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Short-term antidepressant treatment of bipolar depression: Are ISBD recommendations useful in clinical practice?
Journal of Affective Disorders 171 (2015) 155–160
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Short-term antidepressant treatment of bipolar depression: Are ISBD recommendations useful in clinical practice? Antonio Tundo a,n, Joseph R Calabrese b, Luca Proietti a, Rocco de Filippis a a b
Istituto di Psicopatologia, Roma, Italy Department of Psychiatry, University Hospital Case Medical Center, Case Western Reserve University, Cleveland, OH, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 22 May 2014 Received in revised form 13 September 2014 Accepted 18 September 2014 Available online 28 September 2014
Objectives: The study aimed to test the effectiveness of the ISBD Guidelines for short-term AD treatment of BP depression. Methods: The study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). Response was defined as a HDRS21 total scoreo 7 at 12 weeks of treatment and remission as a Z50% reduction of baseline HDRS21 total score sustained for 8 weeks. Results: Response was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with BP-II disorder without significant differences (χ² ¼ 3.0, p¼0.219). The remission rate did not differ significantly among groups (χ² ¼3.8, p ¼0.151). The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (χ² ¼10.1, p¼ 0.006). Concerning AD safety, one patient with BP-I depression committed a suicide attempt and ADemerging switch was observed in 2.9% of patients, 2 with BP-I and 1 with BP-II disorder. Limitations: The observational nature of the study and unblinded outcomes assessment. Conclusions: Our findings confirm the usefulness of ISBD Guidelines for short-term AD treatment of BP depression. These patients appear to have similar response and remission rate to those observed in UP depression and do not exhibit significant switch rates or risk of suicide. Our results are limited to patients with pure bipolar depression (excluding those with broadly defined mixed states), treated with ADsmood stabilizers combination. We suggest to partially modify ISBD Recommendations 1 and 4, to include potential responders and to improve safety. & 2014 Published by Elsevier B.V.
Keywords: Antidepressants Bipolar depression Short-term treatment
1. Introduction Major depression episodes are the most frequent presentation of bipolar disorder (Judd et al., 2002, 2003) and are associated with high morbidity and mortality (mostly suicidality), and disruption of patients' daily functioning (Calabrese et al., 2004; Vazquez et al., 2013). Despite the high prevalence and clinical significance of this condition, the treatment of bipolar depression remains controversial. In particular, evidence on short-term efficacy and safety of antidepressants (ADs), the prevalent treatment in everyday clinical practice (Baldessarini et al., 2007), is surprisingly scanty and inconclusive. Two meta-analyses on this topic have reached opposite conclusions regarding the superiority of ADs over placebo in treatment of acute bipolar depression (Gijsman et al., 2004; Sidor and MacQueen, 2011). Similarly, two naturalistic studies directly comparing the response rate to ADs in bipolar and unipolar depression provided divergent
n
Corresponding author. Tel.: þ 39 063610955; fax þ39 0636002828. E-mail address: [email protected] (A. Tundo).
http://dx.doi.org/10.1016/j.jad.2014.09.019 0165-0327/& 2014 Published by Elsevier B.V.
results (Ghaemi et al., 2004; Tondo et al., 2013). In addition, there is conflicting evidence on AD safety in bipolar disorders in terms of the risk of induced switch and linked cycle acceleration, as well as suicidality (Truman et al., 2007; Leon et al., 2011; Amit and Weizman, 2012; Yerevanian and Choi, 2013). Given the clinical importance of this topic and the inconsistency of experimental evidence, the International Society for Bipolar Disorder's (ISBD) task force recently provided 12 consensus recommendations on AD use in bipolar disorders, 10 of which can be applied for short-term treatment of bipolar depression (Pacchiarotti et al., 2013). In short: ADs may be used in BP-I or BP-II depression in patients with a history of previous positive response to ADs (Recommendation Number 1); Serotonin-norepinephrine reuptake inhibitors or tri- and tetracyclics should be considered only after other antidepressants have been tried (Recommendation Number 12);
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In patients with BP-I disorder, ADs should be prescribed with a mood stabilizer (Recommendation Number 4); AD should be avoided in patients with mixed states, i.e. a depressive episode with two or more concomitant core manic symptoms in the presence of psychomotor agitation, during manic or depressive episodes with mixed features, a previous course with predominantly mixed state (Recommendations Numbers 2, 9, 10 and 11), in patients with high mood instability or rapid cycling (Recommendation Number 8), and in patients with a history of past mania, hypomania, or mixed episodes emerging during AD treatment (Recommendation Number 7) Patients treated with ADs should be closely monitored for signs of hypomania or mania and increased psychomotor agitation, in which case ADs should be discontinued (Recommendation Number 6). These recommendations have been formulated by clinical and academic experts based on their own experience and judgment guided by the scanty available research findings but, to the best of our knowledge, no study has verified their effectiveness in clinical practice.
1.1. Aims of the study The aim of the present study was to test the effectiveness of the ISBD Guidelines for short-term AD treatment of bipolar depression in a clinical sample. We partially adapted the ISBD Recommendations Numbers 1 and 4 according to our experience, with the aim to extend the indications for ADs and to improve ADs safety (see Section 2). Our hypothesis is that when the above-mentioned ISBD recommendations are followed, ADs are effective and safe in BP-I and BP-II depression as well as in unipolar depression.
2. Material and methods 2.1. Participants This observational study includes consecutive patients seen from January 2005 to December 2009 at the Istituto di Psicopatologia in Rome, Italy. Inclusion criteria were: (1) age 18–75 years; (2) meeting DSM-IV diagnostic criteria for recurrent major depressive disorder (unipolar depression), or for bipolar I or bipolar II disorder (American Psychiatric Association (APA), 1994); (3) meeting DSM-IV criteria for a current major depressive episode (MDE) (APA, 1994); and (4) a 21-item Hamilton Depression Rating Scale [HDRS21 (Hamilton, 1960)] total score Z 14 at intake. Only the first observed MDE (index depressive episode) was considered for patients experiencing more than one MDE during the observation period. Exclusion criteria were: (1) meeting DSM-IV diagnostic criteria for rapid-cycling bipolar disorder (APA, 1994), (2) broadly defined mixed state (manic, hypomanic or depressive episodes with mixed features, depressive episodes with two or more concomitant core manic symptoms in the presence of psychomotor agitation), (3) high mood instability, (4) previous course with predominantly mixed states, and (5) a history of past manic, hypomanic or mixed episodes emerging within 8 weeks after introducing an AD [ISBD nomenclature task force criteria for treatment-emerging switch (Tohen et al., 2009)]. Partially in contrast with ISBD Recommendation Number 1, we did not exclude all patients with a history of previous AD non-response, but only patients with unipolar and bipolar chronic depressions, defined according to DSM IV criteria as a depressive episode lasting at least 2 years (APA, 1994).
Written informed consent for the anonymous use of clinical records was collected routinely at each patient's first visit. A local ethical committee approved the study procedures. 2.2. Assessments All subjects were evaluated, treated, and followed by the first author (AT), an experienced psychiatrist specialized in mood disorders. Initial diagnostic assessments were based on semistructured interviews to assess the presence of DSM-IV criteria for mood disorders. About 30% of subjects underwent full, structured, SCID-I based diagnostic assessment (First et al., 1996), to confirm the results of semi-structured clinical examinations. During the first visit, demographic (gender, age, marital status, education level, and employment status) and clinical characteristics were collected, including age at onset, duration of illness, number of previous episodes, delusional episodes of any polarity, occurrence of switch to mania or hypomania, lifetime Axis I comorbidities, hospital admissions, suicide attempts, alcohol and/or drug use. When possible, data collected from patients were corroborated with information obtained from other informants as well as any available previous medical records. At intake and at each follow-up visit, typically every 1–4 weeks for the first 3 months and every 1–2 months thereafter, depressive symptoms were assessed using HDRS21. 2.3. Treatments Treatment was chosen by the first author (AT) based on clinical experience and in line with recent ISBD recommendations. All study participants were treated with one or more antidepressants. Serotonin-norepinephrine reuptake inhibitors (SNRI) and tri- and tetracyclics (TCA) were prescribed only after other ADs had been tried. In some contrast to ISBD recommendations, patients with either BP-I or BP-II disorder were treated with one or more mood stabilizer(s). Mood stabilizers included lithium carbonate, valproate, carbamazepine, and the atypical antipsychotics (olanzapine, aripiprazole, quetiapine). Patients were closely monitored for signs of hypomania, mania, or increased psychomotor agitation, in which case the ADs were discontinued. 2.4. Outcome measures Primary outcomes were remission and response and the temporal trend of HDRS21 total score over the 12 weeks of treatment. Secondary outcome was safety, i.e. suicide attempts and AD-emerging switch. Remission was defined as a HDRS21 total scoreo7 at 12 weeks of treatment and response as aZ50% reduction of baseline HDRS21 total score sustained for 8 weeks. This criterion is more conservative than the one suggested by ISBD Task Force report on the nomenclature of course and outcome in bipolar disorders, requiring that the remission/response criteria be met after 2–4 weeks (Tohen et al., 2009). AD-emergent switch was defined as a manic, hypomanic or mixed episodes occurring within 8 weeks from the beginning of AD treatment (Tohen et al., 2009). Patients with an AD-emergent switch in the first 8 weeks of treatment were considered nonresponders/remitters. 2.5. Statistical analysis Baseline demographic and clinical characteristics were compared among patients groups using χ² test, analysis of variance or Kruskal– Wallis test, depending on the level of measurement and the distribution of the characteristic of interest. Following significant tests, post-hoc pairwise comparisons were performed using Bonferroni correction to the probability level. The two primary outcomes
A. Tundo et al. / Journal of Affective Disorders 171 (2015) 155–160
(50% reduction of baseline HDRS21, HDRS21 scoreo7 at 12 weeks) were analyzed separately and compared among patient groups using the χ² test. Logistic regression analyses were also carried out to compare the outcomes among patient groups after controlling for age, gender, comorbidity and baseline HDRS21 total score. The significance level was set at po0.05. The temporal trend of the HDRS21 total score was examined in the study groups using a mixed-effect analysis and controlling for the effect of gender, age, comorbidity, and HDRS21 total score. All the analyses were carried out using IBM SPSS, version 20.0.
3. Results One hundred and forty seven (36%) out of the 402 patients initially considered were excluded because they had a diagnosis of rapid cycling bipolar disorder (N¼16, 4.3%), chronic depression (N¼ 32, 7.9%), or the presence of broadly defined mixed states regardless of the formal diagnosis (N¼ 99, 26.7%). The study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). The demographic and clinical characteristics of the diagnostic groups are provided in Table 1. Patients with BP-I disorder were significantly more likely to be single and younger, and had an earlier onset of illness. In addition, they were more likely to have had a past suicide attempt (26.5% in BP-I, 13.5% in BP-II, 3.9% in UP patients; χ²¼21.6, po0.001) and a prior hospitalization. Compared with the UP or BP-II groups, those with BP-I had less Axis I comorbidity, mostly panic disorder (UP 39.0%, BP-I 6.1%, BP-II 17.3%; χ²¼23.6, po0.001), but were more likely to experience delusions, predominantly during mania. Compared with the other diagnostic groups, patients with BPII disorder had significantly more previous MDEs. Mood switching was present only in patients with bipolar disorder. At intake, the HDRS21 total score was higher in patients with BP-I than UP disorder. Table 2 shows the AD treatment data. Significant differences among groups included the more frequent use of SSRI in BP-I than in BP-II and UP patients, and a higher dosage of TCA in UP and BPII compared with BP-I. No other significant differences among the three groups were found in terms of other antidepressants, doses, and combination strategies. The mood stabilizer(s) that were used in association with ADs in bipolar patients were: lithium (6.9%), anticonvulsant (48.5%), lithium and anticonvulsant (25.7%), two or more anticonvulsants (3%), atypical antipsychotics with or without lithium or anticonvulsant (15.9%).
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3.1. Response and remission Thirty-three (12.9%) of the 255 participants dropped out during the study. The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (χ²¼10.1, p¼0.006). In 4 patients with UP depression, response lasted less than 8 weeks and in two of them remission was not sustained. Moreover, 3 patients, 2 with BP-I and 1 with BP-II disorder, experienced a manic (N¼1) or hypomanic (N¼ 2) switch during the first 8 weeks of AD treatment. Response to treatment (Z 50% reduction of baseline HDRS21 total score) was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with bipolar-II disorder. The difference among the three groups was not significant (χ²¼3.0, p¼0.219). Remission (HDRS21 total scoreo7) was achieved in a lower percentage of patients with UP disorder (51.3%) compared with patients with BP-I (61.2%) and BP-II disorder (65.4%), but again the difference among groups failed to reach statistical significance (χ²¼3.8, p¼0.151). Logistic regression analyses, adjusted for age, gender, comorbidity and baseline HDRS21 total score, confirmed that response and remission rates were similar across the three diagnostic categories. 3.2. Trend of HDRS scores Fig. 1 shows the estimated temporal trend of the HDRS21 total score over the 12 weeks of treatment by diagnosis. The temporal trend did not differ significantly among the three diagnostic groups. 3.3. Safety Concerning AD safety, one patient with BP-I depression committed a suicide attempt and AD-emerging switch was observed in 3 patients (2.9% of the bipolar sample), 2 with BP-I and 1 with BPII disorder. Patients with UP disorder had no AD-induced switch or suicide attempt.
4. Discussion To the best of our knowledge, this is the first study evaluating the effectiveness and safety of short term AD treatment of bipolar depression in a clinical sample selected and treated according to the ISBD Guidelines (Pacchiarotti et al., 2013). Our findings show that
Table 1 Demographic and clinical characteristics of study participants (N ¼ 255). Variable
UP (n¼ 154)
BP-I (n¼ 49)
BP-II (n¼ 52)
F or chi-square
p-Value
Post-hoc tests
Age at baseline (yrs), mean (SD) Men, N (%) Married, N (%) Education (yrs). Mean (SD) Employed full time, N (%) Age of onset (yrs), mean (SD) Total months of illness before intake, mean (SD) Previous MDE's, mean (SD) Delusional episodes (any polarity), N (%) Suicidal act, N (%) Hospital admission, N (%) Mood switch, N (%)
48.8 35 112 12.9 81 38.5 128.8 3.8 0 6 7 0
41.8 19 27 13.4 28 29.8 142.5 3.4 44 13 25 20
(12.8) (38.8) (55.1) (3.0) (57.1) (12.0) (131.4) (5.9) (89.7) (26.5) (51) (40.8)
46.6 18 35 12.8 32 32.8 166.3 6.7 3 7 5 21
(13.2) (34.6) (67.3) (2.7) (61.5) (12.9) (126.3) (7.8) (5.8) (13.5) (9.6) (40.4)
4.675 6.0 12.1 0.594 3.8 8.296 1.882 5.711 210.9 21.6 65.9 74.5
o 0.05 o 0.05 o 0.05 0.55 0.43 o 0.001 0.154 o 0.0.001 o 0.001 o 0.001 o 0.001 o 0.001
UP 4BP-I UP oBP-I & BP-II UP 4BP-I
(42.9) (8.2) (8.1) (2.8)
29 6 1 19.9
(55.8) (11.5) (1.9) (2.5)
(14.7) (22.7) (72.7) (3.3) (52.6) (15.1) (115.2) (4.9) (0) (3.9) (4.5) (0)
UP 4BP-I BP-I I4UP UP oBP-II oBP-I UP oBP-II oBP-I UP oBP-II oBP-I BP-I & BP-II 4UP
Lifetime comorbidity Axis I, N (%) Alcohol abuse, N (%) Substance use, N (%) HDRS 21 at intake, mean (SD)
102 5 2 19.9
(66.2) (3.2) (1.2) (2.9)
21 4 4 21.0
Abbreviations: UP ¼ recurrent unipolar depression; BPI ¼ bipolar I depression; BPII ¼ bipolar II depression.
9.9 5.4 5.4 3.007
o 0.05 0.07 0.07 0.05
UP 4BP-I
UP 4BPI
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Table 2 Antidepressant treatment in unipolar (UP; N ¼ 154), bipolar-I (BP-I; N ¼ 49), and bipolar II (BP-II; N ¼ 52) depressed patients*. Drug
UP (n ¼ 154) N (%)
BP-I (n¼ 49) N (%)
BP-II (n¼ 52) N (%)
Chisquare
pPost-hoc tests UP (n¼ 154) BP-I (n ¼ 49) Value Mean dose Mean dose (SD) (SD)
SSRI
113 (73.4) 46 (93.9)
36 (69.2)
10.6
5 28 5 16
0.9 3.8 2.5 3.376
0.005 BP-I 4 UP & BP-II 0.384 0.151 0.280 0.497
Venlafaxine TCA Othersb Two AD's of a different class
20 67 13 59
(13.0) 3 (6.1) (43.5) 17 (34.7) (8.4) 8 (16.3) (38.3) 17 (34.7)
(9.6) (53.8) (9.6) (30.8)
BP-II (n¼ 52) Mean dose (SD)
F
p-Value
Post-hoc tests
33.1 (13.5)a
40.1 (23.8)
38.6 (20.4)
3.1 o 0.05
187.5 (78.8) 123.1 (49.3)
175.0 (43.3) 81.6 (30.6)
255 (67.1) 133.0 (65.1)
1.8 p¼ 0.188 5.7 o 0.004 BP Io UP & BP- II
no post-hoc difference
Abbreviations: UP ¼ Recurrent unipolar depression; BPI ¼ bipolar I depressio; BPII ¼ bipolar II depression. SSRI¼ Selective serotonin reuptake inhibitor; SNRI ¼ Serotonin-norepinephrine reuptake inhibitor; TCA ¼ Tricyclic. n
a b
Per cent totals do not equal 100as participants could be on more than one medication. Fluoxetine-equivalent; \widehat\widehat Imipramine-equivalent. Mirtazapine, Mianserine, Bupropion.
25 Unip
HDRS score
20
Bip-I
15
Bip-II
10 5 0
baseline
4
8
12
Weeks Fig. 1. Temporal trend of the HDRS over the 12 weeks of treatment by diagnosis. Results from mixed-effects linear regression.
neither response or remission rates to 12 weeks of AD treatment, nor the temporal trend of HDRS scores, differed significantly among patients with BP-I, BP-II and UP depression. However, response and remission were more sustained in patients with BP than UP disorder. With regards to safety, 1 patient with BP depression attempted suicide and 3 had an AD-emergent switch. Suicide behavior and AD-emergent switch were absent in patients with UP depression. The two samples show that BP patients were more prone to mood switch and suicidality than UP patients. Previous mood switching was about 40% in BP-I and II, 0% in UP patients; previous suicidal attempts were 26.5% in BP-I, 13.5% in BP-II, 3.9% in UP patients. From a clinical perspective, the use of ADs in our patients with BP depression appeared to be safe and effective. Nevertheless, clinicians should keep in mind that these results are true only for patients with pure bipolar depression, i.e., after excluding patients with broadly defined mixed states (about 25% of our bipolar sample) treated with an ADs-mood stabilizers combination. As reported in previous studies, ADs should be avoided in mixed depressive episodes (mixed depression, agitated depression, major depression with subthreshold bipolarity etc.) because in these cross-sectional pictures ADs use may increase manic symptoms severity (Goldberg et al., 2007), the risk of nonresponse (Rihmer et al., 2013), “activation syndrome” (Takeshima and Oka, 2013), switch (Sato et al., 2004) and suicidality (Musil et al., 2013). The results of present study indicate that the traditional ADs are effective and safe in the treatment BP-I and BP-II as well as in unipolar disorder when prescribed as recommended in the ISBD Guidelines. However, the ADs were only prescribed in conjunction
with mood stabilizer. SNRIs and TCAs were only used after other ADs were shown to be unsuccessful. These prescriptive routines were identical to those reported in the ISBD Guidelines with the exception that the antidepressants were utilized adjunctive to mood stabilizers in patients with either BP-I and II. This modification was intended to protect against antidepressant-induced switching and supported by an evidence base suggesting that the concomitant use of mood stabilizers decreases switch rates (Boerlin et al., 1998; Henry et al., 2001; Bottlender et al., 2002; Sachs et al., 2007) and mitigate (mostly lithium) AD-emergent suicidality (Yerevanian and Choi, 2013). In some contrast to the ISBD Guidelines, patients with bipolar disorder accompanied with rapid cycling, high mood instability, a previous course with predominantly mixed states, or a history of past antidepressants induced manic, hypomanic or mixed episodes emerging within 8 weeks of AD treatment were excluded from this study. In addition, the criteria employed were somewhat broader than that found in the ISBD Guidelines because we did not exclude patients with a history of previous negative response to ADs, except for those with chronic depression. This change was made based upon our clinical experience as well as the fact that this particular ISBD Recommendation was only supported with D level evidence (“poor evidence level”) and by only two studies (Pacchiarotti et al., 2011; Post et al., 2012), one of which limited to study entry to bipolar I depression. Our impression is that the exclusion of patients with a previous history of nonresponse to AD is not justifiable. Although we are unable to directly verify in our sample if previous nonresponse to ADs predicted or did not predict ADs response during the index episode, we found that ADs are effective in a subgroup of patients with bipolar depression (including previous AD non responders) as well as in unipolar depression. In light of these findings, we propose that the field reconsider ISBD Recommendation Number 1 and allow such patients to be treated with the traditional antidepressants given based upon the mediocre evidence base. Our findings confirm the usefulness of ISBD Guidelines for the short-term AD treatment of bipolar depression. Consensus recommendations provided by ISBD clinical and academic experts do support the use of the traditional antidepressants in a subpopulation of patients with BP depression. These patients appear to have response and remission rates that resemble the rates observed in UP depression and do so without significant switch rates or risk of suicide. Our suggestion to partially modify ISBD Recommendations Numbers 1 and 4, aimed to include potential responders and to improve safety, is supported by the results of the current study but warrants further confirmation.
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These results and conclusion should be interpreted keeping in mind some limitations: (1) the observational nature of the study and the lack of randomization or placebo controls; (2) the unblinded outcomes assessment; (3) the potential impact of clinically selected ADs and mood stabilizer treatment. Yet, despite these limitations, we believe these preliminary data provide useful information to support clinician-decision making in a very problematic area of unmet medical need, the short-term treatment of the depressed phase of bipolar disorder. Over recent years, it has become increasingly that bipolar disorder is a very heterogeneous category of illness accompanied by vastly different clinical presentations, natural history, and psychobiology. The identification of more homogeneous phenotypes based on treatment outcome is urgently needed to improve clinical outcomes. While it is widely recognized that most patients with bipolar depression do not benefit from traditional antidepressants, clinicians need reliable criteria to identify those that would benefit from such treatment. Overall, the findings from this pragmatic clinical study support the recommendations made by the ISBD Task Force. Further large observational multicenter studies are needed to confirm these findings.
Conflict of interest Dr. Tundo, Dr. Proietti, and Dr. de Filippis have no disclosures. Dr. Calabrese has received federal funding from the Department of Defense, Health Resources Services Administration and National Institute of Mental Health. Dr. Calabrese has received research support from Abbott, AstraZeneca, Bristol– Myers Squibb, Cephalon, Cleveland Foundation, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, NARSAD, Repligen, Stanley Medical Research Institute, Takeda, and Wyeth. Dr. Calabrese consulted to or served on advisory boards of Abbott, AstraZeneca, Bristol–Myers Squibb, Cephalon, Dainippon Sumitomo, EPI-Q, Inc., Forest, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Lundbeck, Merck, Neurosearch, OrthoMcNeil, Otsuka, Pfizer, Repligen, Schering-Plough, Servier, Solvay, Supernus, Synosia, Takeda, and Wyeth. Dr. Calabrese has provided CME lectures supported by AstraZeneca, Bristol–Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Sanofi Aventis, ScheringPlough, Pfizer, Solvay, and Wyeth. No speaker bureaus for the past 7 years. No stock, no equity, and no patents.
Contributors Antonio Tundo designed the study, he wrote the protocol. All authors managed the literature searches and analyses, undertook the statistical analysis, wrote the first draft of the manuscript and contributed to, and all have approved the final manuscript.
Role of the funding source This study was funded by the Fondazione dell'Istituto di Psicopatologia Onlus (Grant no. 01/2011), Rome, Italy.
Acknowledgments The authors thank Roberta Necci for her technical help and support in translation.
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The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am. J. Psychiatry 170 (11), 1249–1262. Post, R.M., Leverich, G.S., Altshuler, L.L., Frye, M.A., Suppes, T., McElroy, S.L., Keck Jr., P.E., Nolen, W.A., Rowe, M., Kupka, R.W., Grunze, H., Goodwin, F.K., 2012. Relationship of prior antideprerssant exposure to long-term prospective outcome in bipolar I disorder out-patients. J. Clin. Psychiatry 73, 924–930. Rihmer, Z., Dome, P., Gonda, X., 2013. Antidepressant response and subthreshold bipolarity in “unipolar” major depressive disorder: implications for practice and drug research. J. Clin. Psychopharmacol. 33, 449–452. Sachs, G.S., Nierenberg, A.A., Calabrese, J.R., Marangell, L.B., Wisniewski, S.R., Gyulai, L., Friedman, E.S., Bowden, C.L., Fossey, M.D., Ostacher, M.J., Ketter, T.A., Patel, J., Hauser, P., Rappaport, D., Martinez, J.M., Allen, M.H., Miklowitz, D.J., Otto, M.W., Dennehy, E.B., Thase, M.E., 2007. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N. Engl. J. Med. 356 (17), 1711–1722. Sato, T., Bottlender, R., Sievers, M., Schroter, A., Kleindienst, N., Moller, H.J., 2004. Evaluating the inter-episode stability of depressive mixed states. J. Affect. Disord. 81 (2), 103–113. Sidor, M.M., MacQueen, G.M., 2011. Antidepressants for acute treatment of bipolar depression: a systematic review and meta-analysis. J. Clin. Psychiatry 72, 156–167. Takeshima, M., Oka, T., 2013. Association between the so-called “activation syndrome” and bipolar II disorder, a related disorder, and bipolar suggestive features in outpatients with depression. J. Affect. Disord. 151, 196–202. Tohen, M., Frank, E., Bowden, C.L., Colom, F., Ghaemi, S.N., Yatham, L.N., Malhi, G.S., Calabrese, J.R., Nolen, W.A., Vieta, E., Kapczinski, F., Goodwin, G.M., Suppes, T., Sachs, G.S., Chengappa, K.R., Grunze, H., Mitchell, P.B., Berk, M., 2009. 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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Short-term antidepressant treatment of bipolar depression: Are ISBD recommendations useful in clinical practice? Antonio Tundo a,n, Joseph R Calabrese b, Luca Proietti a, Rocco de Filippis a a b
Istituto di Psicopatologia, Roma, Italy Department of Psychiatry, University Hospital Case Medical Center, Case Western Reserve University, Cleveland, OH, USA
art ic l e i nf o
a b s t r a c t
Article history: Received 22 May 2014 Received in revised form 13 September 2014 Accepted 18 September 2014 Available online 28 September 2014
Objectives: The study aimed to test the effectiveness of the ISBD Guidelines for short-term AD treatment of BP depression. Methods: The study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). Response was defined as a HDRS21 total scoreo 7 at 12 weeks of treatment and remission as a Z50% reduction of baseline HDRS21 total score sustained for 8 weeks. Results: Response was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with BP-II disorder without significant differences (χ² ¼ 3.0, p¼0.219). The remission rate did not differ significantly among groups (χ² ¼3.8, p ¼0.151). The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (χ² ¼10.1, p¼ 0.006). Concerning AD safety, one patient with BP-I depression committed a suicide attempt and ADemerging switch was observed in 2.9% of patients, 2 with BP-I and 1 with BP-II disorder. Limitations: The observational nature of the study and unblinded outcomes assessment. Conclusions: Our findings confirm the usefulness of ISBD Guidelines for short-term AD treatment of BP depression. These patients appear to have similar response and remission rate to those observed in UP depression and do not exhibit significant switch rates or risk of suicide. Our results are limited to patients with pure bipolar depression (excluding those with broadly defined mixed states), treated with ADsmood stabilizers combination. We suggest to partially modify ISBD Recommendations 1 and 4, to include potential responders and to improve safety. & 2014 Published by Elsevier B.V.
Keywords: Antidepressants Bipolar depression Short-term treatment
1. Introduction Major depression episodes are the most frequent presentation of bipolar disorder (Judd et al., 2002, 2003) and are associated with high morbidity and mortality (mostly suicidality), and disruption of patients' daily functioning (Calabrese et al., 2004; Vazquez et al., 2013). Despite the high prevalence and clinical significance of this condition, the treatment of bipolar depression remains controversial. In particular, evidence on short-term efficacy and safety of antidepressants (ADs), the prevalent treatment in everyday clinical practice (Baldessarini et al., 2007), is surprisingly scanty and inconclusive. Two meta-analyses on this topic have reached opposite conclusions regarding the superiority of ADs over placebo in treatment of acute bipolar depression (Gijsman et al., 2004; Sidor and MacQueen, 2011). Similarly, two naturalistic studies directly comparing the response rate to ADs in bipolar and unipolar depression provided divergent
n
Corresponding author. Tel.: þ 39 063610955; fax þ39 0636002828. E-mail address: [email protected] (A. Tundo).
http://dx.doi.org/10.1016/j.jad.2014.09.019 0165-0327/& 2014 Published by Elsevier B.V.
results (Ghaemi et al., 2004; Tondo et al., 2013). In addition, there is conflicting evidence on AD safety in bipolar disorders in terms of the risk of induced switch and linked cycle acceleration, as well as suicidality (Truman et al., 2007; Leon et al., 2011; Amit and Weizman, 2012; Yerevanian and Choi, 2013). Given the clinical importance of this topic and the inconsistency of experimental evidence, the International Society for Bipolar Disorder's (ISBD) task force recently provided 12 consensus recommendations on AD use in bipolar disorders, 10 of which can be applied for short-term treatment of bipolar depression (Pacchiarotti et al., 2013). In short: ADs may be used in BP-I or BP-II depression in patients with a history of previous positive response to ADs (Recommendation Number 1); Serotonin-norepinephrine reuptake inhibitors or tri- and tetracyclics should be considered only after other antidepressants have been tried (Recommendation Number 12);
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In patients with BP-I disorder, ADs should be prescribed with a mood stabilizer (Recommendation Number 4); AD should be avoided in patients with mixed states, i.e. a depressive episode with two or more concomitant core manic symptoms in the presence of psychomotor agitation, during manic or depressive episodes with mixed features, a previous course with predominantly mixed state (Recommendations Numbers 2, 9, 10 and 11), in patients with high mood instability or rapid cycling (Recommendation Number 8), and in patients with a history of past mania, hypomania, or mixed episodes emerging during AD treatment (Recommendation Number 7) Patients treated with ADs should be closely monitored for signs of hypomania or mania and increased psychomotor agitation, in which case ADs should be discontinued (Recommendation Number 6). These recommendations have been formulated by clinical and academic experts based on their own experience and judgment guided by the scanty available research findings but, to the best of our knowledge, no study has verified their effectiveness in clinical practice.
1.1. Aims of the study The aim of the present study was to test the effectiveness of the ISBD Guidelines for short-term AD treatment of bipolar depression in a clinical sample. We partially adapted the ISBD Recommendations Numbers 1 and 4 according to our experience, with the aim to extend the indications for ADs and to improve ADs safety (see Section 2). Our hypothesis is that when the above-mentioned ISBD recommendations are followed, ADs are effective and safe in BP-I and BP-II depression as well as in unipolar depression.
2. Material and methods 2.1. Participants This observational study includes consecutive patients seen from January 2005 to December 2009 at the Istituto di Psicopatologia in Rome, Italy. Inclusion criteria were: (1) age 18–75 years; (2) meeting DSM-IV diagnostic criteria for recurrent major depressive disorder (unipolar depression), or for bipolar I or bipolar II disorder (American Psychiatric Association (APA), 1994); (3) meeting DSM-IV criteria for a current major depressive episode (MDE) (APA, 1994); and (4) a 21-item Hamilton Depression Rating Scale [HDRS21 (Hamilton, 1960)] total score Z 14 at intake. Only the first observed MDE (index depressive episode) was considered for patients experiencing more than one MDE during the observation period. Exclusion criteria were: (1) meeting DSM-IV diagnostic criteria for rapid-cycling bipolar disorder (APA, 1994), (2) broadly defined mixed state (manic, hypomanic or depressive episodes with mixed features, depressive episodes with two or more concomitant core manic symptoms in the presence of psychomotor agitation), (3) high mood instability, (4) previous course with predominantly mixed states, and (5) a history of past manic, hypomanic or mixed episodes emerging within 8 weeks after introducing an AD [ISBD nomenclature task force criteria for treatment-emerging switch (Tohen et al., 2009)]. Partially in contrast with ISBD Recommendation Number 1, we did not exclude all patients with a history of previous AD non-response, but only patients with unipolar and bipolar chronic depressions, defined according to DSM IV criteria as a depressive episode lasting at least 2 years (APA, 1994).
Written informed consent for the anonymous use of clinical records was collected routinely at each patient's first visit. A local ethical committee approved the study procedures. 2.2. Assessments All subjects were evaluated, treated, and followed by the first author (AT), an experienced psychiatrist specialized in mood disorders. Initial diagnostic assessments were based on semistructured interviews to assess the presence of DSM-IV criteria for mood disorders. About 30% of subjects underwent full, structured, SCID-I based diagnostic assessment (First et al., 1996), to confirm the results of semi-structured clinical examinations. During the first visit, demographic (gender, age, marital status, education level, and employment status) and clinical characteristics were collected, including age at onset, duration of illness, number of previous episodes, delusional episodes of any polarity, occurrence of switch to mania or hypomania, lifetime Axis I comorbidities, hospital admissions, suicide attempts, alcohol and/or drug use. When possible, data collected from patients were corroborated with information obtained from other informants as well as any available previous medical records. At intake and at each follow-up visit, typically every 1–4 weeks for the first 3 months and every 1–2 months thereafter, depressive symptoms were assessed using HDRS21. 2.3. Treatments Treatment was chosen by the first author (AT) based on clinical experience and in line with recent ISBD recommendations. All study participants were treated with one or more antidepressants. Serotonin-norepinephrine reuptake inhibitors (SNRI) and tri- and tetracyclics (TCA) were prescribed only after other ADs had been tried. In some contrast to ISBD recommendations, patients with either BP-I or BP-II disorder were treated with one or more mood stabilizer(s). Mood stabilizers included lithium carbonate, valproate, carbamazepine, and the atypical antipsychotics (olanzapine, aripiprazole, quetiapine). Patients were closely monitored for signs of hypomania, mania, or increased psychomotor agitation, in which case the ADs were discontinued. 2.4. Outcome measures Primary outcomes were remission and response and the temporal trend of HDRS21 total score over the 12 weeks of treatment. Secondary outcome was safety, i.e. suicide attempts and AD-emerging switch. Remission was defined as a HDRS21 total scoreo7 at 12 weeks of treatment and response as aZ50% reduction of baseline HDRS21 total score sustained for 8 weeks. This criterion is more conservative than the one suggested by ISBD Task Force report on the nomenclature of course and outcome in bipolar disorders, requiring that the remission/response criteria be met after 2–4 weeks (Tohen et al., 2009). AD-emergent switch was defined as a manic, hypomanic or mixed episodes occurring within 8 weeks from the beginning of AD treatment (Tohen et al., 2009). Patients with an AD-emergent switch in the first 8 weeks of treatment were considered nonresponders/remitters. 2.5. Statistical analysis Baseline demographic and clinical characteristics were compared among patients groups using χ² test, analysis of variance or Kruskal– Wallis test, depending on the level of measurement and the distribution of the characteristic of interest. Following significant tests, post-hoc pairwise comparisons were performed using Bonferroni correction to the probability level. The two primary outcomes
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(50% reduction of baseline HDRS21, HDRS21 scoreo7 at 12 weeks) were analyzed separately and compared among patient groups using the χ² test. Logistic regression analyses were also carried out to compare the outcomes among patient groups after controlling for age, gender, comorbidity and baseline HDRS21 total score. The significance level was set at po0.05. The temporal trend of the HDRS21 total score was examined in the study groups using a mixed-effect analysis and controlling for the effect of gender, age, comorbidity, and HDRS21 total score. All the analyses were carried out using IBM SPSS, version 20.0.
3. Results One hundred and forty seven (36%) out of the 402 patients initially considered were excluded because they had a diagnosis of rapid cycling bipolar disorder (N¼16, 4.3%), chronic depression (N¼ 32, 7.9%), or the presence of broadly defined mixed states regardless of the formal diagnosis (N¼ 99, 26.7%). The study sample included 255 patients with mood disorders (154 UP, 49 BP-I, 52 BP-II). The demographic and clinical characteristics of the diagnostic groups are provided in Table 1. Patients with BP-I disorder were significantly more likely to be single and younger, and had an earlier onset of illness. In addition, they were more likely to have had a past suicide attempt (26.5% in BP-I, 13.5% in BP-II, 3.9% in UP patients; χ²¼21.6, po0.001) and a prior hospitalization. Compared with the UP or BP-II groups, those with BP-I had less Axis I comorbidity, mostly panic disorder (UP 39.0%, BP-I 6.1%, BP-II 17.3%; χ²¼23.6, po0.001), but were more likely to experience delusions, predominantly during mania. Compared with the other diagnostic groups, patients with BPII disorder had significantly more previous MDEs. Mood switching was present only in patients with bipolar disorder. At intake, the HDRS21 total score was higher in patients with BP-I than UP disorder. Table 2 shows the AD treatment data. Significant differences among groups included the more frequent use of SSRI in BP-I than in BP-II and UP patients, and a higher dosage of TCA in UP and BPII compared with BP-I. No other significant differences among the three groups were found in terms of other antidepressants, doses, and combination strategies. The mood stabilizer(s) that were used in association with ADs in bipolar patients were: lithium (6.9%), anticonvulsant (48.5%), lithium and anticonvulsant (25.7%), two or more anticonvulsants (3%), atypical antipsychotics with or without lithium or anticonvulsant (15.9%).
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3.1. Response and remission Thirty-three (12.9%) of the 255 participants dropped out during the study. The dropout rate was significantly higher for patients with UP (18.2%) than for patients with BP-I (2%) and BP-II (7.7%) disorder (χ²¼10.1, p¼0.006). In 4 patients with UP depression, response lasted less than 8 weeks and in two of them remission was not sustained. Moreover, 3 patients, 2 with BP-I and 1 with BP-II disorder, experienced a manic (N¼1) or hypomanic (N¼ 2) switch during the first 8 weeks of AD treatment. Response to treatment (Z 50% reduction of baseline HDRS21 total score) was achieved by 64.9% of patients with UP disorder, 75.5% of patients with BP-I disorder and 75.0% with bipolar-II disorder. The difference among the three groups was not significant (χ²¼3.0, p¼0.219). Remission (HDRS21 total scoreo7) was achieved in a lower percentage of patients with UP disorder (51.3%) compared with patients with BP-I (61.2%) and BP-II disorder (65.4%), but again the difference among groups failed to reach statistical significance (χ²¼3.8, p¼0.151). Logistic regression analyses, adjusted for age, gender, comorbidity and baseline HDRS21 total score, confirmed that response and remission rates were similar across the three diagnostic categories. 3.2. Trend of HDRS scores Fig. 1 shows the estimated temporal trend of the HDRS21 total score over the 12 weeks of treatment by diagnosis. The temporal trend did not differ significantly among the three diagnostic groups. 3.3. Safety Concerning AD safety, one patient with BP-I depression committed a suicide attempt and AD-emerging switch was observed in 3 patients (2.9% of the bipolar sample), 2 with BP-I and 1 with BPII disorder. Patients with UP disorder had no AD-induced switch or suicide attempt.
4. Discussion To the best of our knowledge, this is the first study evaluating the effectiveness and safety of short term AD treatment of bipolar depression in a clinical sample selected and treated according to the ISBD Guidelines (Pacchiarotti et al., 2013). Our findings show that
Table 1 Demographic and clinical characteristics of study participants (N ¼ 255). Variable
UP (n¼ 154)
BP-I (n¼ 49)
BP-II (n¼ 52)
F or chi-square
p-Value
Post-hoc tests
Age at baseline (yrs), mean (SD) Men, N (%) Married, N (%) Education (yrs). Mean (SD) Employed full time, N (%) Age of onset (yrs), mean (SD) Total months of illness before intake, mean (SD) Previous MDE's, mean (SD) Delusional episodes (any polarity), N (%) Suicidal act, N (%) Hospital admission, N (%) Mood switch, N (%)
48.8 35 112 12.9 81 38.5 128.8 3.8 0 6 7 0
41.8 19 27 13.4 28 29.8 142.5 3.4 44 13 25 20
(12.8) (38.8) (55.1) (3.0) (57.1) (12.0) (131.4) (5.9) (89.7) (26.5) (51) (40.8)
46.6 18 35 12.8 32 32.8 166.3 6.7 3 7 5 21
(13.2) (34.6) (67.3) (2.7) (61.5) (12.9) (126.3) (7.8) (5.8) (13.5) (9.6) (40.4)
4.675 6.0 12.1 0.594 3.8 8.296 1.882 5.711 210.9 21.6 65.9 74.5
o 0.05 o 0.05 o 0.05 0.55 0.43 o 0.001 0.154 o 0.0.001 o 0.001 o 0.001 o 0.001 o 0.001
UP 4BP-I UP oBP-I & BP-II UP 4BP-I
(42.9) (8.2) (8.1) (2.8)
29 6 1 19.9
(55.8) (11.5) (1.9) (2.5)
(14.7) (22.7) (72.7) (3.3) (52.6) (15.1) (115.2) (4.9) (0) (3.9) (4.5) (0)
UP 4BP-I BP-I I4UP UP oBP-II oBP-I UP oBP-II oBP-I UP oBP-II oBP-I BP-I & BP-II 4UP
Lifetime comorbidity Axis I, N (%) Alcohol abuse, N (%) Substance use, N (%) HDRS 21 at intake, mean (SD)
102 5 2 19.9
(66.2) (3.2) (1.2) (2.9)
21 4 4 21.0
Abbreviations: UP ¼ recurrent unipolar depression; BPI ¼ bipolar I depression; BPII ¼ bipolar II depression.
9.9 5.4 5.4 3.007
o 0.05 0.07 0.07 0.05
UP 4BP-I
UP 4BPI
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Table 2 Antidepressant treatment in unipolar (UP; N ¼ 154), bipolar-I (BP-I; N ¼ 49), and bipolar II (BP-II; N ¼ 52) depressed patients*. Drug
UP (n ¼ 154) N (%)
BP-I (n¼ 49) N (%)
BP-II (n¼ 52) N (%)
Chisquare
pPost-hoc tests UP (n¼ 154) BP-I (n ¼ 49) Value Mean dose Mean dose (SD) (SD)
SSRI
113 (73.4) 46 (93.9)
36 (69.2)
10.6
5 28 5 16
0.9 3.8 2.5 3.376
0.005 BP-I 4 UP & BP-II 0.384 0.151 0.280 0.497
Venlafaxine TCA Othersb Two AD's of a different class
20 67 13 59
(13.0) 3 (6.1) (43.5) 17 (34.7) (8.4) 8 (16.3) (38.3) 17 (34.7)
(9.6) (53.8) (9.6) (30.8)
BP-II (n¼ 52) Mean dose (SD)
F
p-Value
Post-hoc tests
33.1 (13.5)a
40.1 (23.8)
38.6 (20.4)
3.1 o 0.05
187.5 (78.8) 123.1 (49.3)
175.0 (43.3) 81.6 (30.6)
255 (67.1) 133.0 (65.1)
1.8 p¼ 0.188 5.7 o 0.004 BP Io UP & BP- II
no post-hoc difference
Abbreviations: UP ¼ Recurrent unipolar depression; BPI ¼ bipolar I depressio; BPII ¼ bipolar II depression. SSRI¼ Selective serotonin reuptake inhibitor; SNRI ¼ Serotonin-norepinephrine reuptake inhibitor; TCA ¼ Tricyclic. n
a b
Per cent totals do not equal 100as participants could be on more than one medication. Fluoxetine-equivalent; \widehat\widehat Imipramine-equivalent. Mirtazapine, Mianserine, Bupropion.
25 Unip
HDRS score
20
Bip-I
15
Bip-II
10 5 0
baseline
4
8
12
Weeks Fig. 1. Temporal trend of the HDRS over the 12 weeks of treatment by diagnosis. Results from mixed-effects linear regression.
neither response or remission rates to 12 weeks of AD treatment, nor the temporal trend of HDRS scores, differed significantly among patients with BP-I, BP-II and UP depression. However, response and remission were more sustained in patients with BP than UP disorder. With regards to safety, 1 patient with BP depression attempted suicide and 3 had an AD-emergent switch. Suicide behavior and AD-emergent switch were absent in patients with UP depression. The two samples show that BP patients were more prone to mood switch and suicidality than UP patients. Previous mood switching was about 40% in BP-I and II, 0% in UP patients; previous suicidal attempts were 26.5% in BP-I, 13.5% in BP-II, 3.9% in UP patients. From a clinical perspective, the use of ADs in our patients with BP depression appeared to be safe and effective. Nevertheless, clinicians should keep in mind that these results are true only for patients with pure bipolar depression, i.e., after excluding patients with broadly defined mixed states (about 25% of our bipolar sample) treated with an ADs-mood stabilizers combination. As reported in previous studies, ADs should be avoided in mixed depressive episodes (mixed depression, agitated depression, major depression with subthreshold bipolarity etc.) because in these cross-sectional pictures ADs use may increase manic symptoms severity (Goldberg et al., 2007), the risk of nonresponse (Rihmer et al., 2013), “activation syndrome” (Takeshima and Oka, 2013), switch (Sato et al., 2004) and suicidality (Musil et al., 2013). The results of present study indicate that the traditional ADs are effective and safe in the treatment BP-I and BP-II as well as in unipolar disorder when prescribed as recommended in the ISBD Guidelines. However, the ADs were only prescribed in conjunction
with mood stabilizer. SNRIs and TCAs were only used after other ADs were shown to be unsuccessful. These prescriptive routines were identical to those reported in the ISBD Guidelines with the exception that the antidepressants were utilized adjunctive to mood stabilizers in patients with either BP-I and II. This modification was intended to protect against antidepressant-induced switching and supported by an evidence base suggesting that the concomitant use of mood stabilizers decreases switch rates (Boerlin et al., 1998; Henry et al., 2001; Bottlender et al., 2002; Sachs et al., 2007) and mitigate (mostly lithium) AD-emergent suicidality (Yerevanian and Choi, 2013). In some contrast to the ISBD Guidelines, patients with bipolar disorder accompanied with rapid cycling, high mood instability, a previous course with predominantly mixed states, or a history of past antidepressants induced manic, hypomanic or mixed episodes emerging within 8 weeks of AD treatment were excluded from this study. In addition, the criteria employed were somewhat broader than that found in the ISBD Guidelines because we did not exclude patients with a history of previous negative response to ADs, except for those with chronic depression. This change was made based upon our clinical experience as well as the fact that this particular ISBD Recommendation was only supported with D level evidence (“poor evidence level”) and by only two studies (Pacchiarotti et al., 2011; Post et al., 2012), one of which limited to study entry to bipolar I depression. Our impression is that the exclusion of patients with a previous history of nonresponse to AD is not justifiable. Although we are unable to directly verify in our sample if previous nonresponse to ADs predicted or did not predict ADs response during the index episode, we found that ADs are effective in a subgroup of patients with bipolar depression (including previous AD non responders) as well as in unipolar depression. In light of these findings, we propose that the field reconsider ISBD Recommendation Number 1 and allow such patients to be treated with the traditional antidepressants given based upon the mediocre evidence base. Our findings confirm the usefulness of ISBD Guidelines for the short-term AD treatment of bipolar depression. Consensus recommendations provided by ISBD clinical and academic experts do support the use of the traditional antidepressants in a subpopulation of patients with BP depression. These patients appear to have response and remission rates that resemble the rates observed in UP depression and do so without significant switch rates or risk of suicide. Our suggestion to partially modify ISBD Recommendations Numbers 1 and 4, aimed to include potential responders and to improve safety, is supported by the results of the current study but warrants further confirmation.
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These results and conclusion should be interpreted keeping in mind some limitations: (1) the observational nature of the study and the lack of randomization or placebo controls; (2) the unblinded outcomes assessment; (3) the potential impact of clinically selected ADs and mood stabilizer treatment. Yet, despite these limitations, we believe these preliminary data provide useful information to support clinician-decision making in a very problematic area of unmet medical need, the short-term treatment of the depressed phase of bipolar disorder. Over recent years, it has become increasingly that bipolar disorder is a very heterogeneous category of illness accompanied by vastly different clinical presentations, natural history, and psychobiology. The identification of more homogeneous phenotypes based on treatment outcome is urgently needed to improve clinical outcomes. While it is widely recognized that most patients with bipolar depression do not benefit from traditional antidepressants, clinicians need reliable criteria to identify those that would benefit from such treatment. Overall, the findings from this pragmatic clinical study support the recommendations made by the ISBD Task Force. Further large observational multicenter studies are needed to confirm these findings.
Conflict of interest Dr. Tundo, Dr. Proietti, and Dr. de Filippis have no disclosures. Dr. Calabrese has received federal funding from the Department of Defense, Health Resources Services Administration and National Institute of Mental Health. Dr. Calabrese has received research support from Abbott, AstraZeneca, Bristol– Myers Squibb, Cephalon, Cleveland Foundation, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, NARSAD, Repligen, Stanley Medical Research Institute, Takeda, and Wyeth. Dr. Calabrese consulted to or served on advisory boards of Abbott, AstraZeneca, Bristol–Myers Squibb, Cephalon, Dainippon Sumitomo, EPI-Q, Inc., Forest, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Lundbeck, Merck, Neurosearch, OrthoMcNeil, Otsuka, Pfizer, Repligen, Schering-Plough, Servier, Solvay, Supernus, Synosia, Takeda, and Wyeth. Dr. Calabrese has provided CME lectures supported by AstraZeneca, Bristol–Myers Squibb, France Foundation, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Sanofi Aventis, ScheringPlough, Pfizer, Solvay, and Wyeth. No speaker bureaus for the past 7 years. No stock, no equity, and no patents.
Contributors Antonio Tundo designed the study, he wrote the protocol. All authors managed the literature searches and analyses, undertook the statistical analysis, wrote the first draft of the manuscript and contributed to, and all have approved the final manuscript.
Role of the funding source This study was funded by the Fondazione dell'Istituto di Psicopatologia Onlus (Grant no. 01/2011), Rome, Italy.
Acknowledgments The authors thank Roberta Necci for her technical help and support in translation.
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