Author's Accepted Manuscript

Variation in response to short-term antide-pressant treatment between patients withcontinuous and non-continuous cycling bipo-lar disorders

Antonio Tundo, Joseph R Calabrese, LucaProietti, Rocco de Fillippis

PII: S0165-0327(14)00746-0DOI: http://dx.doi.org/10.1016/j.jad.2014.11.036Reference: JAD7127

To appear in: Journal of Affective Disorders

Received date: 20 September 2014Revised date: 18 November 2014Accepted date: 19 November 2014

Cite this article as: Antonio Tundo, Joseph R Calabrese, Luca Proietti, Rocco deFillippis, Variation in response to short-term antidepressant treatmentbetween patients with continuous and non-continuous cycling bipolardisorders, Journal of Affective Disorders, http://dx.doi.org/10.1016/j.jad.2014.11.036

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Variation in response to short-term antidepressant treatment between patients with

continuous and non-continuous cycling bipolar disorders

Antonio Tundo*1, Joseph R Calabrese2, Luca Proietti1, Rocco de Fillippis1

*Corresponding author:

Antonio Tundo, M.D., Istituto di Psicopatologia

Via Girolamo da Carpi, 1 – 00196 Roma (Italia).

Telephone ++39-06-3610955,

Fax ++39-06-36002828

e-mail: tundo@istitutodipsicopatologia.it

1Istituto di Psicopatologia, Roma, Italy 2 Department of Psychiatry, University Hospital Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA

Abstract Objectives The study aimed to compare effectiveness and safety of short-term antidepressant treatment between patients with continuous (CCC) and non-continuous (N-CCC) cycling bipolar disorders. Methods The study sample included 101 patients with bipolar disorder, 22 (21.8%) CCC and 79 (78.2%) N-CCC. Response was defined as a HDRS21 total score <7 at 12 weeks of treatment and remission as a ≥50% reduction of baseline HDRS21 total score sustained for 8 weeks. Results Compared with N-CCC patients, CCC patients achieved a significantly lower percentage of response (respectively 50% vs. 82.3%, χ²=9.6, p=0.002) and remission (respectively 40.9% vs. 69.6%, χ²=6.11, p=0.013). Adjusted logistic regression analysis indicated that CCC patients were 4.3 times more likely to be non-responders and 3.3 times more likely to be non-remitters than N-CCC patients. Concerning AD safety, 1 (5.0%) CCC patient committed a suicide attempt and AD-emerging switch was observed in 2 patients with N-CCC (2.5%) and in 1 with CCC (4.5%). Limitations The observational nature of the study, retrospective assessment of course, and unblinded outcomes assessment. Conclusions Our findings indicate that the presence or absence of a free interval identifies two different forms of bipolar disorders with different response not only to prophylactic treatment, as previous reported, but also to short-term ADs. We submit that clinicians should take into consideration their patients' pattern of cycling when prescribing short- term AD treatment. Moreover, subtypes of bipolar disorders might be used as moderators of treatment response in studies assessing the efficacy or the effectiveness of antidepressant treatment. Keywords Bipolar disorders, bipolar depression, short‐term treatment, antidepressants, course, outcome

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Introduction

In 1854, Jules Baillarger firstly described a special form of mental illness (La folie à duble forme, or

“dual form insanity”) characterized by regular cycling between melancholia and mania and

included in this form a specific pattern of presentation that was accompanied by the direct transition

from depression to mania, or vice versa, without an intervening free interval (Baillarger, 1854). The

Author, as well as his followers (Ritti, 1883; Ballet, 1894), regarded the form characterized by

absence of free interval as a distinct from those in which mania and depression occurred separately

and considered this distinction as significant. The presence/absence of a free interval in manic-

depressive illness had not received adequate clinical attention until 1980 when Koukopoulos et al.,

investigating the different pattern of manic-depressive cycles, found that 39% of patients with

bipolar disorders had a course without free intervals and called this pattern “continuous circular

cycling” (Koukopoulos et al., 1980). Subsequent studies confirmed that an average of 27% (6%-

38%) of patients with bipolar disorders experience continuous circular cycling (Azorin et al., 2011;

Grof et al., 1987; Haag et al., 1986; Maj et al., 1989) and related this course of illness to a low

response rate to long-term treatment with lithium (Grof et al., 1987; Haag et al., 1986; Koukopoulos

et al., 1995; Maj et al., 1989). Recently, Tundo et al (2013) have noted that continuous circular

cycling identifies a subset of patients with bipolar disorder that differ remarkably from those with

free intervals in clinical presentation, outcome and response to long-term treatment. Patients with

continuous cycling have a later onset of illness, different polarity at onset (more likely to be

depressive than mixed) and polarity of subsequent episodes (more likely to be depressive and

manic/hypomanic rather than mixed). In addition to being at increased risk for depressive and

hypomanic/manic episodes, these patients also exhibited a higher rate of switch and a lower rate of

response to complex regimens of long-term prophylaxis including lithium with or without

antiepileptics and the atypical antipsychotics. Based upon this evidence we proposed that the

continuous and non-continuous cycling represented two distinct subtypes of bipolar disorder and

hypothesized that these subtypes would exhibit a different response rate to the ‘short-term’

antidepressant (AD) treatment of depressive episodes (defined as being antidepressant exposure no

longer than 12 weeks). To our knowledge, no studies have investigated this issue.

Aims of the study

The primary aim of this practice-based clinical study was to compare 12-week clinical outcomes

associated with the traditional ADs in subjects presenting with continuous circular cycling versus

those without continuous circular cycling. The key secondary aims were to evaluate safety across

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these two cohorts focusing primarily on switch rates and suicide attempts. We hypothesized that

traditional ADs would be less effective in continuous patterns of cycling than those with non-

continuous cycling and that switch rates would be higher in those with continuous cycling

compared to those with non-continuous presentations.

Material and methods

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 bipolar I

(BP-I) or bipolar II (BP-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 ≥14 at intake. Only the

first observed MDE (index depressive episode) was considered for patients experiencing more than

one MDE during the observational 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 feature, depressive episode with two or more

concomitant core manic symptoms in the presence of psychomotor agitation), (3) high mood

instability, (4) previous course with predominantly mixed state, and (5) a history of past manic,

hypomanic or mixed episodes emerging within 8 weeks after introducing an AD [International

Society for Bipolar Disorders (ISBD) nomenclature Task Force criteria for treatment-emerging

switch (Tohen et al., 2009)]. These selection criteria are very similar to those recently proposed by

ISBD Guidelines for AD use in bipolar disorders (Pacchiarotti et al., 2013) . In contrast with ISBD

recommendations, we did not exclude all patients with a history of previous AD non-response, but

only those with chronic depression, defined according to DSM IV criteria as a depressive episode

lasting at least 2 years (American Psychiatric Association, 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.

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 semi-

structured 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

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confirm the results of semi-structured clinical examinations. During the first visit demographic

(gender, age, marital status, education level, and employment status) and clinical characteristic were

collected, including age at onset, duration of illness, number and polarity of previous episodes,

delusional episodes of any polarity, pattern of course, occurrence of switch to (hypo)mania, life

time Axis I comorbidities, hospital admissions, suicide attempts, alcohol abuse, drug use. To

increase the reliability of the retrospective assessment of the pattern of course of illness,

information collected from patients, when possible, was corroborated by information obtained from

other informants as well as any available past medical records.

Using Koukopoulos’ criteria (Koukopoulos et al., 1980), we identified four patterns of course: 1)

MDI (a cycle starting with (hypo)mania, followed by depression and then by a free interval); 2)

DMI (a cycle starting with depression, followed by (hypo)mania and then by a free interval); 3) CC

(continuous cycling) where episodes of depression and (hypo)mania alternate without a free interval

lasting at least one month; and 4) IRR (when the sequence of depression-(hypo)mania-free interval

is irregular). As suggested by Koukopoulos et al., we also distinguished continuous cycling with a

long cycle, i.e. less than 2 cycles per year, from those with short cycles, i.e. ≥ 2 cycles per year. The

reference period for the identification of pattern of course was the previous 24 months. For the

purpose of this study we classified patients as having a non-continuous circular course (N-CCC)

when they experienced a DMI, MDI or IRR pattern of course and compared them to patients having

continuous cycling with a long-cycle pattern of course (CCC). Patients with continuous cycling

short cycles course, corresponding to DSM IV criteria for rapid cycling bipolar disorder (Maj et al.,

1999), were excluded from the study.

At intake and at each follow-up visit, typically every 1-4 weeks for 3 months and every 1-2 months

thereafter, depressive symptoms were assessed using HDRS21.

Treatments

Treatment was chosen by the first author (AT) based on his clinical experience and in line with

international standards. 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. Patients were closely monitored during treatment

for signs of hypomania or mania and increased psychomotor agitation, in which case ADs were

discontinued. The treatment strategy was consistent with recent ISBD guidelines by Pacchiarotti et

al., 2013. In some contrast to ISBD recommendations and in order to improve safety, patients with

either BP-I and BP-II disorder were treated with one or more mood stabilizer(s) included lithium

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carbonate, valproate, carbamazepine and atypical antipsychotics (olanzapine, aripiprazole,

quetiapine).

Outcome measures

Primary outcomes were remission and response rates and the temporal trend of HDRS21 total score

over the 12 weeks of treatment. Secondary outcome was safety, i.e. the incidence of suicide attempts

and AD-emergent switch. Remission was defined as a HDRS21 total score < 7 within 12 weeks of

treatment and response as a ≥ 50% reduction in HDRS21 total score from intake sustained for 8

weeks. This criterion is more conservative than the one suggested by the ISBD Task Force report on

nomenclature and outcome in bipolar disorder (Tohen et al., 2009) which only requires that

remission/response criteria are met after 2-4 weeks. AD-emergent switch was defined as a manic,

hypomanic or mixed episodes occurring within 8 weeks after introducing an AD treatment (Tohen

et al., 2009). Patients with an AD-emergent switch in the first 8 weeks of treatment were considered

non-responders/remitters.

Statistical Analysis

Comparisons between patients groups on baseline demographic and clinical characteristics were

carried out using the χ²-test, the t-test or Mann-Whitney test, depending on the level of

measurement and the distribution of the characteristic of interest. The two primary outcomes (50%

reduction of baseline HDRS21, HDRS21 score < 7 at 12 weeks) were analyzed separately and

compared among patient groups using the χ²-test. Multiple logistic regression analysis was also

carried out to compare the outcomes between patient groups after adjusting for age, gender,

comorbidity and baseline HDRS21 total score. The significance level was set at p<0.05. 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.

Results

Sixteen (12%) out of the 117 patients initially considered were excluded because they exhibited a

rapid cycling pattern of presentation. The study sample includes 101 patients, 49 (48.5%) with BP-I

and 52 (51.5%) with BP-II disorder. The CCC pattern of cycling was present in 22 patients (21.8%)

and the N-CCC in 79 patients (78.2%). CCC was more frequent in patients with BP-I (26.5%) than

BP-II (17.3%) disorder (χ² =1.26, p=0.26). For demographic and clinical characteristics of the two

groups see Table 1. Compared with patients with N-CCC, those with CCC bipolar disorder 1) were

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significantly less likely to be employed full time, 2) had more previous depressive episodes and

mood switches, and 3) had higher HDRS21 total scores at intake (Table 1). After diagnosis was

updated to meet DSM-5 criteria (APA 2013), we do not find differences between CCC and N-CCC

groups as regard the following specifiers: with anxious distress, with melancholic features and with

mood congruent/incongruent psychotics features. Table 2 shows the AD treatment data, which

revealed no significant differences between the two groups in terms of classes of antidepressants,

doses and combination strategies employed. The mood stabilizer(s) that were used in association

with ADs were: lithium (6.9%), anticonvulsant (48.5%), lithium and anticonvulsant (25.7%), two or

more anticonvulsants (3%), atypical antipsychotic with or without lithium or anticonvulsant

(15.9%). The pattern of use of mood stabilizers was significantly different between the two study

groups (χ²=24.6, p<0.001). Specifically, use of lithium and anticonvulsant combination was more

frequent in patients with CCC course than in patients with N-CCC course (63.6% and 15.8%,

respectively), while the use of anticonvulsant monotherapy was more frequent in patients with N-

CCC course than in patients with CCC course (56.6% and 18.2%, respectively).

Response and remission

Five (4.9%) of 101 participants dropped out during the study and this dropout rate did not

significantly differ between patients with CCC (0%) and N-CCC (6.3%). Three patients, 2 with N-

CCC and 1 with CCC disorder, experienced a manic (N=1) or hypomanic (N=2) switch during the

first 8 weeks of AD treatment. Response to treatment (≥ 50% reduction of baseline HDRS21 total

score) was achieved by 50% of patients with CCC bipolar disorder and 82.3% of patients with N-

CCC bipolar disorder. The difference among the two groups was significant (χ²=9.6, p=0.002).

Using a logistic regression analysis, adjusted for age, gender, comorbidity and baseline HDRS21

total score we found that, compared with patients N-CCC patients, CCC patients were more than 4

times more likely to be non-responders (OR=4.35, 95%CI 1.47-12.87, p=0.008). Remission

(HDRS21 total score <7) was achieved in a significant lower percentage of CCC patients (40.9%)

compared with NCC patients (69.6%, χ²=6.11 p=0.013). Adjusted logistic regression analysis

indicated that CCC patients were more than 3 times more likely to be non-remitters than N-CCC

patients (OR=3.30, 95% CI 1.16-9.69, p<0.05). In all patients response and remission were

sustained for more than 8 weeks.

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Trend of HDRS scores

Figure 1 show the estimated temporal trend of the HDRS21 total score over the 12 weeks of

treatment by type of course. The HDRS21 total score decline during treatment was slower in CCC

patients. Specifically, scores in this group were significantly higher at 8 and 12 weeks compared

with N-CCC patients (t=-2.73, p=0.007; t=-3.64, p<0.001, respectively). No other differences were

found between the patient groups at each time point.

Safety

Concerning AD safety, 1 (5.0%) patient with CCC bipolar disorder committed a suicide attempt and

AD-emerging switch was observed in 2 patients with N-CCC (2.5%) and in 1 with CCC (4.5%).

Discussion

The findings of the present study indicate that a substantial proportion of patients with bipolar

disorders have a continuous circular cycling course without free intervals and that these patients

significantly differ from those with free intervals on socio-demographic characteristics and clinical

presentation, in line with previous studies (Azorin et al., 2011; Koukopoulos et al., 1980; Tundo et

al., 2013).

Moreover, our results show that the effectiveness of AD short-term treatment was lower in patients

with CCC than with N-CC bipolar depression. These differences remained after controlling for the

effect of potentially confounding variables and, within 12 weeks of treatment, the CCC sample was

>4 times more likely to be non-responder and >3 times more likely to be non-remitter than the N-

CCC sample. However the safety of ADs use, in terms of AD emerging switch, did not differ in the

two groups. AD emerging switch rate in our study is surprisingly lower (3 out of 96 completers,

3.1%) than that reported in the literature (8-15%) (Vazquez et al, 2013). This difference should be

related to both our selection criteria and our treatment strategies. As reported in the Participants

section, we excluded from the study patients with mixed depression or rapid cycling course, i.e.,

with the clinical features related to an increased risk of mood switching during AD treatment

(Vazquez et al, 2013, Pacchiarotti et al, 2013). Furthermore, as reported in the Treatments section,

we prescribed TCA and SNRI, considered to be at high risk of inducing switch (Pacchiarotti et al,

2013), only after more modern ADs had been tried and co-treated all patients with one or more

mood stabilizer(s) to minimize switch rates (Henry et al., 2001; Sachs et al., 2007).

In summary, the present study indicates that the presence or absence of a free interval identifies two

different forms of bipolar disorders. These forms differ not only in the response to long-term

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treatment, as previous reported (Grof et al., 1987; Haag et al., 1986; Koukopoulos et al., 1995,

1980; Maj et al., 1989; Tundo et al., 2013), but also in the response to short-term AD treatment of

the depressive episode. Our findings provide useful information for clinical practice as well as for

research on treatment of bipolar depression. With regard to clinical practice, we submit that

clinicians should careful explore their patients’ pattern of course in the previous 2 years in order to

improve their ability to predict the short-term response to AD treatment of depressive episode and

prognosis. To our knowledge, regrettably no studies have investigated the efficacy of treatments

alternative to classic antidepressants, such as second generation antipsychotics or electroconvulsive

therapy, for patients with continuous cycling in an acute depressive episode . So, our results have

clinical implications and underscore the urgency to identify new treatment strategy for CCC

depressed patients.

As to the research implications, our subtypes of bipolar disorders might be used as moderators of

treatment response in studies assessing the efficacy or the effectiveness of antidepressant treatment.

Our study results have several limitations which should be considered such as the observational

nature of the study, the retrospective assessment of the pattern of course, the lack of randomization

or placebo controls, and the unblinded nature of outcomes data.

Furthermore, our results cannot be generalized to all patients with bipolar depression, but only to

those selected and treated according ISBD guideline for ADs use in bipolar depression (Pacchiarotti

et al., 2013). We prescribed ADs only in patients with pure bipolar depression, i.e., after excluding

patients with broadly defined mixed states, and in conjunction with mood stabilizers. As suggested

by results of previous studies, ADs should be avoided in mixed depressive episodes because in

these cross-sectional pictures their use may increase manic symptoms severity (Goldberg et al.,

2007) and the risk of “activation syndrome”(Takeshima and Oka, 2013), switch (Sato et al., 2004)

and suicidality (Musil et al., 2013).

Despite these limitations, we believe that these findings might contribute to better sub-typing

patients with bipolar disorders for clinical and research purposes.

Future studies are warranted to confirm the findings presented and to elucidate biological and

genetic moderators that may explain the differences between these different patterns of presentation

and course.

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Role of funding source This study was funded by the “Fondazione dell’Istituto di Psicopatologia Onlus”, Rome, Italy 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.

Conflict oe 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, Schering-Plough, Pfizer, Solvay, and Wyeth. No speaker bureaus for the

past 7 years. No stock, no equity, and no patents.

Acknowledgements

The authors thank Roberta Necci for her technical help and support in translation.

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Table 1: Demographic and clinical characteristics of study participants (N= 101) 

CCC (n=22) N-CCC (n=79) chi-square, t-test or M-W test

p

Age (yrs), mean (SD) 46.9 (13.6) 43.6 (13.0) 1.05 0.295 Men, N (%) 9 (40.9) 28 (35.4) 0.22 0.638 Married, N (%) 13 (59.1) 49 (62.0) 0.263 0.877 Education (yrs). Mean (SD) 12.0 (2.9) 13.4 (2.8) -1.89 0.062 Employed full time, N (%) 8 (36.4) 52 (65.8) 6.5 0.039 Age of onset (yrs), mean (SD)

34.6 (13.6) 30.4 (12.1) 1.40 0.165

Total months of illness before intake, mean (SD)

147.8 (145.6) 156.6 (124.6) 958.5 0.461

HDRS 21 at intake, mean (SD)

21.5 (2.3) 20.1 (2.4) 2.44 0.018

Previous course of illness Number of depressive episodes, mean (SD)

7.0 (7.3) 4.6 (6.9) 584.5 0.018

Delusional episodes (any polarity), N (%)

10 (45.4) 37 (46.8) 0.013 0.909

Suicidal act, N (%) 4 (18.2) 16 (20.3) 0.046 0.829 Hospital admissions, N (%) 10 (45.5) 20 (25.3) 3.34 0.068 Mood switch, N (%) 16 (72.7) 25 (31.6) 12.04 0.001 Lifetime comorbidity Axis I 7 (31.8) 43 (54.4) 3.66 0.160 Alcohol abuse, N (%) 3 (13.6) 7 (8.9) 0.440 0.507 Substance use, N (%) 2 (9.1) 3 (3.8) 2,199 0.532

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Table 2: Antidepressant treatment in patients with  CCC and N‐CCC  bipolar disorder*

 CCC (n= 22)    

N‐CCC (n= 79)  

CCC (n= 22) 

N‐CCC (n= 79) 

Drug  N (%)  N (%) chi‐

squarep‐

valuemean dose 

(SD) mean dose 

(SD) t or M‐W 

test p‐

value

SSRI  19 (86.4)  63 (79.7) 0.493  0.48233.7 

(17.7^)  41.2 (23.3)^  ‐1.292  0.200

TCA   12 (54.5)  33 (41.8) 1,137  0.286125 

(89.2)^^ 109.5 (46)^^  0.767  0.488

Venlafaxine  3 (13.6)  5 (6.3)  1,260  0.262 225 (75)  225 (75)  0  1 

Others°  4 (18.2)  9 (11.4)  0.707  0.400 n.v.  n.v.  n.v.  n.v. Two AD's of a different class  7 (31.8)  26 (32.9) 0.009  0.923 * Per cent totals do not equal 100 as participants could be on more than one medication ^ Fluoxetine‐equivalent; ^^ Imipramine‐equivalent ° Mirtazapine, Mianserine, Pramipexole 

Abbreviations: CCC= Continuous Circoular  Cycling; N‐CCC= Non Continuous Circoular Cycling   SSRI = Selective Serotonin Reuptake Inhibitor; TCA= Tricyclic 

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Figure 1. Estimated trend of HDRS scores over the 12 weeks of treatment in the two study groups.

0

5

10

15

20

25

baseline 4 8 12

HD

RS

scor

e

weeks

N-CCCCCC