Psychiatric Times.
No. 3
Comorbidity of Bipolar and Panic Disorders and Its Consequences
By Dean F. MacKinnon, MD |
March 1, 2007
Dr MacKinnon is associate professor in the department
of psychiatry at Johns Hopkins University
School of Medicine. He reports that he
has no conflicts of interest concerning the subject
matter of this article.
Evidence for the model
Glucocorticoids and related neurohormones, as well as monoaminergic neurotransmitters, have both direct and indirect effects on neuronal plasticity—some positive, some negative. For example, cortisol is known to inhibit the growth of new neurons in the hippocampus in humans41 and, based on animal studies,42 presumably in the amygdala as well. High cortisol tone, whether a primary deficit, a secondary result of the stress response, or externally induced by prednisone(Drug information on prednisone), may thus result in deficient cellular substrate in the amygdala (and possibly in the hippocampus) with which to form and revise conditioned responses. Factors that diminish available serotonin (such as low-functioning alleles of SERT) also diminish the salutary effects of brain-derived neurotrophic factor,43 again impinging on plasticity and emotional conditioning.
Treatment of panic disorder and bipolar disorder
In clinical settings, mania and depression are generally more pressing clinical problems than panic and thus more likely to receive therapeutic attention44; however, patients suffer severely from panic attacks. Treatment of panic disorder using conventional methods is perilous in the context of bipolar disorder. In patients with bipolar disorder, it appears that antidepressants commonly used to prevent panic attacks may exacerbate cycling.45 On the other hand, drugs used to relieve anxiety when panic occurs (eg, benzodiazepines) may become abused or foster dependency in a population of patients whose mood disorder puts them at high risk for chemical dependency.46 Although there is a role for these treatments, they must be used with caution. One possible solution would be using medications proved effective for both disorders independently. However, the only antimanic agent with reported efficacy in controlling panic is divalproex.47
Since there are no placebo-controlled trials of treatment for panic attacks with bipolar disorder,48 it is prudent to make mood stabilization the first priority. There is reason to hope that one can address both problems with 1 treatment. If the root of both problems is a deficit in emotional conditioning, as described in the model, the same neurotrophic factors most useful in treating bipolar disorder, such as lithium(Drug information on lithium),49 may have benefit in treating panic disorder in the context of bipolar disorder. At least one study has found that anxiety comorbidity increases the likelihood of bipolar response to lithium relative to anticonvulsants,50 while in another, panic comorbidity was a robust predictor of bipolar response to lamotrigine(Drug information on lamotrigine).51
When patients who are acutely manic or depressed demand treatment for ongoing panic attacks, it is reasonable to offer lithium or other antimanic agents supplemented by benzodiazepines as needed to suppress attacks when they emerge. Because of the risk of habituation, it is prudent to replace benzodiazepines with definitive treatment of panic attacks if they persist after the mood is stabilized.
Thinking beyond pharmacology, if one is open to the idea that the distress from panic and bipolar disorders is often caused as much by their residual, conditioned effects as by their acute symptoms, then one will keep in focus the goal of improving a patient's global functioning through rehabilitative, or reconditioning, therapies while optimizing the pharmacological regimen.
References
1. MacKinnon DF, Zamoiski R. Panic comorbidity with bipolar disorder: what is the manic-panic connection? Bipolar Disord. 2006;8:648-664.
2. Chen YW, Dilsaver SC. Comorbidity of panic disorder in bipolar illness: evidence from the Epidemiologic Catchment Area Survey. Am J Psychiatry. 1995;152:280-282.
3. Simon NM, Otto MW, Weiss RD, et al. Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD. J Clin Psychopharmacol. 2004;24: 512-520.
4. Goodwin RD, Hoven CW. Bipolar-panic comorbidity in the general population: prevalence and associated morbidity. J Affect Disord. 2002;70:27-33.
5. Rihmer Z, Szadoczky E, Furedi J, et al. Anxiety disorders comorbidity in bipolar I, bipolar II and unipolar major depression: results from a population-based study in Hungary. J Affect Disord. 2001;67:175-179.
6. Altindag A, Yanik M, Nebioglu M. The comorbidity of anxiety disorders in bipolar I patients: prevalence and clinical correlates. Isr J Psychiatry Relat Sci. 2006;43:10-15.
7. Savino M, Perugi G, Simonini E, et al. Affective comorbidity in panic disorder: is there a bipolar connection? J Affect Disord. 1993; 28:155-163.
8. MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord. 2005;7:441-448.
9. Frank E, Cyranowski JM, Rucci P, et al. Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch Gen Psychiatry. 2002;59:905-911.
10. Birmaher B, Kennah A, Brent D, et al. Is bipolar disorder specifically associated with panic disorder in youths? J Clin Psychiatry. 2002;63:414-419.
11. Feske U, Frank E, Mallinger AG, et al. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am J Psychiatry. 2000;157:956-962.
12. MacQueen GM, Hajek T, Alda M. The phenotypes of bipolar disorder: relevance for genetic investigations. Mol Psychiatry. 2005;10:811-826.
13. MacKinnon DF, Zandi PP, Gershon E, et al. Rapid switching of mood in families with multiple cases of bipolar disorder. Arch Gen Psychiatry. 2003;60:921-928.
14. Dilsaver SC, Chen YW, Swann AC, et al. Suicidality, panic disorder and psychosis in bipolar depression, depressive-mania and pure-mania. Psychiatry Res. 1997; 73:47-56.
15. Schurhoff F, Bellivier F, Jouvent R, et al. Early and late onset bipolar disorders: two different forms of manic-depressive illness? J Affect Disord. 2000;58:215-221.
16. Goldstein BI, Herrmann N, Shulman KI. Comorbidity in bipolar disorder among the elderly: results from an epidemiological community sample. Am J Psychiatry. 2006; 163:319-321.
17. MacKinnon DF, McMahon FJ, Simpson SG, et al. Panic disorder with familial bipolar disorder. Biol Psychiatry. 1997;42:90-95.
18. Doughty CJ, Elisabeth WJ, Joyce PR, et al. Bipolar-panic disorder comorbidity within bipolar disorder families: a study of siblings. Bipolar Disord. 2004;6:245-252.
19. MacKinnon DF, Zandi PP, Cooper J, et al. Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. Am J Psychiatry. 2002; 159:30-35.
20. Stine OC, Xu J, Koskela R, et al. Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect. Am J Hum Genet. 1995;57:1384-1394.
21. MacKinnon DF, Xu J, McMahon FJ, et al. Bipolar disorder and panic disorder in families: an analysis of chromosome 18 data. Am J Psychiatry. 1998;155:829-831.
22. Rotondo A, Mazzanti C, Dell'Osso L, et al. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry. 2002;159:23-29.
23. Watson S, Gallagher P, Ritchie JC, et al. Hypothalamic-pituitary-adrenal axis function in patients with bipolar disorder. Br J Psychiatry. 2004;184:496-502.
24. Coplan JD, Lydiard RB. Brain circuits in panic disorder. Biol Psychiatry. 1998;44:1264-1276.
25. Holsboer F, von Bardeleben U, Buller R, et al. Stimulation response to corticotropin-releasing hormone (CRH) in patients with depression, alcoholism and panic disorder. Horm Metab Res Suppl. 1987;16:80-88.
26. Vieta E, Martinez-De-Osaba MJ, Colom F, et al. Enhanced corticotropin response to corticotropin-releasing hormone as a predictor of mania in euthymic bipolar patients. Psychol Med. 1999;29:971-978.
27. Bailey JE, Argyropoulos SV, Lightman SL, Nutt DJ. Does the brain noradrenaline network mediate the effects of the CO2 challenge? J Psychopharmacol. 2003; 17:252-259.
28. Joyce PR, Fergusson DM, Woollard G, et al. Urinary catecholamines and plasma hormones predict mood state in rapid cycling bipolar affective disorder. J Affect Disord. 1995;33:233-243.
29. Woo JM, Yoon KS, Yu BH. Catechol O-methyltransferase genetic polymorphism in panic disorder. Am J Psychiatry. 2002;159:1785-1787.
30. Kirov G, Murphy KC, Arranz MJ, et al. Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry. 1998; 3:342-345.
31. Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT. Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet. 2005;133: 110-115.
32. Maron E, Tasa G, Toru I, et al. Association between serotonin-related genetic polymorphisms and CCK-4-induced panic attacks with or without 5-hydroxytryptophan pretreatment in healthy volunteers. World J Biol Psychiatry. 2004;5:149-154.
33. Blumberg HP, Kaufman J, Martin A, et al. Amygdala and hippocampal volumes in adolescents and adults with bipolar disorder. Arch Gen Psychiatry. 2003;60:1201-1208.
34. Massana G, Serra-Grabulosa JM, Salgado-Pineda P, et al. Amygdalar atrophy in panic disorder patients detected by volumetric magnetic resonance imaging. Neuroimage. 2003;19:80-90.
35. Drevets WC. Neuroimaging abnormalities in the amygdala in mood disorders. Ann N Y Acad Sci. 2003; 985:420-444.
36. Sakai Y, Kumano H, Nishikawa M, et al. Cerebral glucose metabolism associated with a fear network in panic disorder. Neuroreport. 2005;16:927-931.
37. LeDoux J. Fear and the brain: where have we been, and where are we going? Biol Psychiatry. 1998;44:1229-1238.
38. Baxter MG, Murray EA. The amygdala and reward. Nat Rev Neurosci. 2002;3:563-573.
39. Monk CS, Nelson EE, Woldehawariat G, et al. Experience-dependent plasticity for attention to threat: behavioral and neurophysiological evidence in humans. Biol Psychiatry. 2004;56:607-610.
40. Gorman JM, Kent JM, Sullivan GM, Coplan JD. Neuroanatomical hypothesis of panic disorder, revised. Am J Psychiatry. 2000;157:493-505.
41. Brown ES, Rush AJ, McEwen BS. Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology. 1999;21: 474-484.
42. Bernier PJ, Bedard A, Vinet J, et al. Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc Natl Acad Sci U S A. 2002;99:11464-11469.
43. Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2004;27: 589-594.
44. Cosoff SJ, Hafner RJ. The prevalence of comorbid anxiety in schizophrenia, schizoaffective disorder and bipolar disorder. Aust N Z J Psychiatry. 1998;32:67-72.
45. Altshuler LL, Post RM, Leverich GS, et al. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152:1130-1138.
46. Clark RE, Xie H, Brunette MF. Benzodiazepine prescription practices and substance abuse in persons with severe mental illness. J Clin Psychiatry. 2004;65:151-155.
47. Keck PE Jr, Taylor VE, Tugrul KC, et al. Valproate treatment of panic disorder and lactate-induced panic attacks. Biol Psychiatry. 1993;33:542-546.
48. Keck PE Jr, Strawn JR, McElroy SL. Pharmacologic treatment considerations in co-occurring bipolar and anxiety disorders. J Clin Psychiatry. 2006;67(suppl 1):8-15.
49. Moore GJ, Bebchuk JM, Wilds IB, et al. Lithium- induced increase in human brain grey matter. Lancet. 2000;356:1241-1242.
50. Henry C, van den BD, Bellivier F, et al. Anxiety disorders in 318 bipolar patients: prevalence and impact on illness severity and response to mood stabilizer. J Clin Psychiatry. 2003;64:331-335.
51. Passmore MJ, Garnham J, Duffy A, et al. Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine. Bipolar Disord. 2003;5:110-114.
