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Treatment-emergent depression with antidepressants in panic disorder
Treatment-Emergent Depression With Antidepressants in Panic Disorder Thomas A. Aronson Two patients with panic disorder received therapeutic doses of antidepressants. They developed endogenomorphic symptoms of major depression according to DSM-III-R criteria despite remission of their panic attacks. Treatment-emergent depression in panic disorder has been previously associated with high potency benzodiazepines. Whether antidepressant medications may unmask a depressive diathesis or are coincidentally associated with depression is discussed in this report. 0 1989 by W.8. Saunders Company.
R
ECENT REPORTS have described the emergence of major depressive episodes in patients with panic disorder treated with alprazolam,’ clonazepam,2m5and lorazepam.6 Lydiard et al.’ observed the emergence of depression in 15 of 46 patients (33%) with panic disorder administered 3 to 10 mg (mean 6.6 mg/d) of alprazolam. None of the patients were depressed at the time they entered the study, nor did they differ from patients who did not become depressed on alprazolam in their past psychiatric or family histories. Investigators at Massachusetts General Hospital (MGH) reported similar experiences, though different incidences, with clonazepam and alprazolam. Ten of 177 patients (5.7%) administered 2 to 3 mg/d of clonazepam experienced a treatment-emergent depression, as opposed to 0.5% of a matched number of patients receiving alprazolam (P < .05).’ Furthermore, contrary to the observation made by Lydiard et al,’ psychiatric history did not predict treatment emergent depression. Forty-seven percent of patients lost to follow-up had a history of dysthymia or major depression v 10% who remained on clonazepam, raising the possibility that treatment-emergent depression contributed to treatment dropout.’ Treatment-emergent depressions associated with alprazolam and clonazepam generally responded to the addition of an antidepressant. The MGH group also found that some depressions associated with clonazepam use remitted with a switch to alprazolam. These divergent uncontrolled reports contradict the clinical research literature on benzodiazepines. Though the literature suggests that benzodiazepines are depressants that can precipitate or worsen major depressive disorder (MDD), there are no controlled studies that substantiate such a claim. A review of the literature found only one report of an increase in depression and suicidality associated with diazepam.’ In fact, Schatzberg and Cole’s review of benzodiazepines in depressive disorder? concluded that while they were clearly inferior to antidepressants in 20 double-blind controlled studies, they did improve depressed patients’ anxiety, agitation, and insomnia. More recent reports suggest that the triazolo-benzodiaze-
From the Department of Psychiatry and Behavioral Science, Health Sciences Center, State University’of New York at Stony Brook, Stony Brook. Address reprint requests to Thomas A. Aronson, M.D., Department of Psychiatry and Behavioral Science, Health Sciences Center, T-IO. State University of New York at Stony Brook, Stony Brook, NY 11794-8101. 0 1989 by W.B. Saunders Company. 0010-440x~89/3003-0011%03.00/0
Comprehensive
Psychiatry, Vol. 1, No. 2 (May/June),
1989: pp 267-27
1
267
268
THOMAS
A. ARONSON
pine, alprazolam, has antidepressant properties,g*” and can even precipitate mania.12-‘3The above reports regarding panic disorder are particularly paradoxical and unexpected for alprazolam. There are also uncontrolled reports of paradoxical, depressogenic responses to antidepressants in affective disorders. There is strong evidence that antidepressants can increase the frequency of bipolar depressions. Antidepressants not only increase the frequency of recurrences and rapid cycling, but also the tendency of the illness to alternate between depression and mania.‘4-‘7 For unipolar disorder, reports in the German literature claim that antidepressants may transform an episodic illness into a chronic depressive illness or a fragile equilibrium near the threshold of depression. “,‘7~‘8There also are reports of an increased frequency of recurrences in unipolar patients treated with antidepressants.lg Lithium has been reported to induce mania when used to augment tricyclic antidepressants in the treatment of refractory depression.*’ The following case reports illustrate the emergence or exacerbation of depressive symptoms in two patients with panic disorder treated with two different tricyclic antidepressants. They complement the previous reports of treatment emergent depression with benzodiazepines. The patients represented two (4%) of 45 consecutively treated patients who met DSM-III-R criteria for panic disorder in our Anxiety Disorders Clinic. Diagnoses were made via semi-structured interviews, and the patients treated naturalistically. CASE REPORTS Case 1 Mrs. A, a married, 26-year-old housewife, described the onset of infrequent panic attacks 8 months previously which spontaneously subsided. Two weeks prior to her first psychiatric contact, the daily panics reccured and she rapidly became housebound. She described feeling demoralized and frightened secondary to the panics. She reported middle insomnia and decreased energy, but only met three of nine DSM-III-R items for MDD. Though she had no prior history of affective disorder, her family history was positive for MDD, suicide (five relatives), and drug abuse. Over the next 2 months her symptoms were controlled with 75 mg nortriptyline (blood level 105 ng/mL; therapeutic range 50 to 150 ng/mL). After 1 month of complete remission of panic and depressive complaints, except for some residual phobic fears, she suddenly developed a new endogenomorphic MDD picture. She had morbid ruminations about death, nightmares of blood, sleep terrors, hypersomnia, decreased appetite, guilt, extreme exhaustion, and a very depressed mood with sustained anxiety, but no panics (eight of nine DSM-III-R items for MDD). An attempt to switch her to phenelzine failed because of medication side effects and she dropped out of treatment.
Case 2 Mrs. B, a 30-year-old physician, described the onset of a panic disorder with mild agoraphobia 4 months previously, shortly following a marital separation. Her panic attacks increased in frequency to once daily, and she began having initial insomnia, fatigue, depressed mood, and difficulty concentrating at work (four of nine DSM-III-R items). She also had no prior history of affective disorder, despite a family history for MDD (two relatives), alcohol abuse (seven relatives), and panic disorder (two relatives). After administration of 200 mg desipramine (blood level 155 ng/mL; therapeutic range 150 to 300 ng/mL) for 2 weeks, her panics subsided, and sleep, concentration, and mood improved. After the third week, the depression suddenly worsened. Despite being panic-free, her fatigue increased. A new onset of hypersomnia, anorexia, weight loss, diurnal variation in mood, poor concentration, diminished interest in activities, and difficulty functioning at work necessitated a leave of absence (seven of nine DSM-III-R items). Following an increase to 300 mg desipramine, she felt normal again after 3 weeks.
TREATMENT-EMERGENT
269
DEPRESSION
DISCUSSION
These two cases complement previous reportslW6that have described depression resulting from the treatment of panic disorder with various high potency benzodiazepines. Secondary depressions are common during the course of panic disorder and agoraphobia, affecting approximately two-thirds of patients.“-23 Panic patients are also at greater risk for primary depressions, which occur temporally separate from and usually prior to the panics and phobias.24 The fact that two patients with panic disorder experienced a major depression is not unusual. That it developed while on antidepressant medication is perplexing. The two patients had a similar treatment course: the onset of a major, endogenomorphic depression following the relief of their panic disorder. They initially presented with subsyndromal depressive symptoms that at the time of the initial interview appeared reactive to their panic disorder, involving more demoralization than depression. Neither had a previous history of MDD, though both had a positive family history. The patients’ panic and depressive symptoms initially improved or remitted during the first month of treatment. Then an endogenormorphic MDD ensued without panic attacks, associated with extreme fatigue, hypersomnia, anorexia, poor concentration, generalized anxiety, a decreased ability to function in their normal activities, and a tearful, depressed mood. One dropped out of treatment, consistent with the MGH group’s retrospective study’ and our prospective follow-up of panic disorder treatment non-completers.25 Other groups have also found that concomitant depression is a negative prognostic predictor of antidepressant treatment outcome in panic disorder and agoraphobia.26s28Mrs. B’s symptoms remitted on higher doses of antidepressants after 3 to 4 weeks. Curiously, lower doses of antidepressants controlled the panics while higher doses were needed for the depression, consistent with most previous dose-response studies of panic disorder,2v-30though not all.” At question remains this puzzling finding of antidepressant-related depression in panic disorder. It could represent a causal association; antidepressants may unmask a depressive diathesis or directly contribute to the development of depression. However, the response of Mrs. B to higher doses of antidepressants makes a causal theory unlikely. A more likely explanation posits a coincidental association reflecting the natural history of panic disorder, and the apparent ability of lower doses of antidepressants to block panic attacks without resolving depression. It suggests that there is a differential response sensitivity to antidepressants for panic attacks and depression, with control of panic sometimes being achieved at doses that are suboptimal for an antidepressant effect. This explanation may also account for the association of treatment-emergent depression with the benzodiazepines, which treat panic but are less effective for depression. This includes alprazolam, which appears to be a less potent antidepressant than the classical tricyclics, and more useful for anxious depressions than melancholia. This finding may reflect the natural history of the disorder, rather than a pharmacologically mobilized side effect. The occurrence of an endogenomorphic MDD in our two patients more likely reflects the close association between panic disorder and MDD, rather than the induction of depression by antidepressants.
270
THOMAS
A. ARONSON
This observation suggests that panic attacks in some patients may represent early symptoms of MDD, that is, a harbinger of MDD with panic attacks rather than a true panic disorder. Given the phenomenological overlap of demoralization, reactive depression, and endogenomorphic depression, it may be difficult to distinguish between the three when patients present early on with panic attacks and dysphoria. Our findings suggest that clinicians should be alert to the worsening of depressive symptoms even while their patients’ panic symptoms improve. Furthermore, patients who present with or develop mixed panic/depressive states may require more aggressive psychopharmaco-therapeutic efforts. Benzodiazepines alone appear to be inadequate. Recent evidence suggests that such patients are also relatively less responsive to conventional tricyclic antidepressant treatment, and may require monamine oxidase inhibitors for improvement.32 Further controlled studies are clearly needed. REFERENCES 1. Lydiard RB, Laraia MT, Ballenger JC, et al: Emergence of depressive symptoms in patients receiving alprazolam for panic disorder. Am J Psychiatry 144:644-665, 1987 2. Pollack MH: Clonazepam: A review of open clinical trials. J Clin Psychiatry 48:12-14, 1987 (suppl) 3. Cohen LS, Rosenbaum JF: Clonazepam: New uses and potential problems. J Clin Psychiatry 4850-55, 1987 (suppl) 4. Spier SA, Tesar GE, Rosenbaum JF, et al: Treatment of panic disorder and agoraphobia with clonazepam. J Clin Psychiatry 47:238-242, 1986 5. Pollack MH, Tesar GE, Rosenbaum JF, et al: Clonazepam in the treatment of panic disorder and agoraphobia: A one year follow-up. J Clin Psychopharmacol6:302-304, 1986 6. Howell EF, Laraia MT, Ballenger JC, et al: Lorazepam treatment of panic disorder. Presented at the New Research Session, 140th Annual Meeting of the American Psychiatric Association, Chicago, May 7-14, 1987 7. Ryan HF, Merrill FB, Scott GE, et al: Increase in suicidal thoughts and tendencies: Association with diazepam therapy. JAMA 203:1137-l 139, 1966 8. Schatzberg AF, Cole JO: Benzodiazepines in depressive disorders. Arch Gen Psychiatry 35:13591365,1978 9. Feighner JP, Aden GC, Fabre LF, et al: Comparison of alprazolam, imipramine, and placebo in the treatment of depression. JAMA 249:3057-3064, 1983 10. Rickels K, Feighner JP, Smith WT: Alprazolam, amitriptylene, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42: 134- 141, 1985 11. Rickels K, Chung HR, Csanalosi IB, et al: Alprazolam, diazepam, imipramine, and placebo in outpatients with major depression. Arch Gen Psychiatry 44:862-866, 1987 12. Pecknold JC, Fleury D: Alprazolam-induced manic episode in two patients with panic disorder. Am J Psychiatry 143:652-653, 1986 13. Goodman WK, Charney DS: A case of alprazolam, but not lorazepam, inducing manic symptoms. J Clin Psychiatry 48:117-l 18, 1987 14. Wehr TA, Goodwin FK: Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 144:1403-1411, 1987 15. Wehr TA, Goodwin FK: Tricyclics modulate frequency of manic-depressive cycles. Chronobiologia 4:161-164, 1977 16. Wehr TA, Goodwin FK: Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry 36:555-559, 1979 17. Kukogulos A, Reginaldi D, Laddomada P, et al: Course of the manic-depressive cycle and changes caused by treatments. Pharmacopsychiatry 13:156-167, 1980 18. Arnold OH, Kryspin-Exner K: Zur Frage de Beeinflussing des Verlaufes des manisch-depressiven Krankheitsgeschehens durch Antidepressiva. Wien Med Wochenschr 45/46:929-934, 1963 19. Van Scheyen JD: Recurrent vital depressions. Psychiatr Neurol Neurochir 76:93-l 12, 1973
TREATMENT-EMERGENT
DEPRESSION
271
20. Price LH, Charney DS, Heninger GR: Manic symptoms following addition of lithium to antidepressant treatment. J Clin Psychopharmacol4:361-362, 1984 21. Munjack M, Moss HB: Affective disorder and alcoholism in families of agoraphobics. Arch Gen Psychiatry 38:869-871, 1981 22. Cloninger CR, Martin RL, Clayton P, et al: A blind follow-up and family study of anxiety neurosis: Preliminary analysis of the St. Louis 500, in DF Klein, J Rabkin (eds); Anxiety: New Research and Changing Concepts. New York, Raven, 198 1 23. Leckman JF, Merikangas KR, Pauls DL, et al: Anxiety disorders and depression: Contradictions between family study data and DSM-III conventions. Am J Psychiatry 140:880-882, 1983 24. Breier A, Charney DS, Heninger CR: Major depression in patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:1129-l 135, 1984 25. Aronson TA, Logue CM: On the longitudinal course of panic disorder: Developmental history and predictors of phobic complications. Compr Psychiatry 28:344-355, 1987 26. Van Valkenberg C, Winokur G, Beher D, et al: Depressed women with panic attacks. J Clin Psychiatry 45367-369, 1984 27. Van Valkenberg C, Akiskal HS, Puzantian V, et al: Anxious depressions: Clinical, family history, and naturalistic outcome: Comparison with panic and major depressive disorders. J Affective Disord 6:67-82, 1984 28. Grunhaus L, Rabin D, Greden JF: Simultaneous panic and depressive disorder: Response to antidepressant treatments. J Clin Psychiatry 47:4-7, 1986 29. Aronson TA: A naturalistic study of imipramine in panic disorder and agoraphobia. Am J Psychiatry 144:1014-1019, 1987 30. 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 (ed): Biology of Agoraphobia. Washington, DC, American Psychiatric, 1984 3 1. Mavissakalian M, Perel J: Imipramine in the treatment of agoraphobia: Dose-response relationships. Am J Psychiatry 142:1032-1036, 1985 32. Grunhaus L: Clinical and psychobiological characteristics of simultaneous panic disorder and major depression. Am J Psychiatry 145:1214-1221, 1988
R
ECENT REPORTS have described the emergence of major depressive episodes in patients with panic disorder treated with alprazolam,’ clonazepam,2m5and lorazepam.6 Lydiard et al.’ observed the emergence of depression in 15 of 46 patients (33%) with panic disorder administered 3 to 10 mg (mean 6.6 mg/d) of alprazolam. None of the patients were depressed at the time they entered the study, nor did they differ from patients who did not become depressed on alprazolam in their past psychiatric or family histories. Investigators at Massachusetts General Hospital (MGH) reported similar experiences, though different incidences, with clonazepam and alprazolam. Ten of 177 patients (5.7%) administered 2 to 3 mg/d of clonazepam experienced a treatment-emergent depression, as opposed to 0.5% of a matched number of patients receiving alprazolam (P < .05).’ Furthermore, contrary to the observation made by Lydiard et al,’ psychiatric history did not predict treatment emergent depression. Forty-seven percent of patients lost to follow-up had a history of dysthymia or major depression v 10% who remained on clonazepam, raising the possibility that treatment-emergent depression contributed to treatment dropout.’ Treatment-emergent depressions associated with alprazolam and clonazepam generally responded to the addition of an antidepressant. The MGH group also found that some depressions associated with clonazepam use remitted with a switch to alprazolam. These divergent uncontrolled reports contradict the clinical research literature on benzodiazepines. Though the literature suggests that benzodiazepines are depressants that can precipitate or worsen major depressive disorder (MDD), there are no controlled studies that substantiate such a claim. A review of the literature found only one report of an increase in depression and suicidality associated with diazepam.’ In fact, Schatzberg and Cole’s review of benzodiazepines in depressive disorder? concluded that while they were clearly inferior to antidepressants in 20 double-blind controlled studies, they did improve depressed patients’ anxiety, agitation, and insomnia. More recent reports suggest that the triazolo-benzodiaze-
From the Department of Psychiatry and Behavioral Science, Health Sciences Center, State University’of New York at Stony Brook, Stony Brook. Address reprint requests to Thomas A. Aronson, M.D., Department of Psychiatry and Behavioral Science, Health Sciences Center, T-IO. State University of New York at Stony Brook, Stony Brook, NY 11794-8101. 0 1989 by W.B. Saunders Company. 0010-440x~89/3003-0011%03.00/0
Comprehensive
Psychiatry, Vol. 1, No. 2 (May/June),
1989: pp 267-27
1
267
268
THOMAS
A. ARONSON
pine, alprazolam, has antidepressant properties,g*” and can even precipitate mania.12-‘3The above reports regarding panic disorder are particularly paradoxical and unexpected for alprazolam. There are also uncontrolled reports of paradoxical, depressogenic responses to antidepressants in affective disorders. There is strong evidence that antidepressants can increase the frequency of bipolar depressions. Antidepressants not only increase the frequency of recurrences and rapid cycling, but also the tendency of the illness to alternate between depression and mania.‘4-‘7 For unipolar disorder, reports in the German literature claim that antidepressants may transform an episodic illness into a chronic depressive illness or a fragile equilibrium near the threshold of depression. “,‘7~‘8There also are reports of an increased frequency of recurrences in unipolar patients treated with antidepressants.lg Lithium has been reported to induce mania when used to augment tricyclic antidepressants in the treatment of refractory depression.*’ The following case reports illustrate the emergence or exacerbation of depressive symptoms in two patients with panic disorder treated with two different tricyclic antidepressants. They complement the previous reports of treatment emergent depression with benzodiazepines. The patients represented two (4%) of 45 consecutively treated patients who met DSM-III-R criteria for panic disorder in our Anxiety Disorders Clinic. Diagnoses were made via semi-structured interviews, and the patients treated naturalistically. CASE REPORTS Case 1 Mrs. A, a married, 26-year-old housewife, described the onset of infrequent panic attacks 8 months previously which spontaneously subsided. Two weeks prior to her first psychiatric contact, the daily panics reccured and she rapidly became housebound. She described feeling demoralized and frightened secondary to the panics. She reported middle insomnia and decreased energy, but only met three of nine DSM-III-R items for MDD. Though she had no prior history of affective disorder, her family history was positive for MDD, suicide (five relatives), and drug abuse. Over the next 2 months her symptoms were controlled with 75 mg nortriptyline (blood level 105 ng/mL; therapeutic range 50 to 150 ng/mL). After 1 month of complete remission of panic and depressive complaints, except for some residual phobic fears, she suddenly developed a new endogenomorphic MDD picture. She had morbid ruminations about death, nightmares of blood, sleep terrors, hypersomnia, decreased appetite, guilt, extreme exhaustion, and a very depressed mood with sustained anxiety, but no panics (eight of nine DSM-III-R items for MDD). An attempt to switch her to phenelzine failed because of medication side effects and she dropped out of treatment.
Case 2 Mrs. B, a 30-year-old physician, described the onset of a panic disorder with mild agoraphobia 4 months previously, shortly following a marital separation. Her panic attacks increased in frequency to once daily, and she began having initial insomnia, fatigue, depressed mood, and difficulty concentrating at work (four of nine DSM-III-R items). She also had no prior history of affective disorder, despite a family history for MDD (two relatives), alcohol abuse (seven relatives), and panic disorder (two relatives). After administration of 200 mg desipramine (blood level 155 ng/mL; therapeutic range 150 to 300 ng/mL) for 2 weeks, her panics subsided, and sleep, concentration, and mood improved. After the third week, the depression suddenly worsened. Despite being panic-free, her fatigue increased. A new onset of hypersomnia, anorexia, weight loss, diurnal variation in mood, poor concentration, diminished interest in activities, and difficulty functioning at work necessitated a leave of absence (seven of nine DSM-III-R items). Following an increase to 300 mg desipramine, she felt normal again after 3 weeks.
TREATMENT-EMERGENT
269
DEPRESSION
DISCUSSION
These two cases complement previous reportslW6that have described depression resulting from the treatment of panic disorder with various high potency benzodiazepines. Secondary depressions are common during the course of panic disorder and agoraphobia, affecting approximately two-thirds of patients.“-23 Panic patients are also at greater risk for primary depressions, which occur temporally separate from and usually prior to the panics and phobias.24 The fact that two patients with panic disorder experienced a major depression is not unusual. That it developed while on antidepressant medication is perplexing. The two patients had a similar treatment course: the onset of a major, endogenomorphic depression following the relief of their panic disorder. They initially presented with subsyndromal depressive symptoms that at the time of the initial interview appeared reactive to their panic disorder, involving more demoralization than depression. Neither had a previous history of MDD, though both had a positive family history. The patients’ panic and depressive symptoms initially improved or remitted during the first month of treatment. Then an endogenormorphic MDD ensued without panic attacks, associated with extreme fatigue, hypersomnia, anorexia, poor concentration, generalized anxiety, a decreased ability to function in their normal activities, and a tearful, depressed mood. One dropped out of treatment, consistent with the MGH group’s retrospective study’ and our prospective follow-up of panic disorder treatment non-completers.25 Other groups have also found that concomitant depression is a negative prognostic predictor of antidepressant treatment outcome in panic disorder and agoraphobia.26s28Mrs. B’s symptoms remitted on higher doses of antidepressants after 3 to 4 weeks. Curiously, lower doses of antidepressants controlled the panics while higher doses were needed for the depression, consistent with most previous dose-response studies of panic disorder,2v-30though not all.” At question remains this puzzling finding of antidepressant-related depression in panic disorder. It could represent a causal association; antidepressants may unmask a depressive diathesis or directly contribute to the development of depression. However, the response of Mrs. B to higher doses of antidepressants makes a causal theory unlikely. A more likely explanation posits a coincidental association reflecting the natural history of panic disorder, and the apparent ability of lower doses of antidepressants to block panic attacks without resolving depression. It suggests that there is a differential response sensitivity to antidepressants for panic attacks and depression, with control of panic sometimes being achieved at doses that are suboptimal for an antidepressant effect. This explanation may also account for the association of treatment-emergent depression with the benzodiazepines, which treat panic but are less effective for depression. This includes alprazolam, which appears to be a less potent antidepressant than the classical tricyclics, and more useful for anxious depressions than melancholia. This finding may reflect the natural history of the disorder, rather than a pharmacologically mobilized side effect. The occurrence of an endogenomorphic MDD in our two patients more likely reflects the close association between panic disorder and MDD, rather than the induction of depression by antidepressants.
270
THOMAS
A. ARONSON
This observation suggests that panic attacks in some patients may represent early symptoms of MDD, that is, a harbinger of MDD with panic attacks rather than a true panic disorder. Given the phenomenological overlap of demoralization, reactive depression, and endogenomorphic depression, it may be difficult to distinguish between the three when patients present early on with panic attacks and dysphoria. Our findings suggest that clinicians should be alert to the worsening of depressive symptoms even while their patients’ panic symptoms improve. Furthermore, patients who present with or develop mixed panic/depressive states may require more aggressive psychopharmaco-therapeutic efforts. Benzodiazepines alone appear to be inadequate. Recent evidence suggests that such patients are also relatively less responsive to conventional tricyclic antidepressant treatment, and may require monamine oxidase inhibitors for improvement.32 Further controlled studies are clearly needed. REFERENCES 1. Lydiard RB, Laraia MT, Ballenger JC, et al: Emergence of depressive symptoms in patients receiving alprazolam for panic disorder. Am J Psychiatry 144:644-665, 1987 2. Pollack MH: Clonazepam: A review of open clinical trials. J Clin Psychiatry 48:12-14, 1987 (suppl) 3. Cohen LS, Rosenbaum JF: Clonazepam: New uses and potential problems. J Clin Psychiatry 4850-55, 1987 (suppl) 4. Spier SA, Tesar GE, Rosenbaum JF, et al: Treatment of panic disorder and agoraphobia with clonazepam. J Clin Psychiatry 47:238-242, 1986 5. Pollack MH, Tesar GE, Rosenbaum JF, et al: Clonazepam in the treatment of panic disorder and agoraphobia: A one year follow-up. J Clin Psychopharmacol6:302-304, 1986 6. Howell EF, Laraia MT, Ballenger JC, et al: Lorazepam treatment of panic disorder. Presented at the New Research Session, 140th Annual Meeting of the American Psychiatric Association, Chicago, May 7-14, 1987 7. Ryan HF, Merrill FB, Scott GE, et al: Increase in suicidal thoughts and tendencies: Association with diazepam therapy. JAMA 203:1137-l 139, 1966 8. Schatzberg AF, Cole JO: Benzodiazepines in depressive disorders. Arch Gen Psychiatry 35:13591365,1978 9. Feighner JP, Aden GC, Fabre LF, et al: Comparison of alprazolam, imipramine, and placebo in the treatment of depression. JAMA 249:3057-3064, 1983 10. Rickels K, Feighner JP, Smith WT: Alprazolam, amitriptylene, doxepin, and placebo in the treatment of depression. Arch Gen Psychiatry 42: 134- 141, 1985 11. Rickels K, Chung HR, Csanalosi IB, et al: Alprazolam, diazepam, imipramine, and placebo in outpatients with major depression. Arch Gen Psychiatry 44:862-866, 1987 12. Pecknold JC, Fleury D: Alprazolam-induced manic episode in two patients with panic disorder. Am J Psychiatry 143:652-653, 1986 13. Goodman WK, Charney DS: A case of alprazolam, but not lorazepam, inducing manic symptoms. J Clin Psychiatry 48:117-l 18, 1987 14. Wehr TA, Goodwin FK: Can antidepressants cause mania and worsen the course of affective illness? Am J Psychiatry 144:1403-1411, 1987 15. Wehr TA, Goodwin FK: Tricyclics modulate frequency of manic-depressive cycles. Chronobiologia 4:161-164, 1977 16. Wehr TA, Goodwin FK: Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry 36:555-559, 1979 17. Kukogulos A, Reginaldi D, Laddomada P, et al: Course of the manic-depressive cycle and changes caused by treatments. Pharmacopsychiatry 13:156-167, 1980 18. Arnold OH, Kryspin-Exner K: Zur Frage de Beeinflussing des Verlaufes des manisch-depressiven Krankheitsgeschehens durch Antidepressiva. Wien Med Wochenschr 45/46:929-934, 1963 19. Van Scheyen JD: Recurrent vital depressions. Psychiatr Neurol Neurochir 76:93-l 12, 1973
TREATMENT-EMERGENT
DEPRESSION
271
20. Price LH, Charney DS, Heninger GR: Manic symptoms following addition of lithium to antidepressant treatment. J Clin Psychopharmacol4:361-362, 1984 21. Munjack M, Moss HB: Affective disorder and alcoholism in families of agoraphobics. Arch Gen Psychiatry 38:869-871, 1981 22. Cloninger CR, Martin RL, Clayton P, et al: A blind follow-up and family study of anxiety neurosis: Preliminary analysis of the St. Louis 500, in DF Klein, J Rabkin (eds); Anxiety: New Research and Changing Concepts. New York, Raven, 198 1 23. Leckman JF, Merikangas KR, Pauls DL, et al: Anxiety disorders and depression: Contradictions between family study data and DSM-III conventions. Am J Psychiatry 140:880-882, 1983 24. Breier A, Charney DS, Heninger CR: Major depression in patients with agoraphobia and panic disorder. Arch Gen Psychiatry 41:1129-l 135, 1984 25. Aronson TA, Logue CM: On the longitudinal course of panic disorder: Developmental history and predictors of phobic complications. Compr Psychiatry 28:344-355, 1987 26. Van Valkenberg C, Winokur G, Beher D, et al: Depressed women with panic attacks. J Clin Psychiatry 45367-369, 1984 27. Van Valkenberg C, Akiskal HS, Puzantian V, et al: Anxious depressions: Clinical, family history, and naturalistic outcome: Comparison with panic and major depressive disorders. J Affective Disord 6:67-82, 1984 28. Grunhaus L, Rabin D, Greden JF: Simultaneous panic and depressive disorder: Response to antidepressant treatments. J Clin Psychiatry 47:4-7, 1986 29. Aronson TA: A naturalistic study of imipramine in panic disorder and agoraphobia. Am J Psychiatry 144:1014-1019, 1987 30. 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 (ed): Biology of Agoraphobia. Washington, DC, American Psychiatric, 1984 3 1. Mavissakalian M, Perel J: Imipramine in the treatment of agoraphobia: Dose-response relationships. Am J Psychiatry 142:1032-1036, 1985 32. Grunhaus L: Clinical and psychobiological characteristics of simultaneous panic disorder and major depression. Am J Psychiatry 145:1214-1221, 1988