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. Author manuscript; available in PMC: 2018 Feb 3.
Published in final edited form as: Bipolar Disord. 2017 Feb 3;19(1):6–12. doi: 10.1111/bdi.12462

Comparison of treatment outcome using two definitions of rapid cycling in subjects with bipolar II disorder

Jay D Amsterdam a, Lorenzo Lorenzo-Luaces a,b, Robert J DeRubeis a,b
PMCID: PMC5367974  NIHMSID: NIHMS839502  PMID: 28160351

Abstract

Objectives

We examined differences in treatment outcome between DSM-IV defined rapid cycling and average lifetime defined rapid cycling in subjects with bipolar II disorder. We hypothesized that the average lifetime definition of rapid cycling may better identify subjects with a history of more mood lability and a greater likelihood of hypomanic symptom induction during long-term treatment.

Methods

Subjects ≥18 years old with bipolar II major depressive episode (n = 129) were categorized into DSM-IV and average lifetime definition of rapid cycling and prospectively treated with either venlafaxine or lithium monotherapy for 12 weeks. Responders (n = 59) received continuation monotherapy for six additional months.

Results

These exploratory analyses found moderate agreement between the two rapid cycling definitions (κ = 0.56). The lifetime definition captured subjects with more chronic courses of bipolar II depression, whereas the DSM-IV definition captured subjects with more acute symptoms of hypomania. There was no difference between rapid cycling definitions with respect to response to acute venlafaxine or lithium monotherapy. However, the lifetime definition was slightly superior to the DSM-IV definition in identifying subjects who went on to experience hypomanic symptoms during continuation therapy.

Conclusions

Although sample sizes were limited, the findings suggest that the lifetime definition of rapid cycling may identify individuals with a chronic rapid cycling course and may also be slightly superior to the DSM-IV definition in identifying individuals with hypomania during relapse-prevention therapy. These findings are preliminary in nature and need replication in larger, prospective, bipolar II studies.

Keywords: antidepressant, bipolar disorder, depression, lithium, mania, mood stabilizer, rapid cycling, venlafaxine

Rapid cycling bipolar disorder has conventionally been defined as four or more manic, depressive, or mixed manic-depressive episodes occurring within the preceding 12 months (1). Although a two-month period of euthymia is required to count episodes of the same polarity (e.g., hypomania to hypomania), a shift from one polarity to the other (e.g., depression towards hypomania) counts towards the specifier. While it is not uncommon for rapid cycling to be present on a chronic or intermittent basis for many years, the syndrome may also be absent in the preceeding 12 months. As a result, a more ‘real world’ definition of rapid cycling syndrome has been proposed that relies on a history of 4 or more affective episodes per year, averaged over the lifetime course of the affective illness (2–4).

Depending upon the ascertainment method used in any particular study, rapid cycling syndrome has been reported in 20–84% of individuals with bipolar disorder (5–7), and may be more common in bipolar II disorder (8). It is generally associated with poor response to antidepressant and mood stabilizer therapies, and it is often thought to be precipitated by antidepressant drugs (7, 9–11), although this association has not been consistently confirmed (12–16). Most practice guidelines for treating rapid cycling bipolar disorder recommend mood stabilizer therapy as first-line treatment, either alone or in combination with an antidepressant (17–19).

In contrast, some researchers have suggested that antidepressants may promote mood stability in some rapid cycling patients with bipolar II disorder (2–4, 13, 20, 21). Several prospective, randomized controlled trials examining rapid cycling bipolar II disorder suggest that short-term and continuation antidepressant monotherapy may be as effective as mood stabilizer therapy in reducing depressive symptoms and preventing depressive relapse. without increasing the incidence of hypomanic symptoms (2–4, 22).

Recently, however, the validity of these findings has been questioned (23, 24). For example, Thase (23) suggested that recent studies showing antidepressant effectiveness in rapid cycling bipolar II disorder (2–4, 22) run counter to accepted treatment guidelines and are methodologically flawed due to the use of the lifetime average definition of rapid cycling, rather than the use of the Diagnostic and Statistical Manual Fourth Edition (DSM-IV) definition of rapid cycling.

This exploratory analysis examined the predictive validity of the DSM-IV definition of rapid cycling versus the average lifetime definition of rapid cycling in a sample of subjects with bipolar II major depressive episode who were randomized to treatment with either antidepressant or mood stabilizer monotherapy (25, 26). We hypothesized that the average lifetime definition of rapid cycling may better identify subjects with a history of more mood lability and a greater likelihood of hypomanic symptom induction during long-term treatment. We explored whether the concordance or discordance of these definitions was a predictor of depression outcomes or treatment-emergent hypomanic symptoms.

Methods

Subjects

Data for this exploratory analysis were derived from NIMH study NCT00602537 (hrrp://clinicaltrials.gov) (25, 26). Briefly, subjects ≥18 years old with a DSM-IV-TR diagnosis of bipolar II disorder and current major depressive episode with a 17-item Hamilton Rating Scale for Depression (HRSD) (27) score ≥16 were enrolled. Exclusion criteria were: history of prior mania or psychosis, a substance use disorder within the preceding three months, sensitivity or non-response to the study medications within the current episode, the presence of an unstable medical condition, or concurrent use of antidepressant or mood stabilizer medication.

Procedures

Written informed consent was obtained in accordance with the ethical standards of the Institutional Review Board (28) with oversight by the local Office of Human Research and an independent Data and Safety Monitoring Board. Psychiatric diagnosis and number of prior depressive and hypomanic episodes were ascertained using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I) (29). Subjects were classified as rapid cycling in each of two ways: (i) DSM IV defined rapid cycling with ≥ 4 affective episodes in the preceding year; and, (ii) average annual lifetime rapid cycling with the average number of major depressive plus hypomanic, and/or sub-syndromal hypomanic episodes being ≥ 4 per year over the course of the illness, as calculated by the following equation: [Total number major depressive episode + syndromal hypomanic episodes + sub-syndromal hypomanic episodes] ÷ Total illness duration (in years).

Structured 28-item HRSD (30) and Young Mania Rating Scale (30) measures were completed by a study clinician blind to treatment condition. Acute monotherapy was administered for 12 weeks with outcomes measured at baseline, and Weeks 1, 2, 4, 6, 8, 10, and 12. Venlafaxine was initiated at 37.5 mg daily and gradually increased to a maximum dose of 375 mg daily by Week 4 of treatment. Lithium was initiated at 300 mg daily and gradually increased to 1200 mg daily by Week 4 based upon a sustained serum lithium level of 0.8–1.5 mEq/L. Response to treatment was defined as a ≥50% reduction in baseline 17-item HRSD score plus a final Clinical Global Impression/Severity (CGI/S) (31) score ≤3. Responders at Week 12 were enrolled into continuation monotherapy on their established dose of double-blind medication for six additional months. Outcome measures were obtained at continuation Weeks 16, 20, 24, 30, and 36. Relapse was defined as a rise in the 17-item HSRD score ≥14 plus CGI/S score of ≥4 for ≥14 days.

Frequency of treatment-emergent syndromal and sub-syndromal hypomanic symptoms was assessed via telephone reports as well as by clinician-elicited information regarding mood conversion symptoms at each study visit, using the YMRS. In addition to DSM-IV definition of hypomania, we employed three definitions of sub-syndromal hypomania that differ in the number and duration of symptoms (2–4). Sub-syndromal episodes were defined as either (i) type I sub-syndromal hypomania with ≥ 4 symptoms lasting ≤ 3 days; (ii) type II sub-syndromal hypomania with ≤ 3 symptoms lasting ≥ 4 days; and, (iii) type III sub-syndromal hypomania with ≤ 3 symptoms lasting ≤ 3 days.

Outcome measures

For the acute phase of treatment, outcomes included the proportion of rapid cycling subjects who responded as well as the proportion of subjects who experienced DSM-IV syndromal hypomania or any sub-syndromal hypomanic episode (as described above). For the continuation phase of the study, the outcomes were the proportion of subjects experiencing depressive relapse during continuation monotherapy and the emergence of syndromal and sub-syndromal hypomanias.

Statistical procedures

Analyses were conducted according to the intent-to-treat principle on a sample size of 129 subjects during the acute phase and on a sample of 55 responders who enrolled in the continuation phase of the study, with two-sided tests of hypotheses and a p <0.05 value. Analyses were conducted using IBM SPSS v. 21 (IBM Corporation, New York, NY, USA).

Generally, our aim was to compare the predictive validity of the DSM-IV definition to the predictive validity of the lifetime average definition of rapid cycling (22). To do this, we examined four distinctions between subjects: (i) subjects who met neither definition of rapid cycling (i.e., ‘non-rapid cyclers’), (ii) subjects who met only DSM-IV defined rapid cycling (i.e., ‘DSM-only rapid cyclers’), (iii) subjects who met only lifetime-defined rapid cycling (i.e., ‘lifetime-only rapid cyclers’), and (iv) subjects who met both DSM-IV and lifetime criteria for rapid cycling i.e., (‘both definition’ rapid cyclers).

Initial analyses summarized demographic and clinical variables at baseline between the four groups. Differences in variables between rapid cycling definitions and between rapid and non-rapid cycling groups were explored using Fisher’s exact test for categorical variables and ANOVAs for continuous variables.

For tests of symptom reduction or treatment emergent sub-syndromal hypomanic episodes, we used non-rapid cyclers as a reference group against which to test the clinical outcomes of subjects who met the criteria for both definitions of rapid cycling or those who met the criteria for one definition but not the other definition of rapid cycling.

Differential response, remission, and sub-syndromal hypomanic episodes between groups were ascertained using logistic regression analyses. Hazard ratios quantifying relapse were estimated using Cox regression test. Due to the limited number of subjects who met criteria for one definition but not the other definition of rapid cycling, we did not formally test interactions with treatment. However, our results did not suggest any differences between the treatments in the effects of rapid cycling status on clinical outcomes.

Results

Enrollment

One-hundred twenty-nine subjects with bipolar II depression were enrolled. There was moderate agreement (κ = 0.56) between the two definitions of rapid cycling. Fifty-six subjects (43.4%) met DSM-IV defined criteria for rapid cycling and 60 subjects (46.5%) met lifetime defined criteria for rapid cycling. Forty-four subjects (34.10%) met criteria for both definitions; while 12 subjects met only DSM-IV rapid cycling criteria (9.3%) and 16 subjects met only the lifetime rapid cycling criteria (14.7%). Fifty-seven subjects (44.18%) met neither definition for rapid cycling.

Subjects who met criteria for both rapid cycling definitions or who only met the lifetime definition tended to have a history of more prior depressive episodes and more hypomanic episodes (Table 1). By contrast, subjects who met criteria for both rapid cycling definitions [mean (M) = 18.69, standard deviation (SD) =7.06] or who only met criteria for the DSM-IV definition (M = 19.29, SD = 9.70) were somewhat younger at the onset of hypomania relative to those who met neither criteria for rapid cycling (M = 24.36, SD = 7.10) or those meeting only lifetime criteria for rapid cycling (M = 21.05, SD = 8.62). Additionally, subjects who met criteria for both rapid cycling definitions (M = 7.75, SD = 13.75) or who only met criteria for the DSM-IV definition (M = 10.25, SD = 19.18) had somewhat briefer current depressive episodes versus subjects who only met lifetime criteria for rapid cycling (M = 16.71, SD = 15.68) or subjects who met neither criteria for rapid cycling (M = 16.18, SD = 14.66). Finally, individuals who only met the DSM-IV definition of rapid cycling had higher baseline scores on the YMRS versus subjects who met only the lifetime definition, or who met both definitions or neither definition of rapid cycling. Thus, the DSM-IV definition of rapid cycling appears to be associated with an early onset vulnerability to hypomania, brief depressive episodes, and more acute hypomanic symptoms. In contrast, the lifetime definition of rapid cycling appears to be associated with a more chronic and recurrent course of bipolar depression (Table 1).

Table 1.

Comparison of baseline variables for 129 subjects with bipolar II disorder by rapid cycling status definitions

Non-RC (n = 57) DSM-IV (n =12) Lifetime (n = 16) Both DSM-IV and Lifetime (n = 44) p-value Pairwise comparisons
n (%) n (%) n (%) n (%) χ2
Female 29 (50.9) 7 (58.3) 9 (56.3) 28 (63.6) 1.63
Non-white 12 (21.1) 4 (33.3) 1 (6.3) 9 (20.5) 1.64
Inter-episode recovery 10 (18.2) 5 (45.5) 5 (33.3) 8 (18.2) 3.57
Hypomanic symptoms 8 (14.0) 6 (50.0) 0 (0) 9 (20.5) 12.72 <0.01 Only DSM > Neither = Only lifetime, Both
Mean (SD) Mean (SD) Mean (SD) Mean (SD) F Pairwise comparisons
Age, years 45.26 (13.92) 44.75 (11.45) 43.38 (15.80) 39.05 (12.63) 1.85
Age of first MDE, years 17.20 (7.33) 19.92 (7.06) 18.46 (8.72) 18.88 (6.11) 0.75
Age of first hypomania, years 24.36 (7.10) 19.29 (9.70) 21.05 (8.62) 18.69 (7.06) 5.15 <0.001 Non-RCr > Both = DSM-IV = Lifetime
No. of prior MDEs 10.55 (16.02) 10.78 (28.25) 30.46 (20.26) 34.27 (36.69) 12.98 <0.001 Non-RC = DSM-IV < Lifetime = Both
No. of prior hypomanias 7.20 (31.56) 22.10 (53.07) 61.39 (43.86) 75.96 (35.25) 31.85 <0.001 Non-RC = DSM-IV < Lifetime = Both
Duration current MDE (months) 16.18 (14.66) 10.25 (19.18) 16.71 (15.68) 7.75 (13.75) 3.23 <0.05
HRSD score 19.93 (3.96) 18.42 (3.45) 20.38 (3.28) 20.70 (3.80) 1.23
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Non-RC = non-rapid cycling definition; MDE = major depressive episodes; HRSD = Hamilton Rating Scale for Depression; YMRS = Young Mania Rating Scale.

Effectiveness

Acute treatment

Overall, 66 subjects (51.2%) met criteria for response: 36 with DSM-IV defined rapid cycling (52.2%) and 30 subjects with lifetime defined rapid cycling (50.0%). Lifetime rapid cycling status was not a predictor of overall response, with 30 rapid cyclers (50.0%) and 36 non-rapid cyclers (52.2%) meeting response criteria (p = 0.86, Fisher’s exact test). Similarly, DSM-IV defined rapid cycling did not significantly predict response. Overall, 51.8% of DSM-IV defined rapid cyclers versus 50.7% of DSM-IV defined non-rapid cyclers met criteria for response (p = 0.52, Fisher’s exact test). Venlafaxine produced an overall response rate of 67.7%, irrespective of whether subjects met DSM-IV defined or lifetime defined rapid cycling criteria (75.8% and 59.4%, respectively; p = 0.19, Fisher’s exact test). Lithium produced an overall response rate of 34.4%, irrespective of whether subjects met DSM-IV defined or lifetime defined rapid cycling criteria (30.6% and 39.3%, respectively) (p = 0.60, Fisher’s exact test). Examining the rates of response between those who met neither definition of rapid cycling, who met both definitions, or who met one but not the other definition of rapid cycling revealed a similar pattern (Table 2). Thus, there was no indication that either rapid cycling definition, independently or jointly, predicted a lower response rate relative to non-rapid cycling status. Similar findings were obtained when using remission criteria as the outcome variable (Table 2).

Table 2.

Comparison of outcomes during acute (n = 129) and continuation (n = 55) treatment for subjects with bipolar II depression by rapid cycling status definitions

Non-RC (n = 57) DSM-IV (n = 12) Lifetime (n = 16) Both DSM-IV and Lifetime (n = 44) p-value
n (%) n (%) n (%) n (%)
Response 28 (49.12) 8 (66.67) 9 (56.25) 21 (47.73) >0.28a
Remission 24 (42.11) 6 (50.00) 7 (43.75) 19 (43.18) >0.62a
Hypomanic symptoms 4 (7.02) 0 (0) 1 (6.25) 2 (4.55) >0.61a
Any hypomanic symptoms + sub-syndromal hypomanic episodes 14 (24.56) 3 (25.00) 5 (31.25) 10 (22.73) >0.59a
(n = 24) (n = 7) (n = 6) (n = 18)
Relapse 4 (16.67) 0 (0) 2 (33.33) 1 (5.56) >0.34b
Any sub-syndromal hypomanic episodes 0 (0) 0 (0) 1 (16.67) 5 (27.78) >0.99a
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Non-RC = non-rapid cycling definition.

p-values from logistic regression using participants who met for neither definition as reference group.

b

p-values from Cox regression using participants who met for neither definition as reference group.

Continuation treatment

Fifty five responders to acute treatment (83%) were enrolled into the continuation phase of the study. Compared to the relapse rate among non-rapid cycling subjects (16.7%, n = 24), relapse rates were not significantly different among rapid cycling subjects who met only the DSM-IV definition (0%, n = 7; χ2 = 0.00, p = 0.99), subjects who met only the lifetime definition (33%, n = 6; χ2 = 0.66, p = 0.42), or subjects who met criteria for both definitions (5.6%, n = 18; χ2 = 0.91, p = 0.34).

Hypomanic symptoms

Acute treatment

Compared to the rate of treatment-emergent hypomanic symptoms (ascertained by YMRS) in non-rapid cycling subjects (7.02%), rates of hypomanic symptoms were not significantly different in rapid cycling subjects who met only the DSM-IV definition (0%, χ2 = 0.00, p > 0.99), subjects who met only the lifetime definition (6.25%, χ2 = 0.01, p = 0.92), or subjects who met criteria for both definitions (5.6%, χ2 = 0.27, p = 0.61). When the frequency of treatment-emergent sub-syndromal hypomanic episodes was examined, there were no significant differences between non-rapid cycling subjects (24.56%) and rapid cycling subjects who met only the DSM-IV definition (25%, χ2 = 0.73, p = 0.97), subjects who met only the lifetime definition (31.25%, χ2= 0.29, p = 0.59), or subjects who met criteria for both definitions (22.73%, χ2 = 0.05, p = 0.83). There were also no differences between treatment conditions in the rates of treatment-emergent hypomanic symptoms or sub-syndromal hypomanic episodes.

Continuation treatment

No syndromal hypomanic episodes occurred during the continuation phase of the study. Sub-syndromal hypomanic episodes occurred exclusively among subjects meeting lifetime defined rapid cycling criteria. The rates of sub-syndromal hypomanic episodes were 0.0% for non-rapid cycling subjects, 0.0% for subjects who met only DSM-IV defined rapid cycling, 16.7% for subjects who met only lifetime defined rapid cycling, and 27.8% for subjects who met both definitions for rapid cycling.

Discussion

We explored the ability of the DSM-IV definition of rapid cycling versus the average lifetime definition of rapid cycling to predict depressive and hypomanic episodes in a sample of subjects with bipolar II depression who were randomized to treatment with either antidepressant or mood stabilizer monotherapy. Most prior studies of rapid cycling bipolar disorder over the past three decades have used DSM-IV criteria of ≥4 affective episodes in the preceding 12 months. This definition was arbitrary in nature with no comparative information available on other definitions of rapid cycling bipolar disorder (12, 32). It was not based upon prospective controlled comparative trials that validated the definition of ≥4 episodes per year in the preceding 12 months as the best diagnostic criteria; nor was it based upon comparison of studies of rapid cycling disorder defined by other episode frequencies. Moreover, the DSM-IV rapid cycling definition was limited to the preceding 12 months and may not have accurately characterize the ‘real world’ nature of rapid cycling disorder (if, indeed, it is a distinct specifier of bipolar disorder). In this regard, rapid cycling may be more frequent in younger individuals (8, 33) with diminishing frequency in older age; and, rapid cycling may be intermittent in character or present for years, but absent in the preceding 12 months. Thus, a rapid cycling individual without at least four affective episodes in the preceding year would not meet the conventional DSM-IV definition of rapid cycling.

To avoid this, we employed the definition of an average of ≥ 4 episodes per year over the lifetime course of the illness (2–4, 22). This definition was designed to capture individuals who had more chronic histories of rapid mood cycling. It comports more closely with ‘real world’ characterization of the rapid cycling syndrome, especially in bipolar II disorder where the symptom course may be either intermittent or continuous for years, but absent in the preceding 12 months. One naturalistic study of 109 bipolar patients followed up to 36 years reported that one-third of rapid cycling patients recovered from rapid cycling syndrome (14); while another prospective study (15) reported the presence of rapid cycling status in 51% of patients taking an antidepressant, with a spontaneous recovery rate of 37% during antidepressant use. Thus, some experts have suggested changes to the definition of rapid cycling that expand the time frame beyond the preceding 12 months (14) and some research suggests greater predictive validity of the DSM-IV definition of rapid cycling in individuals with severe manic symptoms (34) or with more mood conversion episodes in the preceding year than the DSM-IV definition requires (32).

Our results suggest few differences between the average lifetime and DSM-IV definition of rapid cycling; although the lifetime definition was somewhat superior in identifying subjects with sub-syndromal hypomanic episodes over time. The DSM-IV definition appeared contaminated with severity of current hypomanic symptoms.

Several caveats should be considered when interpreting the present findings. This study was exploratory in nature and not specifically powered to detect statistically significant differences in effectiveness or mood conversion rates between different definitions of rapid cycling. It was limited to subjects with bipolar II disorder and was based upon data derived from a single site study. It is possible that our results would be different if we included subjects with bipolar I disorder or if our sample size was substantially larger. In this regard, however, we would also note that this study may represent one of the largest sample sizes of bipolar II subjects studied to date that examined different definitions of rapid cycling.

In particular, we note that the number of patients fitting one definition and not the other is limited, and this makes comparison between definitions difficult. Thus, our analyses, especially in the continuation phase of the study, should be interpreted with caution. While we note that the kappa statistic suggests a moderate level of agreement between rapid cycling definitions, it also implies a certain degree of difference between the definitions. However, we acknowledge that the limited sample size makes a definitive assessment of the difference in predictive validity of outcomes difficult. Our current analyses may thus be taken to suggest that if differences exist between the definitions they are likely not large.

We would note that the results of this exploratory analysis are not definitive. The failure to identify a significant difference between the two defined rapid cycling groups does not mean that differences do not exist. Larger sample sizes would be needed to detect small differences in effectiveness and mood conversion rates between groups.

We note that our definition of rapid cycling was based upon an average lifetime frequency of ≥4 episodes per year over the course of the illness, and that this definition is as arbitrary as that of the DSM IV definition. It is also possible that the frequency of treatment-emergent manic symptoms during acute and continuation monotherapy in the current study may have differed between rapid cycling groups had we studied subjects with bipolar I disorder or subjects administered other antidepressant therapies.

Finally, we note that a lower maximum daily dose of venlafaxine may have produced fewer hypomanic symptoms; however, the overall rate of treatment-emergent hypomanic symptoms was similar in both the venlafaxine and lithium conditions. Moreover, the relatively low mood conversion rate among both definition groups may have resulted from the inclusion of more mildly ill individuals with a lower propensity for antidepressant-induced hypomanic symptoms. Future work should further explore diagnostic and other predictors of effectiveness and hypomania in larger populations of subjects with rapid and non-rapid cycling bipolar II disorder.

Conclusions

Although not definitive, results from this study comport with findings from our prior trials (22) and suggest that rapid cycling status does not predict poor response to either venlafaxine or lithium monotherapy, irrespective of the definition used to categorize rapid cycling syndrome. Moreover, the results suggest that the lifetime definition of rapid cycling may be more valid in characterizing the syndrome in that it was superior in predicting sub-syndromal hypomanic episodes and was not contaminated by current hypomanic symptoms.

Acknowledgments

This research was supported by NIMH grant MH060353. Additional support for the preparation of this manuscript was provided by NIH grant MH080097 and The Jack Warsaw Fund for Research in Biological Psychiatry of the University of Pennsylvania Medical Center. Results from this study have not been previously presented in abstract form, and are not under consideration for publication elsewhere.

Footnotes

The clinicalTrials.gov identifier for the study is BPII NCT00602537

Disclosures

The authors of this paper are not members of any pharmaceutical industry-sponsored advisory board or speaker’s bureau, and have no financial interest in any pharmaceutical or medical device company.

References

  • 1.American Psychiatric Association (APA) Diagnostic and statistical manual of mental disorders. 5. Arlington, VA: American Psychiatric Publishing; 2013. [Google Scholar]
  • 2.Amsterdam JD, Wang C-H, Shwarz M, Shults J. Venlafaxine versus lithium monotherapy of rapid and non-rapid cycling patients with bipolar II major depressive episode: A randomized, parallel group, open-label trial. J Affect Disord. 2009;112(1–3):219–30. doi: 10.1016/j.jad.2008.03.029. [DOI] [PubMed] [Google Scholar]
  • 3.Amsterdam JD, Luo L, Shults J. Efficacy and mood conversion rate during long-term fluoxetine v lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. Br J Psychiatry. 2012;202:301–6. doi: 10.1192/bjp.bp.111.104711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Amsterdam JD, Luo L, Shults J. Effectiveness and mood conversion rate of short-term fluoxetine monotherapy in patients with rapid cycling bipolar II depression versus patients with nonrapid cycling bipolar II depression. J Clin Psychopharm. 2013;33(3):420–4. doi: 10.1097/JCP.0b013e31828ea89e. [DOI] [PubMed] [Google Scholar]
  • 5.Ghaemi SN, Rosenquist KJ, Ko JY, Baldassano CF, Kontos NJ, Baldessarini RJ. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry. 2004;161:163–5. doi: 10.1176/appi.ajp.161.1.163. [DOI] [PubMed] [Google Scholar]
  • 6.Goodwin FK, Ghaemi SN. Understanding manic-depressive illness. Archiv Genl Psychiatry. 1998;55:23–5. doi: 10.1001/archpsyc.55.1.23. [DOI] [PubMed] [Google Scholar]
  • 7.Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5:407–420. doi: 10.1046/j.1399-5618.2003.00067.x. [DOI] [PubMed] [Google Scholar]
  • 8.Maj M, Pirozzi R, Formicola AM, Tortorella A. Reliability and validity of four alternative definitions of rapid-cycling bipolar disorder. Am J Psychiatry. 1999;156:1421–24. doi: 10.1176/ajp.156.9.1421. [DOI] [PubMed] [Google Scholar]
  • 9.Goldberg JF, Ghaemi SN. Benefits and limitations of antidepressants and traditional mood stabilizers for treatment of bipolar depression. Bipolar Disord. 2005;7(Suppl 5):3–12. doi: 10.1111/j.1399-5618.2005.00251.x. [DOI] [PubMed] [Google Scholar]
  • 10.Leverich GS, Altshuler LL, Frye MA, Suppes T, McElroy SL, Keck PE, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry. 2006;163(2):232–9. doi: 10.1176/appi.ajp.163.2.232. [DOI] [PubMed] [Google Scholar]
  • 11.Ghaemi SN. Treatment of rapid-cycling bipolar disorder: Are antidepressants mood destabilizers? Am J Psychiatry. 2008;165(3):300–2. doi: 10.1176/appi.ajp.2007.07121931. [DOI] [PubMed] [Google Scholar]
  • 12.Grunze HC. Switching, induction of rapid cycling, and increased suicidality with antidepressants in bipolar patients: Fact or overinterpretation? CNS Spectr. 2008;13(09):790–5. doi: 10.1017/s1092852900013912. [DOI] [PubMed] [Google Scholar]
  • 13.Parker G, Tully L, Olley A, Hadzi-Pavlovic D. SSRIs as mood stabilizers for bipolar II disorder? A proof of concept study. J Affect Disord. 2006;92(2–3):205–14. doi: 10.1016/j.jad.2006.01.024. [DOI] [PubMed] [Google Scholar]
  • 14.Koukopoulos A, Sani G, Koukopoulos AE, Minnai GP, Girardi P, Pani L, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord. 2003;73(1–2):75–85. doi: 10.1016/s0165-0327(02)00321-x. [DOI] [PubMed] [Google Scholar]
  • 15.Wehr TA, Sack DA, Rosenthal NE, Cowdry RW. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry. 1988;145(2):179–84. doi: 10.1176/ajp.145.2.179. [DOI] [PubMed] [Google Scholar]
  • 16.Kupfer DJ, Chengappa KNR, Gelenberg AJ, Hirschfeld RMA, Goldberg JF, Sachs GS, et al. Citalopram as adjunctive therapy in bipolar depression. J Clin Psychiatry. 2001;62(12):985–90. doi: 10.4088/jcp.v62n1212. [DOI] [PubMed] [Google Scholar]
  • 17.Frances AJ, Kahn DA, Carpenter D, Docherty JP, Donovan SL. The Expert Consensus Guidelines for treating depression in bipolar disorder. J Clin Psychiatry. 1997;59:73–9. [PubMed] [Google Scholar]
  • 18.Bauer MS, Callahan AM, Jampala C, Petty F, Sajatovic M, Schaefer V, et al. Clinical practice guidelines for bipolar disorder from the Department of Veterans Affairs. J Clin Psychiatry. 1999;60(1):9–21. doi: 10.4088/jcp.v60n0104. [DOI] [PubMed] [Google Scholar]
  • 19.Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013;170(11):1249–62. doi: 10.1176/appi.ajp.2013.13020185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Parker G, Parker K. Which antidepressants flick the switch? Austral New Zealand J Psychiatry. 2003;37(4):464–8. doi: 10.1046/j.1440-1614.2003.01207.x. [DOI] [PubMed] [Google Scholar]
  • 21.Parker G. Managing bipolar II disorder: some personal perspectives. Austral Psychiat. 2015:116–119. doi: 10.1177/1039856214568219. [DOI] [PubMed] [Google Scholar]
  • 22.Lorenzo-Luaces L, Amsterdam J, Soeller I, DeRubeis R. Rapid versus non-rapid cycling bipolar II depression: response to venlafaxine and lithium and hypomanic risk. Acta Psychiatrica Scandinavica. 2016:459–469. doi: 10.1111/acps.12557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Thase ME. Antidepressants and rapid-cycling bipolar II disorder: dogma, definitions and deconstructing discrepant data. Br J Psychiatry. 2013;202(4):251–2. doi: 10.1192/bjp.bp.112.120550. [DOI] [PubMed] [Google Scholar]
  • 24.Eppel AB. Antidepressants in rapid-cycling bipolar disorder. Br J Psychiatry. 2013;203:75. doi: 10.1192/bjp.203.1.75. [DOI] [PubMed] [Google Scholar]
  • 25.Amsterdam JD, Lorenzo-Luaces L, Soeller I, Li SQ, Mao JJ, DeRubeis RJ. Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study. J Affect Disord. 2015;185:31–7. doi: 10.1016/j.jad.2015.05.070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Amsterdam JD, Lorenzo-Luaces L, Soeller I, Li SQ, Mao JJ, DeRubeis RJ. Effectiveness and mood conversions in short-term venlafaxine versus lithium monotherapy of bipolar type II major depressive episode: A randomized, double-blind, prospective study. Br J Psychiatry. 2016;2008:359–365. doi: 10.1192/bjp.bp.115.169375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Williams JBW. A structured interview guide for the Hamilton Depression Rating Scale. Arch Gen Psychiatry. 1988;45(8):742–7. doi: 10.1001/archpsyc.1988.01800320058007. [DOI] [PubMed] [Google Scholar]
  • 28.International Conference on Harmonisation Working Group. Wiley Encyclopedia of Clinical Trials. Wiley-Blackwell; 1994. International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.First MB, Spitzer RL, Gibbon M, Williams JB. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, research version, patient edition with psychotic screen (SCID-I/P W/PSY SCREEN) New York, NY: Biometrics Research, New York State Psychiatric Institute; 2001. [Google Scholar]
  • 30.Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Brit J Psychiatry. 1978;133(5):429–35. doi: 10.1192/bjp.133.5.429. [DOI] [PubMed] [Google Scholar]
  • 31.Guy W. ECDEU assessment manual for psychopharmacology. US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. [Google Scholar]
  • 32.Kupka RW, Luckenbaugh DA, Post RM, Suppes T, Altshuler LL, Keck PE, Jr, et al. Comparison of rapid-cycling and non-rapid-cycling bipolar disorder based on prospective mood ratings in 539 outpatients. Am J Psychiatry. 2005;162(7):1273–80. doi: 10.1176/appi.ajp.162.7.1273. [DOI] [PubMed] [Google Scholar]
  • 33.Coryell W, Solomon D, Turvey C, Keller M, Leon AC, Endicott J, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry. 2003;60(9):914–20. doi: 10.1001/archpsyc.60.9.914. [DOI] [PubMed] [Google Scholar]
  • 34.Bowden CL, Calabrese JR, McElroy SL, Rhodes LJ, Keck PE, Jr, Cookson J, et al. The efficacy of lamotrigine in rapid cycling and non–rapid cycling patients with bipolar disorder. Biol Psychiatry. 1999;45(8):953–958. doi: 10.1016/s0006-3223(99)00013-x. [DOI] [PubMed] [Google Scholar]

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