in agoraphobia. CONCLUSION
AND SOME FUTURE RESEARCH
DIRECTtONS
Recent research with imipramine in agoraphobia has convincingly demonstrated that the drug enhances the therapeutic effects of exposure-based treatments. There is also evidence to suggest that, in general, doses 2 150 mg/d may be required for this facilitatory effect on the reduction of fears. A combination of systematic instructions for self-directed exposure and imipramine may thus be a most effective and cost efficient treatment yielding marked improvement and near asymptomatic functioning in 75% of patients afflicted with this condition.E The major problem with imipramine for clinical practice, however, is that side effects, especially those mimicking anxiety symptoms, do not allow optimal dose build up in approximately 40% of even the most motivated and compliant patients. “*15 However, the extent of imipramine’s effects without concurrent exposure is not clear and the relationship between the antipanic, antiphobic and antidepressant action of the drug remains to be elucidated. In this respect, it will be important to know how imipramine alone compares with exposure-based behavioral treatment and whether these treatments effect differential rates and patterns of improvement consistent with their postulated mode of action, e.g., anxiety, panic, and depression with the drug and phobic anxiety and avoidance with exposure. It is also important to note that the phenomenological complexity of the agoraphobic syndrome which encompasses generalized, panic, and phobic anxiety dimensions underscores the need for greater specificity and clarity of symptom dimensions. For example, patients do not readily differentiate between spontaneous and situational panic attacks (phobic anxiety) and the definition of panic is essentially that of a sudden and intense fear. In future efforts to delineate the mode of action of treatments, it may be preferable to study separately the physiological-biochemical (somatic symptoms, actual heart rate measurements, MHPG, etc.), the subjective-cognitive (fear) and
IMIPRAMINE
IN AGORAPHOBIA
405
behavioral (avoidance) response systems which cut across traditionally defined clinical subtypes of anxiety. Finally, several pharmacological approaches to dissect and characterize the mixed clinical effects of imipramine in agoraphobia also present themselves. We are currently conducting a prospective dose stratified controlled trial with imipramine investigating possible differential dose-plasma level response curves for the various symptom domains of agoraphobia which would indicate separate pharmacological mechanisms of action on these symptoms. Studies using new antidepressants with less aversive side effects and more selective neurobiochemical action should also be considered. In addition to being better tolerated than imipramine, and hence accessible to a greater proportion of patients, such agents are likely to elucidate possible differential neurochemical mediation of imipramine’s antipanic, antiphobic, and antidepressant effects. Interestingly, a recent pilot study in 13 agoraphobic patients reported no effect on panic, anxiety and phobic symptoms with bupropion, an effective antidepressant with strong dopaminergic but no serotonergic or noradrenergic activity. 22 However, the choice of antidepressants with selective noradrenergic and serotonergic effects (for example, oxaprotiline and fluvoxamine, respectively) may prove more promising in dissecting imipramine’s mixed and prominent effects on these two neurotransmitter systems implicated in the control of anxiety. I6 REFERENCES 1. Mavissakalian M: Pharmacological treatment of anxiety disorders. J Clin Psychiatry 43:487-491, 1982 2. Sheehan DV, Ballenger J, Jacobsen G: Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Arch Gen Psychiatry 3751-59, 1980 3. Zitrin CM, Klein DF, Woerner MG: Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatry 37:63-72, 1980 4. Zitrin CM, Klein DF, Woerner MG: Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatry 40: 125- 138, 1983 5. Marks IM, Gray S, Cohen D, et al: Imipramine and brief therapist-aided exposure in agoraphobics having self-exposure homework. Arch Gen Psychiatry 40:153- 162, 1983 6. Ballenger JC, Peterson GA, Laraia M, et al: A study of plasma catecholamines in agoraphobia and the relationship of serum tricyclic levels to treatment response, in Ballenger JC ted): Biology of Agoraphobia. Washington, DC, American Psychiatric Press, 1984 7. Telch MJ, Agras WS, Taylor CB, et al: Combined pharmacological and behavioral treatment for agoraphobia. Behav Res Ther 23:325-335, 1985 8. Mavissakalian M, Michelson L: Agoraphobia: Relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. J Clin Psychiatry 47:117- 122, 1986 9. Mavissakalian M, Michelson L, Dealy RS: Pharmacological treatment of agoraphobia: Imipramine vs imipramine with programmed practice. Br J Psychiatry 143:348-355, 1983 10. Garakani H, Zitrin CM, Klein DF: Treatment of panic disorder with imipramine alone. Am J Psychiatry 143:348-355, 1984 11. Munjack DJ, Rebal R, Shaner R, et al: Imipramine versus propranolol for the treatment of panic attacks: A pilot study. Compr Psychiatry 26:80-89, 1985 12. Sweeney DR, Gold MS, Pottash ALC, et al: Plasma levels of tricyclic antidepressants in panic disorder. Int J Psychiatry Med 13:93-96, 1983 13. Jobson K, Linnoila M, Gillam J, et al: Successful treatment of severe anxiety attacks with tricyclic antidepressants: A potential mechanism of action. Am J Psychiatry 135:863864, 1978 14. Nurnberg MG, Coccaro EF: Response of panic disorder and resistance of depression to imipramine. Am J Psychiatry 139:1060-1061, 1982
406
MATIG MAVISSAKALIAN
15. Mavissakalian M, Perel J: Imipramine in the treatment of agoraphobia: Dose response relationships. Am J Psychiatry 142:1032-1036, 1985 16. Mavissakalian M, Perel JM, Michelson L: The relationship of plasma imipramine and N-desmethylimipramine to improvement in agoraphobia. J Clin Psychopharmacol4:36-40, 1984 17. Appleby IL, Klein DF, Sachar ET, et al: Biomedical indices of lactate-induced panic: A preliminary report, in Klein DF, Rabkin J (eds): Anxiety: New Research and Changing Concepts. New York, Raven, 1981 18. Liebowitz MR, Klein DF: Agoraphobia: Clinical features, pathophysiology, and treatment, in Chambless DL, Goldstein AJ (eds): Agoraphobia: Multiple Perspectives on Theory and Treatment. New York, Wiley, 1982 19. Mavissakalian M, Michelson L: The role of self-directed practice in behavioral and pharmacological treatments of agoraphobia. Behav Ther 14:506-519, 1983 20. Ko GN, Elsworth JD, Rogh RH, et al: Panic-induced elevation of plasma MHPG levels in phobic-anxious patients. Arch Gen Psychiatry 40~425-440, 1983 21. Stewart JW, Quitkin FM, Liebowitz MR, et al: Efficacy of desipramine in depressed outpatients: Response according to research diagnostic criteria, diagnoses and severity of illness. Arch Gen Psychiatry 40~202-207, 1983 22. Sheehan DV, Davison J, Manschreck T, et al: Lack of efficacy of a new antidepressant (bupropion) in the treatment of panic disorder with phobias. J Clin Psychopharmacol 3:2831, 1983
A
LTHOUGH THERE EXISTS LITTLE DOUBT that imipramine (and phenelzine) is clinically useful in the treatment of agoraphobia, ’ practical questions such as dosing and theoretical questions pertaining to its mode of action remain. In this brief and selective review, three controversial areas will be discussed in light of the literature and recent findings from the author’s clinic. THEROLEOFEXPOSURE Table 1 summarizes recent controlled studies with imipramine where it can be seen that the majority of studies included exposure treatment either in the form of therapist assisted in vivo sessions, systematic instructions for self-directed in vivo exposure or support and encouragement to enter hitherto avoided situations.*-* With the exception of the study by Marks et al., 5 all have obtained superior results with imipramine compared to placebo demonstrating a facilitative interactive effect of the drug with exposure. However, the extent of imipramine’s effectiveness without concurrent exposure is not clear.7*9-11 In one of the studies’ where countertherapeutic instructions refraining patients from entering phobic situations were given, imipramine had no effect on phobias and panic. In contrast, three other studies9-l1 suggest that imipramine given without any instructions regarding exposure may be clinically effective in the treatment of panic disorder and agoraphobia. However, numbers in these studies were small and placebo control absent. Thus, the most confident conclusion one can draw from the literature is that imipramine enhances the effectiveness of exposure treatments. Furthermore, in our equally enhanced the effects of instructional and therapist study, * imipramine assisted treatment and this enhancement was not related to frequency or duration of self-directed exposure practices. Taken together with the negative results with counter-exposure instructions and the promising results without any instructions, the literature seems to suggest that some exposure may be needed for imipramine’s
From the Western Psychiatric Institute and Cfinic, Department of Psychiatry, School of Medicine, University of Pittsburgh. Address reprint requests to Matig Mavissakalian. M.D., Western Psychiatric Institute and Clinic, Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O’Hara St. Pittsburgh, PA 15213. Supported by Grant No. MH40141 fmm the National Institute of Mental Health. @ 1986 by Grune & Stmtton, Inc. OOIO- 440X/86/2 704- 0017%03.00/O Comprehensive
Psychiafry, Vol. 27, No. 4 (July/August),
1986: pp 401-406
401
MATIG MAVISSAKALIAN
402
Table 1. Recent Studies With lmipramine in Agoraphobia
No Exposure Sheehan et al. (1980) Zitrin et al. (1980) Zitrin et al. (1983) Marks et al. (1983) Mavissakalian et al. (1983) Ballenger et al. (1984) Garakani et al. (1984) Telch et al. (1985) Munjack et al. (1985) Mavissakalian and Michelson (1986)
Informal/Instructional Exposure
Systematic Therapist-Assisted Exposure
+ + + _
_
?+ + ?+ ??i-
+ +
+
+, lmipramine effect. No imipramine effect. ?,’ No placebo control.
effects in agoraphobia and tentatively raises the possibility that the drug may render even unstructured or incidental exposures to phobic stimuli therapeutic. From a practical perspective, there is evidence to suggest that systematic programming of exposure may have additional benefits since, in our study,9 the combination of imipramine and exposure instructions was consistently superior on phobic, panic, and depression measures compared to imipramine alone. This mutual potentiation of exposure in vivo and imipramine provides strong empirical support for combining pharmacological and behavioral treatments in clinical practice. therapeutic
IMIPRAMINE
DOSE
The literature also displays considerable variation in imipramine dosage. Three studies 3*47which found significant imipramine effects had mean imipramine dosages approximating 200 mg/d which is considerably higher than the 158 mg/d average in the study by Mark’s et a1.5 which failed to find significant drug effects. In a study achieving a mean daily dosage of 126 mg, improvement was judged by Munjack et al.” to be somewhat less than previous reports using higher dosages. To complicate matters, several reports have suggested that even miniscule doses or plasma concentrations of imipramine-desipramine can be effective in alleviating agoraphobia and panic attacks. 12-14 Furthermore, Marks et al5 reported that neither imipramine dosage nor plasma concentrations correlated with improvement and response and Ballenger et al. 6 did not find clear differences between different levels of total tricyclic serum concentration although they noted a tendency for agoraphobics maintained in the lower range (100 to 150 ng/mL) to respond better clinically than those maintained at 200 to 250 ng/mL. With this confusing background, correlational and stratified dosage analyses were conducted in 31 patients treated with imipramine in our study and revealed a consistent positive relationship between dosage of imipramine and response. I5 Although this was not a prospectively designed study to assess dose-response relationships by the balanced and random assignment of patients to fixed imipra-
IMIPRAMINE
IN AGORAPHOBIA
403
mine dosages, and despite the exposure confound, the results provided empirical support to recommendations that optimal response in agoraphobia may require imipramine doses of 150 mg / d or greater. Indeed, recovery rates among the group of patients given imipramine doses in the range of 25 to 125 mg/d (mean: 66.7 mg/d) were no better than the one third obtained with placebo whereas three fourths of the patients given doses between 150 to 200 mgld (mean: 186.8 mgld) had recovered. Furthermore, there was a positive relationship between total plasma imipramine levels and improvement in agoraphobia in a subsample of 15 of these agoraphobic patients whose steady imipramine dose approximated a weight adjusted fixed protocol of 2.5 mg/kg/d. I6 These findings were interpreted as compelling evidence in favor of a specific pharmacological effect with imipramine in agoraphobia although, clearly, future placebo controlled dose-response studies without the concurrent exposure will be needed for a definitive characterization of imipramine’s effects in agoraphobia. ANTIPANIC, ANTIPHOBIC, OR ANTIDEPRESSANT ACTION? To date, reports that imipraminer7*r8 can block the panicogenic effect of lactate infusion in agoraphobic and panic disordered patients provide persuasive evidence in favor of its specific antipanic effect. Consistent with the view that imipramine’s major therapeutic effect in agoraphobia is in its suppression of panic attacks are findings that patients who have specific phobias without panic attacks do not respond or respond very poorly to the drug. 4 Since fear of panic is a central phenomenon in agoraphobia and since patients do not seem to distinguish between their experience of spontaneous attacks and panic provoked by phobic situations, it has been generally assumed that successful control of suppression of spontaneous panic attacks eliminates their potential to sensitize, reinforce, and maintain phobic anxiety and avoidance. A number of observations, however, have begun to challenge this general assumption and have suggested a specific antiphobic effect instead. Thus, in our study, significant imipramine effects were found on phobic and depressive measures but not on two separate panic indices. * Similarly, the significant dose and plasma level effects were limited to phobic and depressive measures. 15~16 The insignificant differences obtained on panic measures were not due to the lack of commensurate levels of improvement in panic with imipramine but rather due to the substantial improvement and response rates in panic with placebo and low drug dosages. This would suggest that improvement in panic was due to nonpharmacological factors, most probably to exposure treatment, which taken together with the findings by Telch et al.,’ calls into question the assumption that the specific effect of imipramine in agoraphobia is the blocking of “spontaneous” panic attacks. On the other hand, our findings that response in agoraphobia was dependent on dose, as well as the bioavailability of imipramine, presents compelling evidence for a specific antiphobic effect with this drug. More specifically, imipramine had a significant effect on the reduction of phobic anxiety experienced during an equivalent amount of in vivo exposure which, in turn, suggests that the drug enhanced the therapeutic process of habituation underlying exposure treatments. lg Indeed, that imipramine has a specific antiphobic effect in agoraphobia has also been shown by Ko et alzo who used exposure to phobic stimuli, rather than lactate infusion, as their challenge condition.
MATIG MAVISSAKALIAN
404
Last but not least, a major disagreement among researchers centers around the role of depression-dysphoria in mediating the therapeutic effects of imipramine in agoraphobia. Thus, although Marks et a1.5 contend that the absence of significant imipramine effects in their study was due to the relatively low pretreatment depression levels of their sample, other studies have not revealed significant correlations with pretreatment depression levels and improvement; nor do they suggest the opposite of what may be expected if the drug’s action was primarily antidepressant in nature, e.g., high depression scores correlating with poor outcome. 2-4 Although, effects on the Beck Depression in our study,* we found significant imipramine Inventory, it is unlikely that the action of imipramine was primarily antidepressant in nature, because patients with major depression were excluded and, as suggested by others, 2-4 higher initial depression levels were not predictive of better outcome. That depression, more appropriately conceived of as secondary dysphoria-demoralization associated with the disabling symptoms, curtailed work, and social activities of agoraphobics would improve in parallel with agoraphobia is hardly surprising. Nevertheless, controlled trials with imipramine in agoraphobics with and without major depressive disorder and utilizing the cut-off score of I 14 on the Hamilton Depression Scale*’ may be necessary to definitively study the relationship of antidepressant and antiphobic-panic effects in agoraphobia. CONCLUSION
AND SOME FUTURE RESEARCH
DIRECTtONS
Recent research with imipramine in agoraphobia has convincingly demonstrated that the drug enhances the therapeutic effects of exposure-based treatments. There is also evidence to suggest that, in general, doses 2 150 mg/d may be required for this facilitatory effect on the reduction of fears. A combination of systematic instructions for self-directed exposure and imipramine may thus be a most effective and cost efficient treatment yielding marked improvement and near asymptomatic functioning in 75% of patients afflicted with this condition.E The major problem with imipramine for clinical practice, however, is that side effects, especially those mimicking anxiety symptoms, do not allow optimal dose build up in approximately 40% of even the most motivated and compliant patients. “*15 However, the extent of imipramine’s effects without concurrent exposure is not clear and the relationship between the antipanic, antiphobic and antidepressant action of the drug remains to be elucidated. In this respect, it will be important to know how imipramine alone compares with exposure-based behavioral treatment and whether these treatments effect differential rates and patterns of improvement consistent with their postulated mode of action, e.g., anxiety, panic, and depression with the drug and phobic anxiety and avoidance with exposure. It is also important to note that the phenomenological complexity of the agoraphobic syndrome which encompasses generalized, panic, and phobic anxiety dimensions underscores the need for greater specificity and clarity of symptom dimensions. For example, patients do not readily differentiate between spontaneous and situational panic attacks (phobic anxiety) and the definition of panic is essentially that of a sudden and intense fear. In future efforts to delineate the mode of action of treatments, it may be preferable to study separately the physiological-biochemical (somatic symptoms, actual heart rate measurements, MHPG, etc.), the subjective-cognitive (fear) and
IMIPRAMINE
IN AGORAPHOBIA
405
behavioral (avoidance) response systems which cut across traditionally defined clinical subtypes of anxiety. Finally, several pharmacological approaches to dissect and characterize the mixed clinical effects of imipramine in agoraphobia also present themselves. We are currently conducting a prospective dose stratified controlled trial with imipramine investigating possible differential dose-plasma level response curves for the various symptom domains of agoraphobia which would indicate separate pharmacological mechanisms of action on these symptoms. Studies using new antidepressants with less aversive side effects and more selective neurobiochemical action should also be considered. In addition to being better tolerated than imipramine, and hence accessible to a greater proportion of patients, such agents are likely to elucidate possible differential neurochemical mediation of imipramine’s antipanic, antiphobic, and antidepressant effects. Interestingly, a recent pilot study in 13 agoraphobic patients reported no effect on panic, anxiety and phobic symptoms with bupropion, an effective antidepressant with strong dopaminergic but no serotonergic or noradrenergic activity. 22 However, the choice of antidepressants with selective noradrenergic and serotonergic effects (for example, oxaprotiline and fluvoxamine, respectively) may prove more promising in dissecting imipramine’s mixed and prominent effects on these two neurotransmitter systems implicated in the control of anxiety. I6 REFERENCES 1. Mavissakalian M: Pharmacological treatment of anxiety disorders. J Clin Psychiatry 43:487-491, 1982 2. Sheehan DV, Ballenger J, Jacobsen G: Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms. Arch Gen Psychiatry 3751-59, 1980 3. Zitrin CM, Klein DF, Woerner MG: Treatment of agoraphobia with group exposure in vivo and imipramine. Arch Gen Psychiatry 37:63-72, 1980 4. Zitrin CM, Klein DF, Woerner MG: Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo. Arch Gen Psychiatry 40: 125- 138, 1983 5. Marks IM, Gray S, Cohen D, et al: Imipramine and brief therapist-aided exposure in agoraphobics having self-exposure homework. Arch Gen Psychiatry 40:153- 162, 1983 6. Ballenger JC, Peterson GA, Laraia M, et al: A study of plasma catecholamines in agoraphobia and the relationship of serum tricyclic levels to treatment response, in Ballenger JC ted): Biology of Agoraphobia. Washington, DC, American Psychiatric Press, 1984 7. Telch MJ, Agras WS, Taylor CB, et al: Combined pharmacological and behavioral treatment for agoraphobia. Behav Res Ther 23:325-335, 1985 8. Mavissakalian M, Michelson L: Agoraphobia: Relative and combined effectiveness of therapist-assisted in vivo exposure and imipramine. J Clin Psychiatry 47:117- 122, 1986 9. Mavissakalian M, Michelson L, Dealy RS: Pharmacological treatment of agoraphobia: Imipramine vs imipramine with programmed practice. Br J Psychiatry 143:348-355, 1983 10. Garakani H, Zitrin CM, Klein DF: Treatment of panic disorder with imipramine alone. Am J Psychiatry 143:348-355, 1984 11. Munjack DJ, Rebal R, Shaner R, et al: Imipramine versus propranolol for the treatment of panic attacks: A pilot study. Compr Psychiatry 26:80-89, 1985 12. Sweeney DR, Gold MS, Pottash ALC, et al: Plasma levels of tricyclic antidepressants in panic disorder. Int J Psychiatry Med 13:93-96, 1983 13. Jobson K, Linnoila M, Gillam J, et al: Successful treatment of severe anxiety attacks with tricyclic antidepressants: A potential mechanism of action. Am J Psychiatry 135:863864, 1978 14. Nurnberg MG, Coccaro EF: Response of panic disorder and resistance of depression to imipramine. Am J Psychiatry 139:1060-1061, 1982
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