Panic disorder occurs in about 1 in 5 individuals who have bipolar disorder. Anxiety amplifies the distress caused by depression and mania, but pharmacological approaches are tricky and under-studied. Frequent comorbidity and evidence of a possible genetic relationship of bipolar and panic disorders are suggestive of a causal relationship between the 2. Thus, it may be fruitful to look more closely at evidence for common biological abnormalities in both disorders to find a pathophysiological mechanism that links mania, depression, and panic attacks. Mood episodes and panic attacks can both be modeled as the result of deficits in amygdala-mediated emotional conditioning.1 From this model, some insight may be gained for potentially helpful treatment strategies for the 2 disorders when they occur together.
Evidence for comorbidity
In nearly every study, substantial numbers of individuals who meet criteria for bipolar disorder—between 15% and 20%, or 10 to 20 times the rate in the general population—also meet criteria for panic disorder.2-5 Others have found more modest elevations in the rate of panic disorder in persons with bipolar disorder.6 A relationship between bipolar and panic disorders has also been recorded when looking from the opposite direction. Anxiety disorder specialists have long noticed high rates of bipolar spectrum disorders in their patients who have panic disorder.7
Clinical presentation and consequences of comorbidity
Symptoms of panic disorder have been associated with greater suicidality in patients who have bipolar disorder.8-10 Panic disorder has predicted a slower treatment response in bipolar disorder,9,11 as well as greater likelihood of substance dependence and other anxiety disorders.4 Panic disorder is associated with more unstable forms of bipolar illness—namely, mixed, rapid-cycling, or rapid-switching states.12,13 Findings from a study of intraepisodic panic attacks in hospitalized patients with bipolar disorder suggest that panic attacks are extremely common—affecting as many as 60% of patients—in bipolar, depressed, and mixed states but are relatively uncommon in patients with pure mania.14
Early-age-at-onset samples tend to have more panic comorbidity than average,15 although elevated bipolar and panic comorbidity is documented throughout the life cycle, including in geriatric populations.16 There is less information on other clinical patterns of comorbidity. The question remains whether panic attacks in individuals with bipolar disorder are identical in form to panic attacks in others. It is also unknown whether panic attacks take a different form when they occur in the context of active mood symptoms or when they occur between mood episodes.
Family/genetic aspects of bipolar and panic comorbidity
The rate of panic comorbidity in family samples with bipolar disorder resembles the rate in population studies.17-18 In these studies, risk for panic disorder is elevated only in family members with a mood disorder. The results from analyses of 2 genetic databases reveal a specific familial risk for panic in some individuals with bipolar disorder.17,19
Molecular evidence of a common genetic risk factor for bipolar and panic disorders remains sparse. A stratified reanalysis of bipolar linkage data from 28 families, which had supported a genetic locus for bipolar disorder on the long arm of chromosome 18,20 revealed that the evidence for the link was carried almost exclusively by the families that had an elevated risk for panic disorder.21 This result remains in doubt, however, since it has not been replicated in other studies. A later study of 3 genes of possible functional relevance to bipolar disorder revealed that panic comorbidity enhanced the evidence of association for individuals with bipolar disorder but without panic disorder.22 This finding also awaits positive replication.
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.