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Original Contributions

Distinct Effects of Antidepressants in Association With Mood Stabilizers and/or Antipsychotics in Unipolar and Bipolar Depression

Moderie, Christophe MD, MSc1; Nuñez, Nicolas MD, MSc1; Comai, Stefano PhD1,2,3; Saint-Laurent, Marie MD1,4; Fielding, Allan MD1,4; Low, Nancy MD1,4; Gobbi, Gabriella MD, PhD1,4

Author Information
Journal of Clinical Psychopharmacology: 3/4 2022 - Volume 42 - Issue 2 - p 118-124
doi: 10.1097/JCP.0000000000001500
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Despite the development of many guidelines for major depression1–4 and more than 25 Food and Drug Administration–approved antidepressants (AD) during the last decades, about 30% of patients do not respond to an adequate pharmacotherapy trial.5,6 International guidelines and clinical studies suggest that unipolar depression nonresponding to 2 adequate trials with AD, also called treatment-resistant depression (TRD), should be treated with a combination of different classes of AD, or augmentation strategies with antipsychotics (AP) and/or lithium and valproic acid (mood stabilizers [MS]).2,7–9 On the other hand, treatment recommendations for depression in bipolar disorder (BD), beside the conventional treatment with MS, suggest management with lamotrigine10 and/or the approved AP: quetiapine11,12 olanzapine,13 lurasidone,14 and newly approved cariprazine.15

Curiously, AD remain the leading treatment prescribed in BD, despite inconsistent evidence regarding their efficacy for BD and the occurrence of adverse events such as treatment-emergent affective switch (TEAS).16–18 Antidepressant monotherapy prescriptions in BD have surged from 17.9% to 40.9% in the last 2 decades.19 This practice results from an extrapolation of the data gathered in unipolar depression and seems justified by the hypothesized intersections between bipolar and unipolar depression.20,21 Naturalistic studies comparing response rates to AD in BD compared with unipolar depression provided divergent results, which could be explained by misdiagnosis,22 the presence of heterogeneous samples and unmatched pharmacotherapies between the groups.23–25 To the best of our knowledge, clinical response rates to AD and combination of augmentation strategies with either AP or MS has not been explored comprehensively between BD and TRD.26 The present naturalistic study conducted at the Mood Disorders Clinic of the McGill University Health Center aims to (1) evaluate the use of pharmacological combinations of AD+AP, AD+MS, and AD+AP+MS in BD compared with TRD and (2) compare the clinical course of BD patients treated with or without AD (AP, MS, or AP+MS).


This retrospective study was approved by the institutional review board of the McGill University (IRB #2020-6323) and was conducted from 2015 to 2020, in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice. Data were retrieved from a research database containing information systematically collected on TRD and BD patients followed at the Mood Disorders Clinic of the McGill University Health Center for 2 or more years (mean, 7.5 years). Diagnoses of major depressive disorder, BD, and comorbidities were confirmed by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, as well as thorough clinical interview by experienced mood disorders specialists and research coordinators. Patients with a mixed episode or with a neurological/developmental disorder and/or a mood disorder secondary to a medical condition were excluded.


Charts of 206 patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for a major depressive episode (MDE) for 2 or more months were reviewed. Study groups comprised the following: 76 patients met criteria for TRD by failing 2 or more pharmacological trials with different AD in monotherapy or combination therapy at an adequate dose and for 3 or more weeks7; 130 met criteria for BD (70 BD I; 60 BD II). No patients were diagnosed with rapid cycling at the time of the study. All BD patients failed to respond to 1 or more trial with MS plus AP. As per clinical guidelines, medications inducing at least a partial response were kept in the pharmacological regimen and an adjuvant or potentiating medicine was then added.27 All patients had at least mild to severe MDE suggested by a score of 13 or higher on the 17-item Hamilton Depression Rating Scale (HAMD-17).28 Patients were not matched for presenting illness severity as it was found no to influence outcomes (improvement, response, and remission) in a large study conducted by Tondo et al.23

Clinical Evaluation

Chart analysis was performed by 2 authors (N.A.N. and G.G.) and evaluated at baseline, before the beginning (T0), and after at least 3 months of an unchanged pharmacological treatment (T3). At T0 and T3, patients were assessed on the following behavioral scales: HAMD-17,29 the Quick Inventory of Depressive Symptomatology30 (QIDS-C16), and the Clinical Global Impression-Severity of Illness31 (CGI-S). Response was defined as a 50% or greater reduction from the pretreatment HAMD-17 score. Remission was defined as a score less than 7 of the HAMD-17 at the end point (T3). The Maudsley Staging Method was used to establish the severity of treatment resistance in TRD patients.32 The Young Mania Rating Scale33 confirmed the absence of hypomanic/manic symptoms at T0 in BD patients.

Reliability and Interrater Agreement for Psychometric Scales

The internal consistency was previously assessed by means of Cronbach α and an acceptable reliability was found for all scales (HAMD-17: α = 0.82; QIDS-C16: α = 0.77).34 Interrater reliability was previously assessed by means of Cohen κ35 on a sample of 140 patients34 with a moderate to good agreement for all behavioral scales (HAMD-17: κ = 0.58; QIDS-C16: κ = 0.61; CGI-S: κ = 0.72).

Statistical Analyses

Group comparisons on demographics of the patients were computed through the Pearson χ2 test or by Fisher exact test (if n ≤ 5 in each subgroup). Changes in scales were analyzed using repeated measures analysis of variance (ANOVA) with diagnosis and use of AD as between-subject factor and time as a within-subject factors, followed by Tukey post hoc test for multiple comparisons when allowed. To compare TRD and BD treated with AD+AP/MS, δ scores (change from baseline) were computed and compared using independent samples t tests. Effect sizes are reported for t tests (Cohen d) and ANOVA (ηp2). Small, medium, and large effect sizes are respectively 0.2, 0.5, and 0.8 for “d” and 0.01, 0.06, and 0.14 for ηp2.35 Analyses were performed using R Statistical Software.36 Significance was set at a P value less than 0.05. Data are presented as mean ± standard deviation (SD), except when otherwise specified.


Characteristics of the Treatment Groups

Two hundred six patients were included in the study (age: 43.81 ± 14.34; Table 1). At T0, the TRD group had a moderate/severe depression (HAMD-17: 23.86 ± 6.04) and the BD group had mild/moderate depression (HAMD-17: 18.30 ± 3.50). The TRD group previously tried on average 4.8 (±2.7) medications and the BD group tried on average 5.2 (±2.5) medications. The TRD showed a moderate level of resistance based on the Maudsley Staging Method (mean ± SEM, 9.7 ± 0.2).32 The BD group did not display current manic/hypomanic episodes (Young Mania Rating Scale: 3.0 ± 0.7). The TRD group received selective serotonin reuptake inhibitors (SSRIs, 51%), serotonin and norepinephrine reuptake inhibitors (SNRIs, 39%), norepinephrine-dopamine reuptake inhibitors (NDRIs, 25%), and tetracyclic AD (18%), whereas the BD group received SSRIs (19%), SNRIs (11%), NDRIs (22%), and tetracyclic AD (3%). Pharmacotherapies as well details on other demographic and clinical characteristics of the study population are detailed in Table 2. Further information can also be found in our previous work.34

TABLE 1 - Sociodemographic and Clinical Characteristics of the Patients With TRD and BD (Baseline)
TRD (n = 76) BD (n = 130) Statistics
Age, mean ± SD, y 47.7 ± 12.5 41.5 ± 14.9 t = 3.18, P = 0.001, d = 0.43
Duration of illness, mean ± SD, y 12.4 ± 12.6 16.2 ± 12.3 t = 2.11, P = 0.04, d = 0.31
Ratio of males:females 34:42 49:81 χ2 = 0.71, P = 0.39
Place of birth χ2 = 3.95, P = 0.41
 Africa 7 (9%) 9 (7%)
 North America 49 (64%) 97 (75%)
 Central or South America 4 (5%) 5 (4%)
 Asia 6 (8%) 11 (8%)
 Europe 10 (13%) 8 (6%)
No. past suicide attempts, mean ± SD 0.5 ± 1.0 1.0 ± 1.7 t = 2.59, P = 0.01, d = 0.33
No. past hospitalizations, mean ± SD 1.6 ± 1.3 3.1 ± 3.4 t = 4.20, P < 0.001, d = 0.50
No. past medications, mean ± SD 4.8 ± 2.7 5.2 ± 2.5 t = 0.81, P = 0.41, d = 0.12
Depression severity, mean ± SD
 HAMD-17 23.9 ± 6.0 18.3 ± 3.5 t = 6.96, P < 0.001, d = 1.08
 QIDS-C16 15.0 ± 3.6 12.3 ± 3.4 t = 5.47, P < 0.001, d = 0.80
 CGI-S 5.2 ± 1.1 4.5 ± 1.2 t = 3.70, P < 0.001, d = 0.52
 Patients with anxiety disorders 47 (62%) 31 (24%) χ2 = 27.8, P < 0.001
 Patients with substance-use disorders 14 (18%) 40 (31%) χ2 = 3.16, P = 0.08
Pharmacological strategy
 AD+AP 35 (46%) 17 (13%) χ2 = 59.78, P < 0.001
 AD+MS 17 (22%) 25 (19%)
 AD+AP+MS 24 (32%) 26 (20%)
 AP 4 (3%)
 MS 8 (6%)
 AP+MS 50 (38%)
Psychotherapy 32 (42%) 96 (73%) χ2 = 19.21, P < 0.001
Significant P values are in boldface format.

TABLE 2 - Pharmacotherapy of the Patients in Each Treatment Group
TRD BD With AD BD Without AD
n Mean ± SD n Mean ± SD n Mean ± SD
 Aripiprazole, mg 6 3.67 ± 3.39 3 3.83 ± 2.75 0
 Lurasidone, mg 3 35.00 ± 21.79
 Olanzapine, mg 3 9.17 ± 3.82 2 5 1 20
 Quetiapine, mg 23 122.83 ± 148.84 10 182.50 ± 152.78 3 154.17 ± 143.80
 Risperdal, mg 5 1.70 ± 0.97 2 2
 Carbamazepine, mg 1 400
 Lamotrigine, mg 7 98.21 ± 99.59 10 125.00 ± 102.74 2 37.50 ± 17.68
 Lithium, mg 3 500.00 ± 173.21 7 857.14 ± 224.40 3 566.67 ± 436.84
 Topiramate, mg 1 25
 Valproic acid, mg 7 350.00 ± 209.66 9 847.22 ± 525.81 3 541.67 ± 190.94
 Aripiprazole, mg 5 4.70 ± 4.55 6 6.67 ± 7.23 11 11.82 ± 7.41
 Lurasidone, mg 3 33.33 ± 11.55 8 44.38 ± 37.17
 Olanzapine, mg 5 7.00 ± 4.47 5 8.50 ± 6.98 10 7.00 ± 6.10
 Paliperidone, mg 4 40.50 ± 39.91 5 86.20 ± 52.46
 Quetiapine, mg 15 125.83 ± 159.41 16 163.91 ± 205.41 21 161.90 ± 146.55
 Risperdal, mg 1 0.5 3 2.00 ± 1.50 5 6.10 ± 10.57
 Gabapentin, mg 3 466.67 ± 230.94
 Lamotrigine, mg 5 135.00 ± 114.02 7 200.00 ± 64.55 9 119.44 ± 52.70
 Lithium, mg 4 300 14 714.29 ± 266.33 30 935.00 ± 311.88
 Topiramate, mg 2 25 2 75.00 ± 35.36
 Valproic acid, mg 13 326.92 ± 247.58 7 817.86 ± 404.84 20 993.75 ± 495.83
Therapeutic range TRD: aripiprazole (2–15 mg); olanzapine (5–20 mg); quetiapine(50–300 mg); risperdal (0.25–3 mg); lamotrigine (25–200 mg); lithium (600–1200, based on therapeutic serum levels); topiramate (N/A); valproic acid (N/A, based on therapeutic serum levels). Therapeutic range BD: aripiprazole (10–30 mg); lurasidone (20–120 mg); olanzapine (5–20 mg); paliperidone (N/A); quetiapine (50–300 mg); risperdal (1–6 mg); carbamazepine (N/A); lamotrigine (25–200 mg); lithium (600–1200, based on therapeutic serum levels); topiramate (N/A); and valproic acid (500–1500, based on therapeutic serum levels).

Response and Remission

Response and remission rates of patients with TRD and BD treated with and without AD did not differ significantly between the 2 groups (P ≥ 0.54; Table 3). In addition, response and remission rates of patients with TRD and BD treated with AD+AP, AD+MS, or AD+AP+MS did not differ between the groups (P ≥ 0.26; Table 3). Of note, no suicide attempt or suicidal behavior occurred during the 3-month follow-up of the patients.

TABLE 3 - Response and Remission Rates of the Patients With TRD and BD Treated With Different Pharmacological Strategies
TRD BD With AD BD Without AD Fisher/χ2
All strategies Response 20 (26%) 13 (19%) 14 (23%) χ2 = 1.22, P = 0.54
Remission 4 (5%) 5 (7%) 2 (3%) P = 0.74
AD+AP Response 12 (34%) 3 (18%) P = 0.52
Remission 3 (9%) 1 (6%) P = 1.00
AD+MS Response 5 (29%) 6 (24%) P = 0.73
Remission 0 (0%) 3 (12%) P = 0.26
AD+AP+MS Response 3 (13%) 4 (15%) P = 1.00
Remission 1 (4%) 1 (4%) P = 1.00

Clinical Outcomes in TRD Versus BD

The longitudinal course of patients with TRD-UP and BD treated with or without AD is illustrated in Figure 1. For the HAMD-17, 2-way repeated measures ANOVA indicated a significant diagnosis × time interaction (F2,185 = 4.99, P = 0.007, ηp2 = 0.06) as well as significant main effects of diagnosis (F2,199 = 6.76, P < 0.001, ηp2 = 0.20) and time (F1,199 = 427.45, P < 0.001, ηp2 = 0.70). Post hoc analysis showed a significantly higher HAMD-17 total score for TRD compared with BD at T0 (with/without AD: P < 0.001) and at T3 (with AD: P = 0.004; without AD: P = 0.003). For the QIDS-C16, there were significant main effects of diagnosis (F2,199 = 21.89, P < 0.001) and time (F1,199 = 441.65, P < 0.001, ηp2 = 0.71), but no significant diagnosis × time interaction (F2,185 = 0.14, P = 0.86, ηp2 = 0.002). For the CGI-S, there were significant main effects of diagnosis (F2,199 = 9.50, P < 0.001, ηp2 = 0.09) and time (F1,199 = 317.39, P < 0.001, ηp2 = 0.63), but no significant diagnosis × time interaction (F2,185 = 0.03, P = 0.97, ηp2 = 0.00).

Effects of different pharmacotherapies in TRD-UP and BD measured with (A) HAMD-17, (B) QIDS, and (C) CGI scales. Values are reported as mean ± SEM. *** P < 0.001. HAMD-17: 17-item Hamilton Depression Rating Scale; QIDS: Quick Inventory of Depressive Symptomatology (Clinician-Rated); CGI: Clinical Global Impression rating scale ; NoAD: No antidepressant, only antipsychotics and/or mood stabilizers; AD: antidepressants plus antipsychotics and/or mood stabilizers; TRD: treatment-resistant depression; BD: bipolar depression.

Clinical Outcomes in TRD Versus BD Treated with an AD and Adjunct AP and/or MS

In Table 4, we compared 3-month changes in behavioral scales between TRD and BD treated with similar pharmacological approaches. Based on the HAMD-17, AD+AP produced a significantly greater improvement in depressive symptoms in TRD compared with BD (t = 2.48, P = 0.02, d = 0.58). No significant findings were seen in other clinical scales (P ≥ 0.10). There was a marginal finding for a greater improvement in TRD than in BD treated with AD+MS (t = 1.81, P = 0.07, d = 0.58) and AD+AP+MS (t = 1.9, P = 0.055, d = 0.55) quantified by the HAMD-17. The other clinical scales failed to reveal significant differences for this outcome (P ≥ 0.21).

TABLE 4 - Change in Clinical Scores in Patient With TRD and BD Treated With the Same Pharmacological Strategies
TRD BD Statistics
AD+AP n = 35 n = 17
 ΔHAMD-17 9.2 ± 8.0 5.1 ± 3.6 t = 2.48, P = 0.02, d = 0.58
 ΔQIDS-C16 5.6 ± 5.1 4.5 ± 3.1 t = 0.92, P = 0.35, d = 0.23
 ΔCGI-S 1.7 ± 1.6 1.4 ± 1.0 t = 0.88, P = 0.38, d = 0.22
AD+MS n = 17 n = 25
 ΔHAMD-17 8.8 ± 4.5 6.3 ± 4.0 t = 1.81, P = 0.07, d = 0.58
 ΔQIDS-C16 5.7 ± 2.6 6.0 ± 3.6 t = 0.34, P = 0.73, d = 0.10
 ΔCGI-S 1.6 ± 1.0 1.8 ± 1.3 t = 0.41, P = 0.68, d = 0.12
AD+AP+MS n = 24 n = 26
 ΔHAMD-17 9.3 ± 4.2 6.9 ± 4.2 t = 1.9, P = 0.05, d = 0.55
 ΔQIDS-C16 5.4 ± 2.4 5.6 ± 3.0 t = 0.25, P = 0.80, d = 0.07
 ΔCGI-S 1.6 ± 0.7 1.6 ± 1.2 t = 0.09, P = 0.92, d = 0.02
Significant P values are in boldface format.


This is the first study, to our knowledge, comparing the clinical trajectory of patients with TRD and BD when treated with similar pharmacotherapies. One of our main findings is the greater reduction of depressive symptoms in the TRD group compared with the BD group when pharmacological combinations included an AD. Although the effect size was small, this distinctiveness in treatment outcomes is in accordance with previous literature reflecting higher nonresponse rates to AD in BD (with or without MS) compared with unipolar depression.24,37

In addition, our results nuances findings from a large naturalistic sample (N = 878) in which the use of short-term AD treatment (with or without MS/AP) generated a significantly greater improvement in BD compared with unipolar depression.23 As patients with unipolar depression augmented with AP or MS composed only one fourth of the total sample, it could not be excluded that simultaneous treatment with MS or AP had contributed to the greater improvement noted in BD patients.

Importantly, in our study, the addition of an AD in the polypharmacy used in BD failed to modify the clinical trajectory. Previous data have suggested that the addition of an AD seems to produce at best a small significant improvement in BD depression.18,38–40 Accordingly, the Canadian Network for Mood and Anxiety Treatments/International Society for Bipolar Disorders guidelines have removed the add-on SSRI/bupropion as a first-line recommendation for depression in BD.41 Moreover, the International College of Neuropsychopharmacology has recently suggested that the addition of an AD does not increase treatment efficacy in treatment-resistant depression in BD.42

The focus given on AD in clinical practice might prevent patients with BD from obtaining an optimal care, such as combinations that include lithium plus lamotrigine or lamotrigine plus quetiapine.42,43 We should be mindful that the addition of an AD also increases the risk of TEAS, cycle acceleration, and overall mood destabilization in patients with BD. Selective serotonin reuptake inhibitors seem to have a lower acute risk of TEAS than other groups such as SNRIs or tricyclic AD (TCAs).16 However, the use of SSRIs still carries a risk of TEAS in the long term, which should deter their use in BD as these patients often require long-term interventions.18

Our study also highlights a greater improvement (medium effect size) in TRD treated with AD+AP compared with BD treated with AD+AP. The synergistic effect of AD+AP is well studied in unipolar depression,44 and preclinical studies have underscored that augmentation with an AP allows for targeting multiple receptors and neurotransmitters systems.45 Interestingly, TRD patients treated with AD+MS or AD+MS+AP also showed a better improvement in depressive symptoms quantified by the HAMD-17 scale compared with BD, even if this result was only close to significance (P = 0.07 for AD+MS and P = 0.055 for AD+MS+AP). These data collected in a natural clinical setting further support the importance of augmentation strategies, which include the use of AP or MS for TRD patients.8,44,46

Although we found a distinct clinical improvement on the severity of depression according to the different pharmacotherapy strategies, we did not observe overall difference in their response or remission rates. Such outcomes should be viewed considering the long period required to achieve remission or euthymic states in depression.21 The observed low rates of remission indeed reflect the refractory nature of patients included in this study. However, no suicide or suicide attempts were reported during the study follow-up underscoring that even if the pharmacological combinations did not lead to remission within 3 months, they may be significant in certain depressive domains, such as preventing suicidal behaviors.

Finally, the distinct pharmacological outcomes between TRD and BD patients in this study likely support an overall different neurobiological footprint within these 2 conditions. Although certain treatments (electroconvulsive therapy, ketamine) do produce improvements in both conditions,42,47 neuroimaging studies have demonstrated neurobiological differences in unipolar and BD including distinct functional and structural alterations in emotion- or reward-processing neural circuits.48 Moreover, we previously highlighted several differences in the psychopathological and sociodemographic characteristics of TRD and BD patients.34 Collectively, these results further strengthen the lack of a continuity between TRD and BD, as previously hypothesized by Angst.49


Several limitations should be considered while interpreting these findings. First, the external validity may be limited by data derived from a University Hospital mood specialized center. The population studied was nonetheless ethnically diverse, with almost 20% of patients born outside of Canada. Second, we did not match the sample of BD to TRD patients according to single pharmacological agents or dosages as well as to depressive severity. Third, the nonblinded retrospective outcome assessments should be considered as well as the limitations of a naturalistic design study. Nevertheless, the findings may reflect real-world interactions of clinically selected pharmacotherapies, as clinical treatment was individualized and adjusted to tolerability to favor the patient's preferences and positive clinical outcomes.2 Although inconsistent across studies, the HAMD might be more sensitive to change in UP patients than in BD patients, which might explain some of the findings.50–53 Treatment-emergent affective switch was not reported as shorter-term studies may not reflect the true risk of mania54 and the absence of proper placebo treated control groups refrains us from assigning causality to the use of a pharmacotherapy compared with the natural history of the disorder.


Our findings support a bidimensional approach for BD and TRD disorders. The combination of AD+AP/MS generates a significantly greater clinical improvement in TRD compared with BD supporting the existence of distinct pharmacological profiles between the 2 disorders. Moreover, no direct clinical benefit of adding AD in BD was found. Further studies linking neurobiological markers and pharmacological outcomes should provide more insight in these clinical questions as to provide personalized management of care of patients experiencing depression.


The authors thank the patients and staff of the Allan Memorial Institute, McGill University Health Center for their contribution to this research program.

The authors gratefully acknowledge the contributions of Pablo Cervantes to this research.


This study was supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders (RQSHA) and the Practice Plan fund of the Department of Psychiatry, McGill University Health Center.

The authors declare no conflicts of interest.


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antidepressants; antipsychotics; bipolar disorder; major depressive disorder; treatment-resistant depression

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