Association of Low-Dose Mood Stabilizers With Treatment Retention in Unipolar Depression: A Retrospective Cohort Study

Association of Low-Dose Mood Stabilizers With Treatment Retention in Unipolar Depression: A Retrospective Cohort Study | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Association of Low-Dose Mood Stabilizers With Treatment Retention in Unipolar Depression: A Retrospective Cohort Study View ORCID Profile Hideyo Sugahara , Shoji Tokunaga doi: https://doi.org/10.1101/2025.06.04.25328948 Hideyo Sugahara a Sugahara Tenjin Clinic, GG Solar Building , Tenjin 3-4-9 Chuo-ku, Fukuoka-city, Fukuoka 810-0001, Japan MD, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Hideyo Sugahara For correspondence: research01{at}mist.ocn.ne.jp Shoji Tokunaga b Clinical Research Support Center, Ehime University Hospital , 454 Shitsukawa, Toon City, Ehime Prefecture, 791-0295, Japan MSc, PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Importance Mood stabilizers are typically reserved for bipolar disorders, yet their role in treating unipolar depression remains underexplored despite clinical need and theoretical rationale. Objective To evaluate the association between low-dose mood stabilizer use and 6-month treatment retention in patients with unipolar and bipolar depression. Design, Setting, and Participants This retrospective cohort study analyzed medical records from a single outpatient psychiatric clinic in Japan between 2016 and 2022, including 300 patients with unipolar or bipolar depression initiating pharmacotherapy (100 patients per year). Exposures Prescription of mood stabilizers (e.g., lithium, valproate), antidepressants, or both. Main Outcomes and Measures The primary outcome was 6-month treatment retention, used as a proxy for pharmacotherapy adherence, reflecting long-term drug tolerability and real-world clinical effectiveness. Retention rates were compared across treatment types using Kaplan–Meier and Cox regression analyses adjusted for demographic and clinical variables. Results Mood stabilizer prescriptions increased from 27% in 2016 to 89% in 2022. Patients with unipolar depression treated with mood stabilizers exhibited significantly higher 6-month retention compared to those on antidepressants alone (adjusted HR: 0.44; 95% CI, 0.24–0.80; p <.01). Side effects were mild and manageable, with high continuation rates observed for low-dose regimens. Conclusions and Relevance Low-dose mood stabilizers, particularly lithium and valproate, were associated with significantly higher treatment retention rates in unipolar depression compared to antidepressants alone. These findings suggest the potential role of mood stabilizers in enhancing treatment adherence and highlight the need for confirmatory prospective studies to evaluate their comparative effectiveness. Question Can low-dose mood stabilizers improve 6-month treatment retention among patients with unipolar depression? Findings In this retrospective cohort study of 185 patients with unipolar depression, treatment with low-dose lithium or valproate was associated with significantly higher 6-month treatment retention compared to antidepressants alone (adjusted HR: 0.44; 95% CI, 0.24–0.80; p <.01). Meaning Low-dose mood stabilizers may improve treatment adherence in unipolar depression, warranting reconsideration of their role in treatment guidelines. Despite pharmacological advances, unipolar depression remains a leading cause of global disability, 1 , 2 with challenges in treatment adherence 3 , 4 and relapse prevention. 5 , 6 Although antidepressants dominate treatment guidelines, 7 , 8 their effectiveness in ensuring adherence 9 , 10 and preventing suicide 11 , 12 remains suboptimal, prompting exploration of alternatives like mood stabilizers. 13 Previous studies have demonstrated lithium’s effectiveness in reducing suicide risk 14 , 15 and managing treatment-resistant depression, 16 , 17 yet its use in unipolar depression remains limited. 18 - 21 The DSM-III’s dichotomous classification 22 , 23 may have contributed to underrecognition of what is called bipolar spectrum 24 - 26 presentations and limited the therapeutic application of mood stabilizers. Furthermore, the rapid expansion of antidepressant medications 27 , 28 —often supported by short-term trials—has overshadowed evidence for alternative approaches. This study aimed to evaluate the association between mood stabilizer use and six-month treatment adherence in patients with unipolar and bipolar depression, addressing the observed increase in their prescription and potential clinical benefits. Methods Study Design This retrospective cohort study was designed to evaluate the impact of mood stabilizers on depressive disorders in light of recent increases in their prescription. Medical records of 300 patients with mood disorders (100 patients per year) from 2016, 2019, and 2022 were reviewed. Key variables assessed included patient demographics, prescribed mood stabilizers and antidepressants, and the frequency of hospital visits within the initial six months of treatment. Hospital visits and medication adherence are essential for evaluating drug effectiveness. 29 - 31 Therefore, we used hospital visit and prescription records as the drug efficacy indicator. 32 - 35 The sample size was calculated to achieve 80% power at a two-sided significance level of 5%, assuming a six-month continuation rate of 35% in 2016 and 50% in 2022, requiring a minimum of 97 participants per year. The study was approved by the Ethics Committee of Tohoku University and complied with the STROBE guidelines. Participants A total of 100 consecutive patients per year were included, beginning on or after April 1 of each respective year. Inclusion criteria were a diagnosis of unipolar or bipolar depression and initiation of treatment at our clinic. Exclusion criteria encompassed visits unrelated to treatment (e.g., family consultations, second opinions), treatment for non-depressive psychiatric or medical conditions, cases not requiring continuous pharmacotherapy (e.g., mild depression, anxiety, or insomnia), diagnostic-only visits, and treatment refusal ( Figure 1 ). The starting date was chosen to minimize seasonal variation. Download figure Open in new tab Figure 1. Flowchart of participant inclusion. Participants were included based on the order of their initial visit date. Exclusion criteria included patients with medical illness or psychiatric conditions other than depression, those without the intention for standard treatment at the clinic, and inappropriate cases such as family consultations. Other reasons for exclusion included an insufficient medical record (2016) and a lack of examination completion at the clinic (2019). Initial assessments included a comprehensive health questionnaire, including the Center for Epidemiologic Studies Depression Scale (CES-D), 36 a 30-minute nursing interview, and a 40–60-minute physician consultation. Treatment adhered to standard guidelines 7 , 8 , 37 recommending medication continuation for 6–9 months after symptom improvement in single episodes and longer for recurrent cases. Although DSM-5 criteria 38 were used, diagnoses of bipolar depression incorporated additional considerations such as subthreshold manic symptoms, affective temperament, and family history, consistent with a bipolar spectrum model. 39 - 41 In 2016, mood stabilizers were predominantly prescribed for bipolar disorder, but their use evolved over time. By 2022, they were also prescribed for conditions such as atypical depression or exhaustion-type depression with suspected mood instability. Off-label use was disclosed to patients, and informed consent was obtained. Patients were informed about the approved indications of lithium and valproate and advised that prescriptions beyond these indications were off-label. Informed consent was documented, and verbal checks were routinely conducted during follow-ups. Suicidal ideation data were extracted from binary responses on intake questionnaires. Patients with persistent suicidal ideation or risk behaviors were treated with risperidone or other antipsychotics as needed. Anxiolytics and hypnotics were prescribed for acute or intermittent symptoms. Investigation Descriptive statistics were computed for baseline variables. It was assumed all patients received mood stabilizers and/or antidepressants. The mean maximum dose and duration of medication use over six months were calculated. Six-month treatment retention rates were analyzed using the Kaplan-Meier method and stratified by age, sex, diagnosis (unipolar or bipolar), suicidal ideation, and CES-D score. Between-year differences were evaluated using Cox regression adjusted for these variables. Due to missing suicidal ideation responses from three patients in 2022, this analysis was conducted on 297 (203 unipolar and 94 bipolar) participants. When evaluating antidepressant and mood stabilizer effects based on treatment adherence, hospital visit duration from the initial consultation cannot reflect the effects of medications introduced later. The group that began concomitant use of the two kinds of drugs after the initial visit had already elapsed some time by the time combination therapy was initiated, so these cases need to be excluded when comparing the administration periods with each monotherapy group. The analysis excluded 18 patients with unipolar depression receiving both medications for this reason. The final analysis included 185 unipolar depression cases. Among unipolar cases, adherence was compared across groups receiving antidepressants, mood stabilizers, or both. Factors influencing six-month retention and reasons for early discontinuation were identified from medical records by two independent nurses, utilizing predefined criteria based on patient-reported outcomes and physician assessments. Disagreements were resolved through consensus. Categorical reasons were aggregated and ranked by frequency. This approach supplements hospital visit records and prescription data, providing comprehensive understanding of medication adherence behaviors. Statistical Analysis ANOVA was used to assess differences in means, while Kaplan-Meier and Cox regression analyses were employed to assess hospital visit retention. All statistical analyses were conducted using EZR 42 (ver. 1.68), a graphical user interface for R, with statistical significance defined as p <.05. Potential biases inherent to the retrospective design were addressed by adjusting for demographic and clinical variables in the Cox regression models. Results Patients Across the three cohorts (2016, 2019, 2022), a total of 300 patients were included. The mean age was 33.1 years (SD 12.6), and 70% were female. The proportion of patients diagnosed with unipolar depression ranged from 59% to 78% across the years ( Table 1 ). Mood stabilizer prescriptions increased from 27% in 2016 to 54% in 2019 and 89% in 2022 (Table2). View this table: View inline View popup Download powerpoint Table 1. Demographic Characteristics of the Participants View this table: View inline View popup Download powerpoint Table 2. Mood Stabilizer and Antidepressant Prescriptions Outcome Retention by Year Kaplan–Meier survival analysis of 6-month treatment adherence rates over 3 years (n=297), adjusted for age, sex, illness, presence of suicidal ideation and CES-D score, showed an increase over time ( Figure 2 ). Cox proportional hazards analysis, adjusting for the same variables, indicated a significant year effect on hospital visits (hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.67–0.99; p=.03), suggesting increased attendance period over time. Download figure Open in new tab Figure 2. Kaplan–Meier and Cox regression analyses comparing treatment retention across 2016, 2019 and 2022 The analysis depicts 6-month retention rates among all participants for each year. Cox regression analysis was adjusted for age, sex, illness, the presence of suicidal ideation (SI), and Center for Epidemiologic Studies Depression Scale (CES-D) score. CI, confidence interval Retention by Treatment Group Patients with unipolar depression (n=185) receiving mood stabilizers demonstrated significantly higher 6-month retention compared to those on antidepressants alone (adjusted HR: 0.44; 95% CI, 0.24–0.80; p <.01). These findings are visually represented in Figure 3 , highlighting the divergence in retention rates over time. Download figure Open in new tab Figure 3. Kaplan–Meier and Cox regression analyses of treatment retention in unipolar depression subgroup (n=185) The analysis compares treatment adherence among participants receiving mood stabilizers, antidepressants, or both. Cox regression analysis was adjusted for age, sex, the presence of suicidal ideation (SI), Center for Epidemiologic Studies Depression Scale (CES-D) score, and year. In the Cox regression model, mood stabilizer (MS) and antidepressant (AD) were represented as binary variables, with 0 indicating not prescribed and 1 indicating prescribed. For all participants diagnosed with unipolar depression (n=185), hazard ratios for MS and AD were calculated, with adjustment for these covariates. CI, confidence interval Assumed Reasons for Treatment Adherence Patients who continued treatment frequently reported subjective improvement or insufficient improvement, while early discontinuation was often attributed to lack of perceived benefit or social factors. Reasons for continuation or dropout were consistently categorized across cohorts. Safety Routinely monitored side effects were mild and manageable in most cases, including gastrointestinal discomfort and tremors in patients taking lithium and somnolence in those on valproate. Dosages were typically low (lithium: 100–600 mg/day; valproate: 100–600 mg/day), contributing to good tolerability. Discussion This retrospective cohort study suggests that mood stabilizers may be associated with improved treatment retention for both bipolar and unipolar depression. Prescription rates increased from 27% in 2016 to 89% in 2022, with improved 6-month retention rates. Patients with unipolar depression receiving mood stabilizers showed higher retention rates, with an adjusted hazard ratio of 0.44. These findings suggest mood stabilizers may enhance treatment adherence even without a bipolar diagnosis. 21 , 43 , 44 The expanded use of mood stabilizers was driven by the clinician’ careful monitoring of patient outcomes, which provided compelling evidence for their effectiveness. The diagnostic distribution showed a 2:1 ratio of unipolar to bipolar depression, differing from U.S. DSM-IV’s 5:1 ratio. 38 Over 45% of patients reported suicidal ideation at baseline, rising to 65% by 2022. Antidepressants may pose risks by inducing manic symptoms, highlighting mood stabilizers’ importance for suicide prevention. 45 , 46 While lithium has proven anti-suicidal properties 14 , 15 and efficacy in treatment-resistant depression, 16 , 17 its use in unipolar depression remains limited in Western countries where antidepressants dominate. 18 - 21 The increasing prescription of mood stabilizers suggests a shift in clinical practice with global implications. The tolerability of low-dose mood stabilizers suggests utility in diverse settings including their potential to reduce relapse rates and improve patients’ quality of life. Future studies should explore whether these benefits extend to other clinical outcomes, such as functional recovery and suicide prevention, particularly in populations with high baseline suicidal ideation. Pharmaceutical market dynamics and antidepressant proliferation 27 , 28 —often approved after brief trials—have overshadowed mood stabilizers. Few new mood stabilizers have been introduced, and lithium remains underprescribed, despite favorable outcomes and minimal side effects at low doses. In this study, adverse events were mild and manageable, supporting broader application of mood stabilizers. Social factors including the COVID-19 pandemic and healthcare changes may have influenced results. 47 , 48 The increase in the proportion of suicidal ideation among participants in this study in 2022 is assumed to reflect this impact. However, the clinic environment remained stable. Patient reports of improvement were common reasons for continued visits, suggesting perceived treatment benefit. Low-dose mood stabilizers offer a promising strategy to enhance treatment adherence in unipolar depression, along with clinical benefits and potential ethical advantages, such as reducing inappropriate antidepressant monotherapy in patients with latent bipolarity. These findings underscore the need for prospective randomized controlled trials comparing adherence and efficacy across diverse populations, including antidepressant monotherapy and combination therapy with antidepressants and mood stabilizers, in order to validate their effectiveness and inform revisions to international treatment guidelines. Limitations While this study provides preliminary evidence supporting the use of low-dose mood stabilizers in unipolar depression, several limitations must be addressed. The retrospective design precludes definitive conclusions about causality, highlighting the need for prospective randomized controlled trials to confirm these findings. Moreover, the use of hospital visits and prescription records as proxies for treatment adherence may not always perfectly capture patient behavior or treatment motivation. Additionally, as the study was conducted at a single clinic in Japan, the generalizability of the results to other healthcare systems or cultural contexts remains uncertain. Future multicenter studies across diverse populations are essential to validate these results. Furthermore, the findings underscore the need to reconsider the role of mood stabilizers in international treatment guidelines, particularly in regions where their use remains limited. Comparative studies examining the efficacy of mood stabilizers in different healthcare settings could provide valuable insights into their broader applicability. Conclusions This study demonstrates that mood stabilizers, particularly lithium and valproate at low doses, are associated with improved treatment retention and manageable side effects in patients with depression including those diagnosed with unipolar depression. These findings highlight the potential role of mood stabilizers to enhance long-term treatment adherence and support the need for future research to inform guideline revisions. Data Availability All relevant data are provided within the manuscript and its tables and figures. Acknowledgements The authors are grateful to Akane Yoshida, Haruka Taniguchi, Honoka Matsunobu, Chie Koga, Fumine Matsubara, and Mei Shirouzu for their contributions to data acquisition and methodological discussions related to this research. Footnotes Data Availability Statement: All relevant data are provided within the manuscript and its tables and figures. Funding Statement: The study was implemented in clinical practice and was not supported by any grants or funding. Conflict of Interest Disclosure: The author declares no conflicts of interest to disclose. Ethics Approval Statement: This study was approved by the Ethics Committee of Tohoku University (approval no: 2024-1-136; approval date: May 29, 2024). Patient Consent Statement: Informed consent was obtained from patients in an optout manner between May and August 2024. This version of the manuscript includes revisions made after re-verifying the data using the clinic electronic billing records. It was found that one participant from the 2019 cohort was ineligible and therefore excluded. In addition, a new eligible participant was added. Furthermore, based on this updated data source, several corrections were made to prescription records, and the number of recorded antidepressant prescriptions was also revised. These changes do not significantly impact the main findings or overall conclusions of this study. REFERENCES 1. ↵ Cosgrove L , Bursztajn HJ , Patterson EH . Industry influence on mental health research: depression as a case example . Front Med . 2024 ; 10 . doi: 10.3389/fmed.2023.1320304 OpenUrl CrossRef PubMed 2. ↵ Solomon DA , Endicott J , Coryell W , et al. Multiple recurrences of major depressive disorder . Am J Psychiatry . 2000 ; 157 ( 2 ): 229 – 233 . doi: 10.1176/appi.ajp.157.2.229 OpenUrl CrossRef PubMed Web of Science 3. ↵ Katon W. A multifaceted intervention to improve treatment of depression in primary care . Arch Gen Psychiatry . 1996 ; 53 ( 10 ): 924 . doi: 10.1001/archpsyc.1996.01830100072009 OpenUrl CrossRef PubMed Web of Science 4. ↵ Zivin K , Kales HC . Adherence to depression treatment in older adults . Drugs Aging . 2008 ; 25 ( 7 ): 559 – 571 . doi: 10.2165/00002512-200825070-00003 OpenUrl CrossRef PubMed Web of Science 5. ↵ Wang Z , Xiao C , Ma X. Standardized treatment strategy for depressive disorder . Adv Exp Med Biol . 2019 ; 1180 : 193 – 199 . doi: 10.1007/978-981-32-9271-0_10 OpenUrl CrossRef PubMed 6. ↵ Bauer M , Severus E , Möller HJ , Young AH . Pharmacological treatment of unipolar depressive disorders: summary of WFSBP guidelines . Int J Psychiatry Clin Pract . 2017 ; 21 ( 3 ): 166 – 176 . doi: 10.1080/13651501.2017.1306082 OpenUrl CrossRef PubMed 7. ↵ Bauer M , Severus E , Köhler S , et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders . Part 2: maintenance treatment of major depressive disorder-update 2015. World J Biol Psychiatry . 2015 ; 16 ( 2 ): 76 – 95 . doi: 10.3109/15622975.2014.1001786 OpenUrl CrossRef PubMed 8. ↵ Davidson JRT . Major depressive disorder treatment guidelines in America and Europe . J Clin Psychiatry . 2010 ; 71 ( Suppl 1 ): e04 . doi: 10.4088/JCP.9058se1c.04gry OpenUrl CrossRef PubMed 9. ↵ Vergouwen ACM , Bakker A , Katon WJ , Verheij TJ , Koerselman F. Improving adherence to antidepressants: a systematic review of interventions . J Clin Psychiatry . 2003 ; 64 ( 12 ): 1415 – 1420 . OpenUrl CrossRef PubMed Web of Science 10. ↵ González De León B , Del Pino-Sedeño T , Serrano-Pérez P , et al. Effectiveness of interventions to improve medication adherence in adults with depressive disorders: a meta-analysis . BMC Psychiatry . 2022 ; 22 : 41 . doi: 10.1186/s12888-022-04120-w OpenUrl CrossRef PubMed 11. ↵ Grunebaum MF , Li S , Mann JJ , Ellis SP , Oquendo MA . Antidepressants and suicide risk in the United States, 1985–1999 . J Clin Psychiatry . 2004 ; 65 ( 10 ): 1456 – 1462 . OpenUrl CrossRef PubMed Web of Science 12. ↵ Möller HJ . Evidence for beneficial effects of antidepressants on suicidality in depressive patients: a systematic review . Eur Arch Psychiatry Clin Neurosci . 2006 ; 256 ( 6 ): 329 – 343 . doi: 10.1007/s00406-006-0650-x OpenUrl CrossRef PubMed Web of Science 13. ↵ Tondo L , Baldessarini RJ . Suicidal behavior in mood disorders: response to pharmacological treatment . Curr Psychiatry Rep . 2016 ; 18 ( 7 ): 71 . doi: 10.1007/s11920-016-0715-0 OpenUrl CrossRef PubMed 14. ↵ Tondo L , Baldessarini RJ . Prevention of suicidal behavior with lithium treatment in patients with recurrent mood disorders . Int J Bipolar Disord . 2024 ; 12 : 326 . doi: 10.1186/s40345-024-00326-x OpenUrl CrossRef 15. ↵ Goodwin FK . Suicide risk in bipolar disorder during treatment with lithium and divalproex . JAMA . 2003 ; 290 ( 11 ): 1467 . doi: 10.1001/jama.290.11.1467 OpenUrl CrossRef PubMed Web of Science 16. ↵ Bauer M , Adli M , Bschor T , et al. Lithium augmentation therapy in refractory depression-update 2002 . Eur Arch Psychiatry Clin Neurosci . 2003 ; 253 ( 3 ): 132 – 139 . doi: 10.1007/s00406-003-0430-9 OpenUrl CrossRef PubMed Web of Science 17. ↵ Rybakowski JK , Suwalska A , Chłopocka-Woźniak M. Potentiation of antidepressants with lithium or carbamazepine in treatment-resistant depression . Neuropsychobiology . 1999 ; 40 ( 3 ): 134 – 139 . doi: 10.1159/000026610 OpenUrl CrossRef PubMed Web of Science 18. ↵ Bschor T. Lithium in the treatment of major depressive disorder . Drugs . 2014 ; 74 ( 8 ): 855 – 862 . doi: 10.1007/s40265-014-0220-x OpenUrl CrossRef PubMed 19. Crossley NA , Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders . J Clin Psychiatry . 2007 ; 68 ( 6 ): 935 – 940 OpenUrl CrossRef PubMed Web of Science 20. Abou-Saleh MT , Müller-Oerlinghausen B , Coppen AJ . Lithium in the episode and suicide prophylaxis and in augmenting strategies in patients with unipolar depression . Int J Bipolar Disord . 2017 ; 5 : 80 . doi: 10.1186/s40345-017-0080-x OpenUrl CrossRef 21. ↵ Undurraga J , Tay KH , Tan D , et al. Lithium treatment for unipolar major depressive disorder: systematic review . J Psychopharmacol . 2019 ; 33 ( 2 ): 167 – 176 . doi: 10.1177/0269881118822161 OpenUrl CrossRef PubMed 22. ↵ American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders . 3rd ed. Washington, DC : American Psychiatric Association ; 1980 . 23. ↵ Maser JD , Weise RE , Kaelber C. International use and attitudes toward DSM-III and DSM-III--R: growing consensus in psychiatric classification . J Abnorm Psychol . 1991 ; 100 ( 3 ): 271 – 279 . doi: 10.1037/0021-843X.100.3.271 OpenUrl CrossRef PubMed Web of Science 24. ↵ Ghaemi SN , Goodwin FK , Ko JY . The bipolar spectrum and the antidepressant view of the world . J Psychiatr Pract . 2001 ; 7 ( 5 ): 287 – 297 . OpenUrl CrossRef PubMed 25. Katzow JJ , Nassir Ghaemi S , Hsu DJ . The bipolar spectrum: a clinical perspective . Bipolar Disord . 2003 ; 5 ( 6 ): 436 – 442 . doi: 10.1046/j.139 OpenUrl CrossRef 26. ↵ Nusslock R , Frank E. Subthreshold bipolarity: diagnostic issues and challenges . Bipolar Disord . 2011 ; 13 ( 6 ): 587 – 603 . doi: 10.1111/j.1399-5618.2011.00957.x OpenUrl CrossRef PubMed Web of Science 27. ↵ Olfson M , Marcus SC . National patterns in antidepressant medication treatment . Arch Gen Psychiatry . 2009 ; 66 ( 8 ): 848 – 856 . doi: 10.1001/archgenpsychiatry.2009.81 OpenUrl CrossRef PubMed Web of Science 28. ↵ Sambamoorthi U , Walkup JT , Crystal S , Olfson M. Diffusion of new generation antidepressant treatment among elderly diagnosed with depression . Med Care . 2003 ; 41 ( 2 ): 180 – 194 . OpenUrl CrossRef PubMed Web of Science 29. ↵ Melfi CA , Sredl K , Croghan TW , et al. The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression . Arch Gen Psychiatry . 1998 ; 55 ( 12 ): 1128 – 1132 . doi: 10.1001/archpsyc.55.12.1128 OpenUrl CrossRef PubMed Web of Science 30. Hirschfeld RMA . Clinical importance of long-term antidepressant treatment . Br J Psychiatry . 2001 ; 179 ( 42 ): s4 – s8 . doi: 10.1192/bjp.179.42.s4 OpenUrl Abstract / FREE Full Text 31. ↵ Marasine NR , Sankhi S. Factors associated with antidepressant medication non-adherence . Turk J Pharm Sci . 2021 ; 18 ( 3 ): 242 – 249 . doi: 10.4274/tjps.galenos.2020.49799 OpenUrl CrossRef PubMed 32. ↵ Lin EHB , Bush T , Korff MV , et al. The role of the primary care physician in patients’ adherence to antidepressant therapy . Med Care . 1995 ; 33 ( 1 ): 67 – 74 . OpenUrl CrossRef PubMed Web of Science 33. Aikens JE . Adherence to maintenance-phase antidepressant medication as a function of patient beliefs about medication . Ann Fam Med . 2005 ; 3 ( 1 ): 23 – 30 . doi: 10.1370/afm.238 OpenUrl Abstract / FREE Full Text 34. Gonzalez J , Noel PH , Lee S , Williams JW . Adherence to mental health treatment in a primary care clinic . J Am Board Fam Med . 2005 ; 18 ( 2 ): 87 – 96 . doi: 10.3122/jabfm.18.2.87 OpenUrl Abstract / FREE Full Text 35. ↵ Simon GE , Ludman EJ , Operskalski BH . Randomized trial of a telephone care management program for outpatients starting antidepressant treatment . Psychiatr Serv . 2006 ; 57 ( 10 ): 1441 – 1445 . doi: 10.1176/ps.2006.57.10.1441 OpenUrl CrossRef PubMed Web of Science 36. ↵ Radloff LS . The CES-D scale: a self-report depression scale for research in the general population . Appl Psychol Meas . 1977 ; 1 ( 3 ): 385 – 401 . doi: 10.1177/014662167700100306 OpenUrl CrossRef 37. ↵ Middleton H , Hull S , Shaw I , Feder G. NICE guidelines for the management of depression . BMJ . 2005 ; 330 ( 7486 ): 267 – 268 . doi: 10.1136/bmj.330.7486.267 OpenUrl FREE Full Text 38. ↵ American Psychiatric Association . Diagnostic and Statistical Manual of Mental Disorders . 5th ed. Arlington, VA : American Psychiatric Publishing ; 2013 . 39. ↵ Angst J , Azorin JM , Bowden CL , et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study . Arch Gen Psychiatry . 2011 ; 68 ( 8 ): 791 – 798 . doi: 10.1001/archgenpsychiatry.2011.87 OpenUrl CrossRef PubMed Web of Science 40. Benazzi F. Various forms of depression . Dialogues Clin Neurosci . 2006 ; 8 ( 2 ): 151 – 161 . doi: 10.31887/DCNS.2006.8.2/fbenazzi . OpenUrl CrossRef PubMed 41. ↵ Angst J , Cui L , Van Meter A , et al. Bipolar spectrum in major depressive disorders . Eur Arch Psychiatry Clin Neurosci . 2018 ; 268 ( 8 ): 741 – 748 . doi: 10.1007/s00406-018-0927-x OpenUrl CrossRef PubMed 42. ↵ Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics . Bone Marrow Transplant . 2012 ; 48 ( 3 ): 452 – 458 . doi: 10.1038/bmt.2012.244 OpenUrl CrossRef PubMed 43. ↵ Cipriani A , Smith K , Burgess S , et al. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder . Cochrane Database Syst Rev . 2006 ;( 3 ): CD003492 . doi: 10.1002/14651858.CD003492.pub2 OpenUrl CrossRef PubMed 44. ↵ Bauer M , Müller-Oerlinghausen B , Kunz D , et al. Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression . Am J Psychiatry . 2000 ; 157 ( 9 ): 1429 – 1435 . doi: 10.1176/appi.ajp.157.9.1429 OpenUrl CrossRef PubMed Web of Science 45. ↵ Smith DJ , Kelly M , Hood K , et al. Unrecognised bipolar disorder in primary care patients with depression . Br J Psychiatry . 2011 ; 199 ( 1 ): 49 – 56 . doi: 10.1192/bjp.bp.110.083840 OpenUrl Abstract / FREE Full Text 46. ↵ Möller HJ , Baldwin DS , Stein DJ , et al. Do SSRIs or antidepressants in general increase suicidality? Eur Arch Psychiatry Clin Neurosci . 2008 ; 258 ( 1 ): 3 – 23 . doi: 10.1007/s00406-008-3002-1 OpenUrl CrossRef 47. ↵ Ueda M , Matsubayashi T , Nordström R. Suicide and mental health during the COVID-19 pandemic in Japan . J Public Health (Oxf) . 2021 ; 44 ( 3 ): 541 – 548 . doi: 10.1093/pubmed/fdab113 OpenUrl CrossRef 48. ↵ Asper M , Niemi ME , Pöllänen E , et al. Effects of the COVID-19 pandemic and previous pandemics, epidemics and economic crises on mental health: systematic review . BJPsych Open . 2022 ; 8 ( 6 ): 587 . doi: 10.1192/bjo.2022.587 OpenUrl CrossRef View the discussion thread. Back to top Previous Next Posted September 30, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Association of Low-Dose Mood Stabilizers With Treatment Retention in Unipolar Depression: A Retrospective Cohort Study Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. 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