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Home , Anxiety disorder, Bipolar disorder, Phobia, Specific phobia

SECTION SPECIAL International Journal of (2003), 6, 139–144. Copyright f 2003 CINP DOI: 10.1017/S1461145703003432 Bipolar : from diagnostic dilemmas to therapeutic challenge

Yehuda Sasson, Miriam Chopra, Eran Harrari, Keren Amitai and Chaim Sheba Medical Centre, Division of , Tel Hashomer, Israel

Abstract

Comorbidity in is the rule rather than the exception – more than 60% of bipolar patients have a comorbid diagnosis – and is associated with a mixed affective or dysphoric state; high rates of suicidality; less favourable response to and poorer overall outcome. There is convincing evidence Downloaded from https://academic.oup.com/ijnp/article/6/2/139/719859 by guest on 28 September 2021 that rates of substance use and disorders are higher among patients with bipolar disorder com- pared to their rates in the general population. The interaction between anxiety disorders and substance use goes both ways: patients with bipolar disorder have a higher rate of substance use and , and vice versa. Bipolar disorder is also associated with borderline and ADHD, and to a lesser extent with weight gain. As more than 40% of bipolar patients have anxiety disorder, it is indicated that while diagnosing bipolar patients, systematic enquiry about different anxiety disorders is called for. This also presents a therapeutic challenge, since agents that effectively treat anxiety disorders are associated with the risk of induced . Therefore, the treating needs to carefully evaluate the potential benefit of treating the anxiety against the potential cost of inducing a manic episode. A possible solution would be to use, when possible, a non-pharmacological intervention, such as a cognitive–behavioural approach. Alternately, it is suggested that the clinician attempts to ensure that the patient receives adequate treatment with stabilizers before slowly and carefully attempting the addition of anti-anxiety compounds with a relatively lower risk of mania induction (e.g. SSRIs compared to TCAs). Received 28 July 2002; Reviewed 13 November 2002; Revised 21 January 2003; Accepted 9 February 2003

Key words: Anxiety disorder, bipolar disorder, SSRIs, .

Introduction they are indeed independent, but this may not be entirely clear in, for example, depressive and anxiety Comorbidity has been defined as the presence of more disorders. than one disorder in a person, for a defined period of Another point to which close should be time (Wittchen, 1996). As the adherence to diagnosis paid is the different definitions being used; while according to diagnostic criteria has been widely ac- some studies use the ‘lifetime’ definition, others look cepted, comorbidity has by default become the rule, at the co-occurrence of two disorders. It is clear that rather than the exception (Van Praag, 1996). the prevalence of comorbidity is greater when the There are three main types of comorbidity: co- ‘lifetime’ definition is used. morbidity of physical and psychiatric disorders, e.g. The third methodological issue which should be and ; comorbidity of taken into account is the population being studied. related disorders, e.g. anxiety and depression; and Population-based studies probably provide a better comorbidity of disorders indirectly related, e.g. estimation of comorbidity rates compared to studies psychotic depression and substance abuse. carried out in primary and secondary care settings, Methodological issues implicated in the research of which introduce the artifact of treatment-seeking into comorbidity include the question of whether the two the sample. The National Comorbidy Survey (NCS) of diagnoses being studied are truly independent of one the (Kessler et al., 1994) which docu- another. The current underlying hypothesis is that mented psychiatric diagnosis of over 8000 individuals in a population-based sample, is an example of a large population-based study. Address for correspondence: Professor J. Zohar, Chaim Sheba Medical Centre, Division of Psychiatry, Tel Hashomer, 52621, Israel. The last methodological issue is the base rate, i.e. the Tel.: 972 3 530 3300 Fax: 972 3 535 2788 chance that two disorders will occur concurrently is of E-mail: [email protected] course higher if the base rates of the two are high. 140 Y. Sasson et al.

Thus, while weighing the significance of the co- Table 1. Axis I comorbidity in bipolar disordera morbidity, one also needs to take these base rates into account. Lifetime % (n) Current % (n) Comorbidity is usually associated with poorer prognosis and also may present a challenge for the None 101 (35) 67 (192) treating psychiatrist. For example, while treating one One or more 65 (187) 33 (96) condition (such as ) in patients with Two or more 42 (120) 13 (37) bipolar disorder, it might also lead to a hypomanic Three or more 24 (68) 6 (16) or even to a manic episode. Adapted from McElroy et al. (2001). However, theoretically comorbidity may advance a No difference in comorbidity between patients with our knowledge. For example, if two disorders fre- bipolar I and bipolar II disorders. quently coexist (e.g. depression and anxiety), this may

shed some light on a possible common psychopatho- rate of eating disorders among patients with bipolar Downloaded from https://academic.oup.com/ijnp/article/6/2/139/719859 by guest on 28 September 2021 logical pathway, therefore providing an important disorder, while patients with eating disorders often lead for innovative research and therapeutic ap- have a higher prevalence of bipolar disorders (Halmi proaches [e.g. obsessive–compulsive disorder (OCD) et al., 1991; Simpson et al., 1992). and addiction]. As comorbidity is common in bipolar disorder Prevalence of bipolar comorbidity (McElroy et al., 2001) a number of questions often arise in this regard. The first relates to the rate of Based on the first 288 patients of the Stanley Foun- comorbid Axis I disorders across diagnostic subtypes dation Bipolar Network (SFBN) (McElroy et al., 2001), (e.g. bipolar I vs. bipolar II). The second is related to the 65% had a comorbid diagnosis. The breakdown of this effect of Axis I psychiatric comorbidity on phenomen- 65% is as follows: 23% had one additional lifetime ology, course, outcome and treatment response. This DSM-IV Axis I diagnosis, 18% had two additional paper will address these issues while reviewing the lifetime Axis I diagnoses, and approx. one quarter relevant literature on comorbidity in bipolar disorder. (24%) had three or more such diagnoses. This 65% figure is in line with the observation of Cassano et al. (1998) who reported that 60% of patients with bipolar Bipolar comorbidity disorder admitted to psychiatric facilities have at least There is convincing evidence that rates of substance one other Axis I disorder (see Table 1). use (Brady and Lydiard, 1992; Regier et al., 1990) and anxiety disorders (Chen and Dilsaver, 1995a,b) are Comorbidity of substance use with bipolar disorder higher among patients with bipolar disorder com- A fairly high lifetime percentage of bipolar patients pared to their rates in the general population. More- (42%) (McElroy et al., 2001) report on substance use. over, it appears that rates of substance use (Kessler This includes 33% of use, 16% use of mari- et al., 1996; Regier et al., 1990), panic disorder (Chen juana, with and each present in 9% and Dilsaver, 1995b) and OCD (Chen and Dilsaver, and , opiates and other con- 1995a) are higher in bipolar patients than in de- tributing 8, 7 and 6% correspondingly (see Table 2). pression patients. The interaction between anxiety Drug abuse is a significant indicator for the course disorders and substance use goes both ways: patients of bipolar disorder, not only with regard to the indi- with bipolar disorder have a higher rate of substance vidual but also in relation to family history of drug use and anxiety disorder, and vice versa; patients with abuse. In a logistic regression carried out by McElroy substance use and anxiety disorders often have bi- et al. (2001) a family history of drug abuse was found polar disorder (Bowen et al., 1995; Brady and Lydiard, to be one of three factors which provided a signifi- 1992; Sonne et al., 1994). cant indicator for lifetime comorbid Axis I disorders Bipolar disorder is associated with borderline per- in patients with bipolar disorder. The other two sonality disorder (Pinto and Akiskal, 1998) and ADHD indicators were early onset of bipolar disorder and (Faraone et al., 1997; Geller et al., 1998). It also has early onset of affective symptoms. been linked with weight gain (Elmslie et al., 2000). However, the comorbidity of bipolar and eating Comorbidity of bipolar and anxiety disorders disorders is less prominent (Kruger et al., 1995; Strakowski et al., 1992, 1993, 1994), yet the interaction The prevalence rate of comorbid bipolar and anxiety between them also goes both ways: there is a higher disorders is similar to that in substance use, i.e. a 42% Bipolar comorbidity 141

Table 2. Comorbidity of substance use disorders with bipolar Table 3. Comorbidity of anxiety disorders with bipolar disorder disorder

Lifetime % (n) Current % (n) Lifetime % (n) Current % (n)

Substance use disorders 42 (122) 4 (12) Anxiety disorders 42 (122) 30 (66) Alcohol 33 (96) 2 (7) Panic disorder/ 20 (58) 9 (27) Marijuana 16 (45) 3 (8) Social 16 (47) 13 (36) 9 (25) 0 (1) Simple phobia 10 (30) 8 (24) Cocaine 9 (27) 1 (2) OCD 9 (27) 8 (22) 8 (24) 0 (1) PTSD 7 (19) 4 (12) Opiate 7 (20) 0 (1) Generalized anxiety disorder 3 (8) 3 (8) 6 (18) 0 (1) Other anxiety disorders 3 (8) 2 (6) Downloaded from https://academic.oup.com/ijnp/article/6/2/139/719859 by guest on 28 September 2021 Adapted from McElroy et al. (2001). Adapted from McElroy (2001). lifetime prevalence (McElroy et al., 2001). This in- there are effective pharmacological compounds which cludes comorbidity with all anxiety disorders, with are quite helpful in the treatment of anxiety disorders. prevalence ranging from as high as 25% for panic On the other hand, these compounds [e.g. selective disorder (Cassano et al., 1998) to as low as 3% for reuptake inhibitors (SSRIs), and tricyclic generalized anxiety disorder (McElroy et al., 2001). anti- (TCAs)] may potentially trigger a Social phobia was found in one study to have a pre- manic episode. It is therefore clinically clear that valence of 16% (McElroy et al., 2001) and in another their concurrent use in patients with bipolar dis- of 10% (Cassano et al., 1998). Conversely, Cassano order should be carried out with great caution. How- et al. (1998) reported a 21% comorbidity of OCD with ever, it raises another question that should thus be bipolar disorder, while McElroy et al. (2001) reported asked which relates not only to the relative efficacy 9%. The latter research group also reported a 10% of the two compounds but also to the ‘switch rate’, comorbidity of simple phobia with bipolar disorder i.e. the potential of the to induce a manic and a 7% comorbidity with post-traumatic episode. disorder (PTSD) (see Table 3). One of the disorders for which findings are widely Bipolar disorder and OCD: treatment implications distributed with regard to comorbidity with bipolar It has been demonstrated in the literature time and disorder is OCD. Lifetime prevalence ranges from again that only serotonin reuptake blockers are effec- 7.3% (Chen and Dilsaver, 1995a) to 35.1% (Kruger tive in OCD (Sasson et al., 1997). It also has been et al., 1995) with interim figures of 21% (Cassano et al., shown that the efficacy of SSRIs in OCD is equal to 1998) and 9% (McElroy et al., 2001). clomipramine (Montgomery and Zohar, 1999). Hence, in the treatment of patients with both disorders an Mental status examination and comorbidity important therapeutic consideration would be the In light of the very high rates of lifetime prevalence of switch rate potency of these two classes of medication. anxiety disorder and substance use in bipolar patients, At least one study (Vieta and Bemardo, 1992) found it is suggested that while examining patients with bi- that in OCD the switch rate to a manic episode is polar disorder, these two conditions and, to a lesser higher with clomipramine compared to SSRIs. It is extent, eating disorders, should be intentionally, therefore suggested that SSRIs should be used initially specifically and systematically explored. It is of course in this subset of patients, due to their lower potential important to diagnose these frequently accompanying of switching to mania on one hand, and their equal comorbid conditions, as they are crucial factors in any clinical potency on the other hand. therapeutic intervention. The second component of the therapeutic inter- vention, in comorbid bipolar disorder and OCD, involves choosing an appropriate . Comorbidity of bipolar disorder: treatment Ideally, if a mood stabilizer has anti-obsessive proper- implications ties or at least an augmentation effect it would be a The high comorbidity of anxiety and bipolar disorders natural first-line treatment in this patient subset. Cur- presents a therapeutic dilemma. On the one hand, rently there are no controlled studies which suggest 142 Y. Sasson et al. which mood stabilizer is preferable in these cases, (Mancini and Amerigen, 1996) and sertra- although some preliminary open case reports suggest line (Katzelnick et al., 1995) were found to be effective that lamotrogine and might be appro- in social phobia, however they can induce mania priate. (Howland, 1996). Gabapentine was found in a small, placebo- controlled study (Pande et al., 1999) to be effective in Bipolar and panic disorders social phobia. As this compound is a mood stabilizer The lifetime prevalence of panic disorder in bipolar and if this finding holds up in further, larger, con- patients ranges from 20% (McElroy et al., 2001) to 16% trolled studies, it may play an important role in this (Figueira, 2000). Anti-panic agents such as SSRIs and comorbid condition. TCAs have been found to be quite effective in the amelioration of panic attacks and in treating anti- Comorbidity of bipolar and borderline

cipatory anxiety. Since TCAs are associated with personality disorder Downloaded from https://academic.oup.com/ijnp/article/6/2/139/719859 by guest on 28 September 2021 higher switching rates than SSRIs in comorbid bipolar and panic disorder (Peet, 1994), SSRIs would probably Criteria-wise, there is an overlap between borderline be the first choice. personality and bipolar II disorder. Symptoms like The data regarding the potential role of mood sta- affective instability, , disinhibition on anti- bilizers such as valproic acid, carbamezapine and depressants and genetic loading with bipolarity are gabapentine in this subset of patients is limited. shared by the two disorders (Akiskal et al., 1985). It is However, one double-blind, placebo-controlled study therefore conceivable that there might be a tendency to (Guay, 1995) suggests that divalproex is effective as a pay more attention to the Axis II diagnosis, rather than mood stabilizer in bipolar patients with panic disorder to the bipolar elements, which of course might lead to and particularly in rapid cycling. Carbamezapine was an erroneous approach. found in an uncontrolled study (Uhde et al., 1988) to be It is clear that more systematic research is needed in effective but further double-blind studies are needed regard to the interface between borderline and bipolar to substantiate this finding. Gabapentine has not personality disorder. However, it makes sense clini- yet been studied in this patient subset but it might cally, in the cases where the diagnosis is not quite theoretically be a useful addition to their treatment clear, to include bipolar in the diagnosis, and to treat, (Perugi et al., 1999). then, accordingly (with mood stabilizers) (Hollander In these cases, again, the ideal medication would be et al., 2001; Pinto and Akiskal, 1998). a compound which has both anti-panic and mood- stabilizing properties, up to the point that this kind of Comorbidity of bipolar disorder with attention medication will be available. Perugi et al. (1999) rec- deficit hyperactivity disorder (ADHD) ommend that divalproex or gabapentine be used as Diagnostically, it might be difficult to sort out ADHD mood stabilizers in this patient subset and therefore a from bipolar disorder as symptoms such as hyper- combination of devalproex or gabapentine with SSRIs activity, distractibility, rapid speech are present in is recommended in attempting to treat these patients. both disorders. Two large studies of children with mania found an Bipolar disorder and social phobia extremely high rate of comorbidity with ADHD – 90% (Faraone et al., 1997; Geller et al., 1998). This high The lifetime prevalence of comorbid bipolar disorder figure might even suggest overlapping rather than and social phobia ranges from 16% (McElroy et al., comorbidity. 2001) to 40% (Cassano et al., 1998), while Kessler et al. The association between bipolar disorder and (1997) suggests a lifetime prevalence of 18%. ADHD is somewhat less overwhelming with ado- One option for treating individuals with social lescents with bipolar disorder, ranging from 22 to phobia is the use of monoamine oxidase inhibitors 88% (Carlson et al., 1999). (MAOIs), which was found to be a very potent com- pound for this specific phobia. However, MAOIs are Comorbidity of bipolar disorder and also associated with switching to bipolar disorder (Himmelhoch, 1998). Elmslie et al. (2000) found that bipolar patients (both Two SSRIs (paroxetine and ) and one male and female) had significantly greater waist-to- mood stabilizer (gabapentine) have been studied in hip ratio than controls. As many of the mood- comorbid bipolar disorder and social phobia. Both stabilizing like lithium, valproic acid, Bipolar comorbidity 143

Diagnosis response to lithium (Young et al., 1993) and poorer overall outcome. Faced with this type of morbidity, combined with Treatment the greater risk for and a less favourable out- come, the clinician needs to utilize the limited avail- able data regarding selection of mood stabilizers (e.g. devalproex or gabapentine) in treating these complex cases. Moreover, children and adolescents who are at high Risk of Treatment of induced comorbid risk for developing bipolar disorder need to be mania condition specifically educated about substance use and anxiety disorders. Thus, the emergence of anxiety disorders Figure 1. Therapeutic challenge.

or substance use in genetically prone families should Downloaded from https://academic.oup.com/ijnp/article/6/2/139/719859 by guest on 28 September 2021 generate consideration of a prodromal bipolar dis- , or atypical are associ- order. The clinician therefore, being aware that co- ated with inducing weight gain, the interpretation morbidity is associated with more severe illness and of this finding is hampered. However, given that poorer outcome, should treat these patients with great obesity is a risk factor for cardiovascular and caution, keeping constantly informed about the latest , the weight gain issue, either primary or sec- data regarding the therapeutic approach to these ondary, needs to be monitored carefully in bipolar intriguing patients. patients. References The therapeutic challenge and bipolar and Akiskal HS, Chen SE, Davis GC, Puzantian VR, Kashgarian anxiety disorders M, Bolinger JM (1985). Borderline: an adjective in search of The high prevalence (42%) of comorbid bipolar and a noun. Journal of Clinical Psychiatry 46, 41–48. anxiety disorders presents both a diagnostic and a Bowen R, South M, Hawkes J (1995). Mood swings in patients with panic disorder Canadian Journal of Psychiatry therapeutic challenge. This high comorbidity indicates 39, 91–94. that while diagnosing bipolar patients, systematic Brady KT, Lydiard RB (1992). Bipolar affective disorder and enquiry about different anxiety disorders is called for. substance abuse. Journal of Clinical Psychopharmacology 12 The therapeutic challenge is that agents that effec- (Suppl. 1), 17–22. tively treat anxiety disorders are associated with the Carlson GA, Lavelle J, Bromet EJ (1999). Medication risk of induced mania. Therefore, the treating psy- treatment in adolescents vs. adults with psychotic mania. chiatrist needs to carefully evaluate the potential ben- Journal of Child Adolescent Psychopharmacology 9, 221–231. efit of treating the anxiety against the potential cost of Cassano GB, Pini S, Saettoni M, Rucci P, Dell’Osso L (1998). inducing a manic episode (see Figure 1). A possible Occurrence and clinical correlates of psychiatric solution would be to use, when possible, a non- comorbidity in patients with psychotic disorders. Journal of Clinical Psychiatry 59, 60–68. pharmacological intervention, such as a cognitive- Chen Y-W, Dilsaver SC (1995a). Comorbidity for behavioural approach. Alternately, it is suggested that obsessive–compulsive disorder in bipolar and unipolar the clinician attempt to ensure the patient receives disorders. Psychiatry Research 59, 57–64. adequate treatment with mood stabilizers before Chen Y-W, Dilsaver SC (1995b). Comorbidity of panic slowly and carefully attempting the addition of anti- disorder in bipolar illness: evidence from the anxiety compounds with a relatively lower risk of Epidemiologic Catchment Area survey. American Journal mania induction (e.g. SSRIs compared to TCAs). of Psychiatry 152, 280–282. Elmslie JL, Silverstone JT, Mann JI, Williams SM, Romans SE (2000). Prevalence of overweight and obesity in bipolar Conclusion patients. Journal of Clinical Psychiatry 61, 179–184. Faraone SV, Biederman J, Wozniak J, Mundy E, Mennin D, Comorbidity in bipolar disorder is the rule rather than O’Donnell D (1997). Is comorbidity with ADHD a marker the exception – more than 60% of bipolar patients for juvenile-onset mania? Academy of Child Adolescent have a comorbid diagnosis. Comorbidity is associated Psychiatry 36, 1046–1055. with a mixed affective or dysphoric state rather than Figueira ML (2000). Comorbid anxiety and bipolar disorders with pure mania (McElroy et al., 1995); higher rates of increasingly recognized. International Medical News, suicidality (Chen and Dilsaver, 1995b); less favourable 2000/3. 144 Y. Sasson et al.

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