Comorbidity of bipolar and anxiety disorders: An overview of trends in research

Table 1 Prevalence of anxiety disorder comorbidity in bipolar disorder: Evidence from meta-analytic and systematic reviews

Details	Any anxiety disorder	Individual anxiety disorders
Meta-analytic reviews
Kowatch et al[29], 2005. 7 studies of child and adolescent BD (n = 362)	Mean prevalence of any anxiety disorder in BD 27% (range 14%-43%)
Vázquez et al[18], 2014. 46 studies of anxiety comorbidity in BD	Lifetime prevalence in epidemiological and clinical studies - mean 47% (range 24%-88%)	Mean prevalence: PD 22% (1%-40%), PHOBIAS 22% (2%-59%), GAD 20% (7%-42%), PTSD 16% (3%-39%), OCD 13% (5%-48%)
Amerio et al[30], 2015. 46 studies of comorbid BD and OCD		Pooled prevalence of OCD in BD 17.0%; pooled prevalence of BD in OCD 18.0%
Nabavi et al[11], 2015. 52 interview-based studies of outpatients and inpatients	Lifetime prevalence of any anxiety disorder in BD 43%	Lifetime prevalence of: PD 17%, GAD 14%, SAD 13%, PTSD 11%, SP PHOBIA 11%, OCD 11%, AGORA 8%
Pavlova et al[19], 2015. 40 studies (n = 14914) of community and clinical population	Lifetime prevalence of anxiety disorder in BD 45%	Lifetime prevalence of: GAD 20%, SOC PHOBIA 20%, PD 19%, PTSD 17%; no differences between BP I and BP II
Tonna et al[31], 2015. 4 studies of adolescent BD- OCD (n = 345)		Pooled prevalence of comorbid OCD in BD among adolescents 23%; greater than adults (14%)
Amerio et al[32], 2016. 14 studies of comorbid BD and OCD in BP I and BP II		Pooled prevalence of OCD in BP I 22%; pooled prevalence of BP I in OCD 4% and of BP II in OCD 13.5%
Preti et al[33], 2016. 28 studies of comorbid BD and GAD (n = 7894)		Current prevalence 12% and lifetime prevalence 15% of GAD in BD
Taskiran et al[34], 2016. 33 studies of child and adolescent BD	Prevalence of any anxiety disorder in BD 44%	Prevalence of: GAD 25%, SEP ANX 22%, OCD 17%, SOC PHOBIA 15%, PD 10%
Pavlova et al[35], 2017. 10 studies of euthymic BD (n = 2120)	Current prevalence of any anxiety disorder in BD 35%	Current prevalence of: GAD 12%, SAD 10%, SP PHOBIA 10%, OCD 7%
Yapici Eser et al[20], 2018. 135 studies of comorbid BD and anxiety disorders	Lifetime prevalence 41% and current prevalence 38% of anxiety disorder in BD; lifetime prevalence 38% in BD I and 34% in BD II; current prevalence 31% in BD I and 37% in BD II	Lifetime prevalence: PD 18%, GAD 13%, SAD 13%, OCD 10%; current prevalence: GAD 15%, PD 13%, SAD 12%, OCD 10%; prevalence PD and SAD significantly affected by proportion of BD I patients
Preti et al[36], 2018. 15 studies of comorbid BD and PD (n = 3391)		Lifetime prevalence: PD 16%; current prevalence: PD 13%; no difference between BP I and BP II
Systematic reviews
Strakowski et al[37], 1994. 4 studies of anxiety comorbidity in BD		Mean prevalence: PD 7%-16%, OCD 8%-13%
Krishnan[38], 2005. 10 studies of anxiety comorbidity in BD	Mean rate 71% (range 49%-92%)	Mean rates: SOC PHOBIA 47%, PTSD 39%, PD 11%, OCD 10%
McIntyre et al[8], 2006. 17 studies of anxiety comorbidity in BD	Lifetime rates 16%-79% in 11 studies; usually 30%50%; current prevalence 15%-56% in 8 studies	AGORA lifetime 22%-62%; current 6%-7%; SP PHOBIA lifetime 2%-67%; current 8% SOC PHOBIA lifetime 4%-47%; current 13%-19% GAD lifetime 3%-43%; current 2%-25% PTSD lifetime 7%-37%; current 4%-40% PD lifetime 2%-38%; current 8%-26% OCD lifetime 2%-31%; current 6%-8%
Tamam[9], 2007. 15 studies of anxiety comorbidity in BD	Lifetime prevalence in epidemiological and clinical studies 24%-93%	Lifetime prevalence of: SOC PHOBIA 5%-47%, PD 6%-43%, OCD 7%-39%, GAD 3%-43%, PTSD 7%-21%
Kauer-Sant'Anna et al[15], 2009. 9 studies of anxiety comorbidity in BD	Lifetime prevalence in epidemiological studies 48%-93%	SP PHOBIA 10%-67%, SOC PHOBIA 8%-47%, PTSD 7%-39%, GAD 3%-42%, PD 5%-33%
Quarantini et al[39], 2009. PTSD prevalence in BD		Lifetime rates of PTSD in BD 16%-39%
Maina et al[16], 2011. 11 studies of anxiety comorbidity in BD	Lifetime prevalence in epidemiological studies 63%-89%; in clinical samples 11%-79%	PD 4%-39%, OCD 3%-35%, GAD 3%-32%, SOC PHOBIA 2%-31%, PTSD 5%-29%
Pallanti et al[40], 2011. 10 studies of comorbid BD and OCD		Lifetime prevalence in epidemiological and clinical studies 15%-35%
Lala et al[41], 2012. 7 studies of elderly patients		PTSD 5%-11%, PD -current 22%, GAD-current 16%, OTHERS 10%-11%
Schaffer et al[10], 2012. 9 studies of anxiety comorbidity in BD	Lifetime prevalence in epidemiological studies 52%-75%	Lifetime prevalence: OCD 10%-25%, PD 14%-27%, PTSD 16%-39%
Latalova et al[22], 2013. 12 studies of anxiety comorbidity in BD	Lifetime prevalence in epidemiological studies 75%; in clinical samples 27%-56%	Lifetime prevalence: SOC PHOBIA 47%-52%, SAD 38%, SP PHOBIA 35%, GAD 30%, PTSD 24% (16%-39%), PD 20%, OCD 14% (3%-35%)
Amerio et al[42], 2014. 64 articles of comorbid BD and OCD		Lifetime prevalence of OCD in BD 11%-21% (mean BP I 15%, BP II 13%); lifetime prevalence of BD in OCD 6%-10% (mean BP I 4%, BP II 9%)
Frías et al[43], 2015. 167 studies of child and adolescent BD	Mean prevalence of any anxiety disorder in BD 54% (range 41%-80%)	GAD and SEP ANX rates higher than other disorders; OCD 36%-39%, PD 18%-23%, PTSD 8%
Sharma[44], 2017. 8 studies of post-partum BD comorbidity		Anecdotal reports of simultaneous onset of comorbid BD-OCD in the postpartum period

BD: Bipolar disorder; BP I: Bipolar disorder subtype I; BP II: Bipolar disorder subtype II; AGORA: Agoraphobia; GAD: Generalized anxiety disorder; OCD: Obsessive compulsive disorder; PD: Panic disorder; PTSD: Post-traumatic stress disorder; SAD: Social anxiety disorder; SEP ANX: Separation anxiety disorder; SOC PHOBIA: Social phobia; SP PHOBIA: Specific phobia.

Table 2 Prevalence of anxiety disorder comorbidity in bipolar disorder: Evidence from open reviews

Ref.	Any anxiety disorder	Individual anxiety disorders
Himmelhoch[45], 1998		Lifetime prevalence of PD in BD 21%; prevalence of BD in PD 14%-34%
Hantouche et al[46], 2002		Prevalence of BD in OCD 11%-16%, cyclothymia 50%-56%
Freeman et al[6], 2002	Lifetime and current rates 32%-79%	SOC PHOBIA lifetime 8%-47%; PTSD lifetime 39%; current 40%-43%; PD lifetime 11%-21%; current 2%-9%; OCD lifetime 9%-21%; current 35%
McIntyre et al[47], 2003	Lifetime rate 92%	Lifetime rates SP PHOBIA 67%, SOC PHOBIA 47%, GAD 42%, PTSD 39%, PD 33%
Sasson et al[12], 2003	Lifetime rate 60%-65%	SOC PHOBIA 10%-40%, OCD 7%-35%, SP PHOBIA 10%, PTSD 7%, GAD 3%
Ghaemi[48], 2004	Lifetime rate > 90%	GAD 50%, PD 20%, OCD 20%
Goldberg et al[2], 2004	Epidemiological studies > 90%; clinical 4%-50%
Issler et al[13], 2004	Lifetime rate 24% to 79%
McIntyre et al[49], 2004	Lifetime rate 42%-90%; current rate 30%	PD 9%-20%, SOC PHOBIA 13%-16%, SP PHOBIA 8%-10%, GAD 3%, OCD 8%-9%, PTSD 4%-7%
Otto et al[50], 2004		Mean prevalence of PTSD in BD 16%
Bauer et al[14], 2005	Lifetime rate 16%-42% and current rate 30%-31% in clinical studies	PTSD lifetime 7%-50%; current 4%-40% PD lifetime 4%-38%; current 8% OCD lifetime 3%-35%; current 6%-8% GAD lifetime 3%-32%; current 2%-3%; SOC PHOBIA lifetime 0%-31%; current 13% SP PHOBIA lifetime 10%-20%; current 8%
Hirschfeld et al[24], 2005	Lifetime rate 42%-92%	PD 21% OCD 21%
Simon et al[51], 2005	Lifetime rate 50%; current rate 30%	PD lifetime rates 14%-38%; PD current rates 4%-9%
Baldassano[52], 2006	Lifetime rate 51%-65%; current rate 7%
Keller[27], 2006	Lifetime rates 51%-65%
MacKinnon et al[53], 2006		Prevalence PD - community studies 12%-35%; clinical studies 5%-63%; family studies 11%-21%
Sajatovic et al[54], 2006	Prevalence 23% among elderly patients	Prevalence PTSD 44%, others 43%, GAD 23%, PD 6%, OCD 5%, AGORA 3%, SOC PHOBIA 0.5%, SP PHOBIA 0.2%
Singh et al[55], 2006	Mean prevalence 55%	Mean prevalence SOC PHOBIA 47%, PTSD 16%, PD 11%, OCD 10%
Dineen Wagner[56], 2006	Prevalence in community studies 29%-50% and clinical samples 14%-76% of anxiety comorbidity in child and adolescent BD	Prevalence: OCD 9%-49%, SOC PHOBIA 3%-33%, GAD 19%-20%, SEP ANX 13%-57%, AGORA 15%-27%, PD 6%-11%, PTSD 18%
Bhagwagar[21], 2007	Lifetime rate > 50%
MacKinnon[57], 2007		Prevalence PD 15%-20%
Mantere[28], 2007	Lifetime rate 42%-56%; current rate 30%
El-Mallakh et al[17], 2008	Lifetime rate 87%-92% in epidemiological studies	Lifetime rates: SAD 5%-52%, GAD 30%-42%, PTSD 16% -39%, OCD 17%-21,% PD 21%
Jolin et al[58], 2008	Mean prevalence 14%-77%% in childhood and adolescent BD	Mean prevalence: SEP ANX 18%-22%, PHOBIA 4%-11%, PD 3%-11%, OCD 3%
Joshi et al[59], 2009	Prevalence in adults and children 12%-76%	Prevalence OCD 15-35%
Sagman et al[60], 2009	Lifetime rate 50%-65%; current rate 30%
Simon[61], 2009	Lifetime rate 51%	Lifetime rate GAD 18%
Bowden[62], 2010	Lifetime rate 92%
Saunders et al[4], 2010	Lifetime rate 65%	Lifetime rate OCD 21%
Andrade-Nascimento et al[63], 2012		Current 15% and lifetime prevalence 16% of GAD in euthymic patients
Jana et al[64], 2012		Mean prevalence of OCD 0%-54% in childhood and adolescent BD
McIntyre et al[65], 2012	Lifetime rate 63%-87%
Perugi et al[66], 2012	Lifetime rate 30%-93%; current rate 30%	Lifetime rate SP PHOBIA 67%, PD 33%
Cazard et al[67], 2013	Mean prevalence 5%-33%	Mean prevalence: SOC PHOBIA 0.5%-47%, PTSD 2%-44%, GAD 3%-42%, OCD 1%-14%
Amerio et al[68], 2015	Mean prevalence 50%	OCD 17%-18%
Chang et al[69], 2016	Lifetime rate 51%-90%; current rate 31%
Ketter[23], 2015	Lifetime prevalence mean 48% (range 17%-79%)
Shi[70], 2015		Prevalence rate of OCD in BD 11%-21%
Tonna et al[71], 2015		Prevalence rate of OCD in BD 21%

BD: Bipolar disorder; BP I: Bipolar disorder subtype I; BP II: Bipolar disorder subtype II; AGORA: Agoraphobia; GAD: Generalized anxiety disorder; OCD: Obsessive compulsive disorder; PD: Panic disorder; PTSD: Post-traumatic stress disorder; SAD: Social anxiety disorder; SEP ANX: Separation anxiety disorder; SOC PHOBIA: Social phobia; SP PHOBIA: Specific phobia.

Table 3 Prevalence of anxiety disorder comorbidity in bipolar disorder: Evidence from epidemiological studies

	Any anxiety disorder	Individual anxiety disorders
Lifetime prevalence rates
ECA[72-74]		OCD 21%, PD 21%
NCS[75-77]	BD 93%	SP PHOBIA 67%, AGORA 62%, SOC PHOBIA 47%, GAD 43%, PTSD 39%, PD 33%, OCD 21%
NCS-R[78-80]	ANY BD 75%, BP I 87%, BP II 83%-89%, ST-BD 63%-72%	SOC PHOBIA 38%, SP PHOBIA 35%, SAD 35%, GAD 30%, PTSD 24%, PD 20%, OCD 14%-23%, AGORA 6%
WMH[81]	Bipolar spectrum 63%, BP I 77%, BP II 75%, ST-BD 53%	1SP PHOBIA 30%, 1SAD 29%, SOC PHOBIA 26%, GAD 20%, PTSD 19%, OCD 12%, PD 11%, AGORA 6%
NESARC[82-84]2	BD 60%, BP I 65%, BP II 45%	PD 53%, GAD 51%, SAD 48%, SP PHOBIA 21%-34%, PD 19%-33%, GAD 18%-32%, SOC PHOBIA 18%-26%, AGORA 0.2%-1%
Edmonton, Alberta, Canada[87]		PHOBIA 54%, PD 18%, OCD 15%
OADP study[88]	33% among adolescents with BD	SEP ANX 18%-22%, PHOBIA 4%-11%, PD 3%-11%, OCD 3%
Zurich Cohort Study[89]	Hypomania - any anxiety disorders 46%- 78%	SOC PHOBIA 10%-36%, AGORA 7%-29%, SP PHOBIA 10%-23%, PD 12%-22%, OCD 5%-6%
National Epidemiologic Survey, Hungary[90]	BD 39%	GAD 14%, SP PHOBIA 13%, PD 11%, AGORA 9%, SOC PHOBIA 8%, OCD 3%
Population-based study from Hungary[91]	BP I 54%, BP II 100%	AGORA 22%-37%, GAD 10%-21%, SP PHOBIA 9%-17%, PD 7%-12%, SOC PHOBIA 4%-12%
Sesto Fiorentino Study, Italy[92]		In BD and ST-BD: GAD 28%-39%, SOC PHOBIA 13%-20%, OCD 16%-17%; PD 6%-16%, SP PHOBIA 4%
EDSP study[93]	BP I 55%, BP II 59%, ST-BD 53% (in 14-24-year-olds with BD)	SP PHOBIA 19%-38%, GAD 10%-18%, SOC PHOBIA 14%-16%, AGORA 5%-16%, OCD 3%-16%, PD 3%-12%, PTSD 9%-11%
Canadian Community Health Survey[94,95]	BD 52%-61%
Singapore Mental Health Study[96]		In BD: OCD 26%, GAD 18%
Current prevalence rates
Australian National Survey[97]	BD 52%	PD 26%, GAD 25%, SOC PHOBIA 19%, PTSD 11%, OCD 9%, AGORA 6%
Australian National Survey[98]	BD 7%-9%	SOC PHOBIA 5%-7%, PTSD 4%-7%, GAD 4%-6%, PD 4%-5%, OCD 4%-5%, AGORA 2%-3%
Canadian Community Health Survey[99]	BD 29%	SOC PHOBIA 17%, PD 13%, AGORA 3%

¹Only for bipolar spectrum disorders; ²National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) prevalence among elderly-generalized anxiety disorder (GAD): lifetime 2.5%; current 1%, and panic disorder (PD)-lifetime 2.5%; current 2%-NESARC prevalence among youth-lifetime anxiety disorder 15%; GAD 29%-PD 22%-Social phobia 14%[85,86]. BD: Bipolar disorder; BP I; Bipolar disorder subtype I; BP II: Bipolar disorder subtype II; ST-BD: Sub-threshold bipolar disorder; ECA: Epidemiologic Catchment Area Study; NCS: National Comorbidity Survey; NCS-R: National Comorbidity Survey-Replication study; WMH: World Mental Health surveys; NESARC: National Epidemiologic Survey on Alcohol and Related Conditions; OADP: Oregon Adolescent Depression Project; EDSP: Early Developmental Stages of Psychopathology study; AGORA: Agoraphobia; GAD: Generalized anxiety disorder; OCD: Obsessive compulsive disorder; PD: Panic disorder; PTSD: Post-traumatic stress disorder; SAD: Social anxiety disorder; SEP ANX: Separation anxiety disorder; SOC PHOBIA: Social phobia; SP PHOBIA: Specific phobia.

Table 4 Prevalence of anxiety disorder comorbidity in bipolar disorder: Evidence from selected large-scale clinical studies

	Any anxiety disorder	Individual anxiety disorders
Stanley foundation studies
McElroy et al[100], 2001 (n = 288)	Lifetime rate 42%; Current rate 30%	PD lifetime 20%, current 9%; SOC PHOBIA lifetime 16%, current 13%; SP PHOBIA lifetime 10%, current 8%; OCD lifetime 9%, current 8%; PTSD lifetime 7%, current 4%; GAD lifetime 3%, current 3%
Suppes et al[101], 2001 (n = 261)	Lifetime rate 44%
Dittmann et al[102], 2002 (n = 152)	Lifetime rate 12%
Levander et al[103], 2007 (n = 350)	Lifetime rate BD 46%; BP I 45%-48%; BP II 38%-58%
Altshuler et al[104], 2010 (n = 711)	Lifetime rate: women 46%, men 29%	Lifetime rates: PD women 21%, men 14%; SOC PHOBIA women 12%, men 10%; SP PHOBIA women 12%, men 4%; OCD women 12%, men 7%; PTSD women 11%, men 3%; AGORA women 3%, men 2%
STEP-BD
Kogan et al[105], 2004 (n = 1000)	Lifetime rate 47%
Perlis et al[106], 2004 (n = 983)	Prevalence rate 38%-69%	SOC PHOBIA 13%-31%, GAD 13%-29%, PD 14%-27%, PTSD 11%-27%, OCD 8%-13%, AGORA 5%-11%
Simon et al[107], 2004 (n = 475)	Lifetime rate BD 51%; BP I/BP II 53%/46%; Current BD 30%; BP I/BP II 34%/19%;	Lifetime BD: SAD 22%, GAD 18%, PD 17%, PTSD 17%, OCD 10%, AGORA 8%; current BD: SAD 13%, PD 8%, OCD 6%, PTSD 5%, AGORA 4%, GAD 2%
Simon et al[108], 2004 (n = 919)	Current rate 32%	GAD 13%, SAD 13%, PD 8%, OCD 7%, PTSD 5%, AGORA 4%
Otto et al[109], 2006 (n = 1000)	Current rate 32%	Current rates: SAD 13%, GAD13%, PD 8%, OCD 7%, PTSD 5%, AGORA 4%
Simon et al[110], 2007 (n = 120)	Lifetime rate 62%; current rate 29%	GAD lifetime 31%, current 13%; SAD lifetime 27%, current 14%; PD lifetime 22%, current 5%; PTSD lifetime 27%, current 11%; OCD lifetime 11%, current 6%; AGORA lifetime 9%, current 2%
Other studies
Vieta et al[111], 2001 (n =129)		PD 2%, SOC PHOBIA 2%, SP PHOBIA 2%, OCD 2%
MacKinnon et al[112], 2002 (n = 192)		Prevalence PD 14%
Henry et al[113], 2003 (n = 318)	Lifetime rates 24%	Lifetime rates: PD 16%, PHOBIAS 11%, OCD 3%
Boylan et al[114], 2004 (n = 138)	Prevalence 56%
Bauer et al[14], 2005 (n = 328)	Lifetime rate 43%; current rate 38%	PTSD lifetime 28%, current 25%; PD lifetime 20%, current 17%; OCD lifetime 11%, current 8%
Mantere[28], 2007 (n = 191)	Lifetime rate: BD 53%, BP I 46%, BP II 60%; current rate: BD 45%, BP I 36%, BP II 52%	PD lifetime 32%, current 24%; SOC PHOBIA lifetime 26%, current 18%; PTSD lifetime 16%, current 10%; GAD lifetime 15%; SP PHOBIA lifetime 8%, current 8%; OCD lifetime 5%, current 2%; AGORA lifetime 3%, current 2%
Azorin et al[115], 2009 (n = 1090)	Lifetime rate 27%	Lifetime rates: GAD 20%, PD 5%, AGORA 4%, SOC PHOBIA 2%, PTSD 2%, OCD 1.5%
Coryell et al[116], 2009 (n = 259)		Lifetime rates: PHOBIA 3%-6%, GAD 1%-5%, PD 1%-4%, OCD 2%
Gao et al[117], 2010 (n = 564)	Prevalence in RCBD 46%
Guo et al[118], 2010 (n = 136763)	Prevalence 36%-37%
Mantere et al[119], 2010 (n =191)	Current rate 31%-44%
Fracalanza et al[120], 2011 (n = 186)	Current rate 33%	Current rates: SAD 39%, PD 31%, OCD 16%, GAD 10%, PTSD 3%
Goes et al[121], 2012 (n = 1416)		Prevalence: PD 23%, SP PHOBIA 10%, SOC PHOBIA 8%, OCD 6%
Chang et al[122], 2012 (n = 325)	Lifetime rates: BP I 27%, BP II 39%	Lifetime rates (BPI/BP II): GAD 10%/29%, PD 5%/9%, SOC PHOBIA 4%/5%, PTSD 3%/2%, OCD 2%/4%, SP PHOBIA 1%/4%
Angst et al[123], 2013 (n = 903)	Mean prevalence: BP I 17%; BP II 27%	Mean prevalence (BP I/BP II): GAD 6%/12%, PD 12%/18%, SOC PHOBIA 5%/8%, OCD 6%/11%
Castilla-Puentes et al[124], 2013 (n = 8129 youth)	Prevalence: Non RCBD 51%; RCBD 65%; BP I 41%-65%; BP II 69%-75%;	Prevalence (RCBD): GAD 55%, SAD 44%, OCD 11%, PTSD 9%, PD 9%, SP PHOBIA 8%
Young et al[125], 2013 (n = 304)	Lifetime rate 22%	PD 40%, SP PHOBIA 24%, OCD 15%, GAD 13%, SAD 10%, AGORA 8%
Asaad et al[126], 2014 (n = 350)	Prevalence 2.3%
Baek et al[127], 2014 (n = 417)	Lifetime rate 30%	Lifetime rates: PD 13%, SP PHOBIA 13%, OCD 13%, SOC PHOBIA 9%

BD: Bipolar disorder; BP I: Bipolar disorder subtype I; BP II: Bipolar disorder subtype II; RCBD: Rapid cycling bipolar disorder; STEP-BD: Systematic Treatment Enhancement Program for Bipolar Disorder.

Table 5 Correlates and impact of anxiety disorder comorbidity in bipolar disorder

	Principal findings	Ref.
Demographic correlates
Age	Higher prevalence in younger patients with BD	[8,20,30,32,40,42]
	No differences in rates according to age	[9,33,36,70]
Gender	Higher prevalence among women	[8-10,14,16-18,24, 40]
	No gender differences	[30,32,33,36,42,52,69,70]
Marital status	No differences according to marital status	[20,70]
Education	Higher levels more comorbidity	[20]
	Lower levels greater comorbidity	[8,9,14,66]
	No effect of education	[33,36,70]
Socioeconomic status	Greater comorbidity among those with lower socioeconomic status	[8,9,14,74]
	No effect of socioeconomic status	[33,36]
Ethnic and cross-national differences	Differences in comorbidity across nations and ethnicities	[11,16,19,30,69,74,135]
Clinical correlates
Age of onset	Lower age of onset is associated with higher levels of comorbidity	[8-10,14,16-18,20,21-24,27,30,31,33,36,40,42,49,52,56,57,60,66,70,136-142]
BP I vs BP II	Greater comorbidity in BP I	[15,17,30,33,49,60,84]
	Greater comorbidity in BP II	[4,9,20,128]
	No clear differences in comorbidity between BP I and BP II	[7,8,10,16,18,19,28,32,36,42,50,52,66,69,78-81,93,137]
Depression	Anxiety comorbidity is associated with more frequent and severe depressive episodes	[8,10,14-17,26,36,42,49,52,57,66,69,137-139,143]
	No clear evidence of predominance of depressive pathology	[19,28,70]
Mania	Anxiety comorbidity is associated with more frequent and severe manic episodes	[8,16,19]
	No clear evidence of association with mania	[14,18,28,36,40,49,70]
Euthymia	Anxiety comorbidity is associated with shorter durations of euthymia	[8,9,14,16,17,21,22,50,52,66,67,69]
Rapid cycling and mixed features	Anxiety comorbidity is associated with rapid cycling and mixed states	[8-10,13,15-18,40,49,52,67,69,141,142]
	No association with rapid cycling and mixed features	[19,28,66,70,144]
Psychotic symptoms	Anxiety comorbidity is associated with psychotic symptoms	[5,8,16,20,22,25,40]
	No association with psychotic symptoms	[70]
Insight	Anxiety comorbidity is associated with greater insight	[9]
Cognitive impairment	Anxiety comorbidity is associated with greater cognitive impairment	[15, 66]
Bipolar spectrum	Anxiety comorbidity is associated with bipolar spectrum disorders	[7,8,40,42,45,46,66,128]
Subsyndromal symptoms	Anxiety comorbidity is associated with subsyndromal symptoms	[14,66,69,139]
Substance-use disorders	Anxiety comorbidity is associated with greater prevalence of substance use and substance use disorders	[5,8-10,12-14,16-18,20,22-25,27,40,42,50,57,60,66,67,69,70,139,141-143]
Other comorbidity	Anxiety comorbidity is associated with greater prevalence of ADHD, eating disorders, personality disorders.	[9,12,14,20,22,42,139,145]
Impact
Course of illness	Anxiety comorbidity is associated with poorer course and outcome in BD in terms of greater illness severity, frequent episodes, and greater risk of hospitalization	[5,8-10,13-18,20,22,23,26,27,33,36,40,42,49,52,56,57,60,70,128,137-139,141-143,146]
Treatment response	Anxiety comorbidity is associated with poorer treatment response in BD	[4-6,8-10,12-14,16-18,22-27,40,49,57,60,66,67,69,137-139,141,142,146,147]
Suicide	Anxiety comorbidity is associated with increased risk of suicidality in BD	[4,5,8-10,13,14-18,21-27,33,36,40,42,49,50,52,57,60,66,67,69,128, 136-139,141,142,148,149]
Functioning	Anxiety comorbidity is associated with impaired functioning in BD	[8-10,14-18,21,22,25,27,33,36,40,42,49,50,66,67,69,128,139]
Quality of life	Anxiety comorbidity is associated with impaired quality of life in BD	[8-10,14-17,21,22,25,27,36,39,42,50,66,67,138,139]
Outcome of BD	Anxiety comorbidity is associated with incomplete remission and recovery in BD	[5,8,10,14,16,17,21,22,26,36,50,66,69,128,138]
Adherence	Anxiety comorbidity is associated with irregular treatment-adherence in BD	[10,16]
Delayed diagnosis-costs-service utilization	Anxiety comorbidity is associated with delayed diagnosis increased health-care utilization and costs in BD	[24,27,41,49 69,137]

BD: Bipolar disorder; BP I: Bipolar disorder subtype I; BP II: Bipolar disorder subtype II; ADHD: Attention deficit hyperactivity disorder.

Table 6 Treatment of anxiety disorder comorbidity in bipolar disorder

	Findings	Ref.
Pharmacotherapy
Evidence base	Few RCTs of treatment of comorbid anxiety disorders in BD	[7-10,15,22,26,49,55,60,141,142,157-162]
	RCTs of treatment of BD reporting change in anxiety symptoms as secondary outcomes	[6,10,26,15,16,25,33,49,162]
Principles of treatment	Mood stabilization is the first priority	[3,6,7,9,10,12,15,48,49,55,128,157-159,162]
Add-on treatments	SGAs e.g., quetiapine and olanzapine first line choices	[6,7,9,10,12,15,17,22,26,33,48,55,128,141,142,158-162]
	SSRIs e.g., paroxetine but risk of mood destabilization	[6,7,9,10,12,15-17,22,25,26,33,48,55,128,157-159,162]
	Anticonvulsants e.g., valproate, lamotrigine and gabapentin but no strong evidence	[6, 7, 9, 10, 12, 15, 17, 22, 25, 48, 55, 60, 67, 158, 159, 162]
	Benzodiazepines only for short-term treatment because of risk of abuse and dependence	[6,7,9,10,15-17,22,33,48,162,163]
Psychotherapy
Evidence base	Psychotherapy such as CBT may be effective in promoting recovery in those with comorbid anxiety and BD but there are only a few RCTs	[10,22,25,26,162,164-171]
Principles of treatment	Psychotherapy such as CBT is a first-line add-on treatment option	[6,7,9,12,10,15,17,22,25,26,67,128,157-159,162,164,165]

BD: Bipolar disorder; RCTs: Randomized controlled trials; SGAs: Second generation antipsychotics; SSRIs: Specific serotonergic reuptake inhibitors; CBT: Cognitive behavioural treatment.