• Bipolar Disorder type I and II
• follow-up study
• Panic Disorder
• Prospective course

Bipolar disorder is a severe, chronic and recurrent illness, with residual symptoms between episodes, that has a prevalence ranging from 1% (bipolar disorder type I) to 6.5% (bipolar spectrum disorders, including bipolar I and II disorders) in the general population (Vieta et al., 1997; Hirschfeld and Vornik, 2004; Merikangas et al., 2007). Patients with bipolar I and II disorder spend half of their lifetime in a symptomatic state and almost all patients are bound to develop affective recurrences during their lifetime (Dittmann et al., 2002, Joffe et al., 2004, Post et al., 2003). Bipolar disorder is associated with high rates of comorbidity. Comorbidity with Axis I disorders is estimated at 50 % in bipolar I patients (Kessler et al., 1994) and 60% in Bipolar II patients (Benazzi, 1997); the most frequent disorders that co-occur in Bipolar II patients are substance abuse (Regier et al., 1990), anxiety disorders (Chen et al., 1995), and eating disorders (Mury et al., 1995). Epidemiological data confirm that panic disorder is highly prevalent in bipolar and unipolar depression; in some studies, panic comorbidity in bipolar patients ranges from 20 to 33% (Dilsaver et al., 1997; Kessler, Rubinow, Holmes, Abelson, and Zhao, 1997; Chen and Dilsaver, 1995a; Rihmer et al., 2001; Mitchell et al., 2004). In clinical samples of bipolar outpatients, the prevalence of panic disorder comorbidity is also high, with reported rates ranging from 2% to 37% (Boylan et al., 2004; Feske et al., 2000; Goodwin et al., 2002; MacQueen et al., 2003; McElroy et al., 2001; Simon et al., 2004; Vieta et al., 2001). The occurrence of panic disorder in bipolar patients was associated with poorer response to treatment, earlier onset of bipolar disorder, elevated rates of comorbid psychopathology, greater levels of depression, more suicidal ideation and increased familial risk of affective disorders (Frank et al., 2002; Pini et al., 1997). Our aims were to: 1) provide a detailed description of the course of illness in bipolar disorder; 2) provide a comparative evaluation of clinical features affecting course of illness in bipolar I and II disorder; 3) investigate the impact of panic disorder comorbidity on illness course.
Study participants were 194 adult subjects recruited from 2004 to 2006 in the Day-Hospital and inpatient ward of the Department of Psychiatry, Neurobiology, Pharmacology, and Biotechnology, Section of Psychiatry of the University of Pisa.
The study enrolled all subjects with a diagnosis of Bipolar I or Bipolar II disorder.
123 (63.4%) subjects received a diagnosis of bipolar I disorder and 71 (36.6%) of Bipolar II disorder.
Patients were enrolled during a depressive episode in 52.1% of cases, 5.6% were hypomanic, 18.7% were manic and 23.6% mixed. 17/194 patients (8.8%) showed a polyphasic index episode (a rapid shift from one polarity to another, without full remission between episodes). 37/194 patients (19.1%) were included during clinical remission.
Follow up period ranged from 16 to 100 weeks (mean 65.2, SD 37) in the total sample and observation length was 65.2 ± 37.0 weeks and was similar in the two diagnostic groups (M 64.7± 37.4 weeks in Bipolar I, M 65.9± 36.5 weeks in Bipolar II).
The mean length of the index episode was 8 (SD=9.9) weeks.
Bipolar II patients entered our study in a depressive phase more frequently (coded as depressive index episode) than Bipolar I patients (2 32.9, p <0.001).
Our subjects spent an average of 25 weeks (SD=28.7) of the follow up period in a symptomatic state with no significant differences between Bipolar I and II patients, nevertheless, the proportion of time spent depressed during follow-up was significantly higher in Bipolar II patients (z 6.10, p <0.001), while Bipolar I patients spent significantly longer time in a manic or hypomanic state (z -2.4, p .016) and such difference broadens if mixed episodes are included (z -5.28, p <0.001).
When we analyzed the length of time spent ill during the follow-up period after excluding the duration of index episode we found that Bipolar II patients spent significantly longer time ill (z 3.98; p .0001) and spent significantly more time depressed as compared to Bipolar I (z 4.40; p <0.001).
Pharmacological treatment was not the main focus of our naturalistic study, but some interesting findings appeared.
Lithium and second generation antipsychotics were prescribed more frequently to Bipolar I than Bipolar II patients. Anticonvulsants were administered in 75% of the entire sample, without differences between groups.
The comparison between Bipolar I and Bipolar II with and without Panic Disorder current comorbidity did not show any clinical and psychopathological difference. This is in contrast with previous experiences which report a negative impact of panic and anxiety disorders in the course of Bipolar I and unipolar depression (Frank et al., 2002; Toniolo et al., 2009).
These findings are of pivotal clinical importance suggesting that Bipolar patients with depressive polarity of onset of illness and in a current depressive phase are more likely to develop a predominantly depressive course with an overall longer time spent ill and a higher number of recurrences with implications for treatment.
Our study does not confirm the data regarding the association between Panic Disorder and poorer course and outcome of Bipolar Disorder. This difference from literature could be due to the short length of observation, or to the characteristics of the sample, that included patients with severe forms of illness, independently from the presence of panic disorder.
Moreover, for a deeper understanding of the influence that a specific anxiety disorder may have on the severity bipolar illness, it would be important to include not only anxiety disorders but also the anxiety spectrum simptomatology that may coexist in Bipolar Disorder patients, since categorical classification may not detect the impact of subsyndromal anxiety symptoms and their subsequent impact on clinical course and outcome of mood disorders.