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Lamotrigine and lithium in primary care psychiatric consultation: adoption and adverse effects

Lamotrigine and lithium in primary care psychiatric consultation: adoption and adverse effects Abstract Background The Collaborative Care Model of psychiatric consultation in primary care has improved outcomes for unipolar depression, but bipolar depressions are challenging for providers and consultants. Although lamotrigine and lithium are both first line medications for bipolar depression, their use in primary care has been declining over the last decade. Objective Our project aimed to quantify the frequency of and adoption of recommendations for lamotrigine and lithium, and their adverse effects, in a Collaborative Care program. Methods Chart review. Results For 620 depressed adult patients (Public Health Questionnaire, 9-item ≥10), lamotrigine and lithium were recommended by psychiatric consultant for 35% and 26% of patients, respectively; and when recommended, were prescribed by primary care providers 50% and 32% of the time, respectively. Eighty-four percent of lithium dosages were 600 mg or less; average serum level 0.32 mEq/l. In follow-up up to 6 months, lithium was associated with no more weight gain than lamotrigine; but 12% of patients receiving lithium had thyroid stimulating hormone increases exceeding the upper limit of normal, occurring in an average of 32 days after the initial prescription. Conclusions (i) In a Collaborative Care program of psychiatric consultation, recommendations for lamotrigine and lithium were very frequent. (ii) Adoption of these recommendations is variable, warranting further investigation. (iii) Like higher doses, low doses of lithium induced hypothyroidism (rapidly)—but not weight gain. Collaborative Care, depression, lamotrigine, lithium, primary health care psychiatry, referral and consultation Key messages Systematic assessment of bipolarity guides psychiatrists’ recommendations. Lamotrigine was recommended in 35% of consultations, lithium in 26%. When recommended, providers actually prescribed: lamotrigine 50% and lithium 32%. Eighty-four percent of lithium prescriptions were for 600 mg daily or less, mean level 0.43 mEq/l. Weight gain on lithium < on lamotrigine but rapid increases in thyroid stimulating hormone seen in 12%. Introduction Primary care providers (PCPs) deliver more mental health care than psychiatrists and psychotherapists combined (1) and prescribe the majority of psychotropic medications (2). But use of lamotrigine and lithium by PCPs has decreased markedly in the last 10 years, with a corresponding increase in the use of 2nd generation antipsychotics (3). Many PCPs understandably regard bipolar disorders as beyond their scope of practice (4). They prefer to transfer patients with bipolar disorder to a specialist. But in the UK in 2019, 10% of psychiatrist posts were unfilled—double the rate in 2013 (5). Likewise, in the USA, most areas have too few psychiatric specialists, a problem forecast to worsen (6). Thus, PCPs are often managing bipolar disorders, even if not by preference. To help make psychiatric assistance more available in primary care, a system for remote psychiatric consultation in primary care was developed at the University of Washington: the Collaborative Care Model (CoCM) (7). This approach has been shown in multiple randomized trials to improve primary care of depression (8). Bipolar disorders, however, have proved challenging in the CoCM (9). Moreover, mood specialists around the world are increasingly suggesting that mood disorders be regarded as a spectrum from unipolar to bipolar, rather than separate conditions (10–12). This complicates identification and management of mood disorders in primary care: if there is no line between unipolar and bipolar disorders, there is no boundary for scope of practice and no clear indication to switch treatments, e.g. from antidepressants to mood stabilizers. In an Oregon (USA) variation of the CoCM (13), we include a system for identifying bipolarity, not just those bipolar disorder as defined by Diagnostic and Statistical Manual (DSM-5) criteria, as long advocated by bipolar experts (14). Consultants’ treatment recommendations are similarly nuanced, but often include lamotrigine and lithium, as these have been consistently recommended for bipolar depression in treatment guidelines from around the world (15). Can a CoCM program help PCPs ‘rediscover’ lamotrigine and lithium? Will PCPs accept a dimensional approach to depression that leads to these medications, without a formal bipolar diagnosis? Using data from our CoCM program, we set out to address these questions. Specifically, we sought to quantify the frequency of consultants’ recommendations for lamotrigine and lithium; the frequency with which these recommendations were implemented by PCPs; the doses of lithium used and adverse effects thereof. Methods Population Our Institutional Review Board approved this inquiry as Exempt Research. We reviewed consecutive CoCM referrals for patients with depression, as defined by a Public Health Questionnaire, 9-item (PHQ-9) ≥10 at the time of consultation or within 3 months prior; whose age was over 18; and who had at least one follow-up PHQ-9 in the 6 months after consultation; for consultations recorded between 1/1/15 and 5/1/19. Because new prescriptions of lamotrigine or low-dose lithium were our primary interest during the design of this study, patients who had received these medications prior to their consult, per 6-year electronic health record (EHR) data, were excluded. This reflects an initial research focus on clinical outcomes with these medications, and limited funding for manual chart review. [Further explanation of this exclusion is presented in the online supplement (16) of a previous publication (17).] Measures The structure of our CoCM variation including data gathered by our in-clinic psychiatric assistant (Mental Health Specialists, MHS) has been described previously (13,17). In brief, the MHS takes warm hand-offs from PCPs who have identified a possible mood or anxiety or other mental disorder. They then conduct a structured interview (same day or scheduled) and chart their findings in the patients’ EHR. Included in the interview are a series of standard measures: the PHQ-9, a widely used tool for quantifying depression; the Generalized Anxiety Disorder, 7-item (GAD-7), an analogous tool for anxiety symptoms (18); and the Composite International Diagnostic Interview (CIDI) version 3.0, a 9-point structured interview from the World Health Organization’s for detecting bipolar disorders (19). All referred patients also complete a questionnaire (with assistance from the MHS as needed) gathering information on variables that have been consistently associated with bipolar disorders, presence of which therefore increases the probability that a depression has bipolarity (20). These non-manic bipolar markers include: family history; age of onset of first depression; course of illness (highly recurrent depressions, post-partum onsets) and response to treatment (including highly overenergized experiences on antidepressants) (21). The CIDI 3.0 elicits a prior history of hypomanic or manic symptoms, serving a role similar to the more widely known Mood Disorder Questionnaire (MDQ), but with higher sensitivity, specificity and predictive values (22,23). Interpretation of the CIDI results in the context of data on non-manic bipolar markers can substantially increase the positive predictive value of CIDI results (24). The PHQ-9 is routinely used in primary care to quantify depression (25). In our program, as in most CoCM programs, all patients complete a PHQ-9 at the time of referral and serially thereafter to track and adjust treatment response. This questionnaire’s item 9 queries degree of suicidal ideation, from 0 to 4. For this study, all responses greater than 0 were regarded as indicating the presence of suicidal ideation. We also administer the GAD-7 initially and serially, for assessment of anxiety symptoms pertinent to a variety of anxiety disorders and also pertinent to bipolar mixed states, where anxiety can be a prominent symptom (26). Consultants’ treatment recommendations were assessed by manual chart review, noting whether a recommendation was made for lamotrigine and/or lithium or neither. PCPs’ prescriptions for lamotrigine and/or lithium were obtained from the EHR, also noting lithium dosages. Data regarding treatment-emergent adverse reactions were obtained from the EHR. Where warranted, individual charts were reviewed to confirm the timing of prescriptions and adverse events. Statistical analysis The primary outcome of interest was the use of lamotrigine and lithium in primary care, as reflected in consultants’ recommendations and PCP’s prescriptions. Linear regression models were used to determine whether three groups—patients receiving lamotrigine, lithium or neither—differed significantly in PHQ-9 or GAD-7 outcomes at 0–3 months and at 3–6 months, after adjusting for differences in baseline scores. All analyses were performed in R version 3.6.1. Results Study sample Medical record data were available for 1476 consultations on patients ≥18 years of age. We excluded 129 patients who had no PHQ-9 or GAD-7 data available within 3 months prior to their psych review; 246 patients whose PHQ-9 within 3 months of their consultation was <10; and 439 patients who had previously received lamotrigine and lithium. Forty-two additional patients were excluded as they did not complete a CIDI or the standard patient questionnaire in the consultation process. This left a study sample of 620 patients whose demographics and prior primary care diagnoses are shown in Table 1. We did not exclude patients with a prior primary care diagnosis of bipolar disorder. In this sample, patients’ average age is 45 (S.D. 16.5); 68% are female. Suicidal ideation was present (PHQ-9 item 9 >0) in 46% of these depressed patients. Table 1. Demographics and primary care psychiatric diagnoses on problem list in Collaborative Care Consultation of depressed patients (2015–19) . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 PTSD, Post-Traumatic Stress Disorder; ADHD/ADD, Attention-Deficit Hyperactivity Disorder/Attention Deficit Disorder. Open in new tab Table 1. Demographics and primary care psychiatric diagnoses on problem list in Collaborative Care Consultation of depressed patients (2015–19) . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 PTSD, Post-Traumatic Stress Disorder; ADHD/ADD, Attention-Deficit Hyperactivity Disorder/Attention Deficit Disorder. Open in new tab Recommendations and prescriptions As in most CoCM programs, in our variation psychiatrists operating remotely make treatment recommendations for patients on whom they consult. With rare exceptions, they do not conduct patient interviews, provide patient education, assist in shared decision-making or write prescriptions. PCPs evaluate the psychiatrist’s recommendations and decide whether, how and when to implement them. Table 2 shows the rate at which psychiatrists recommended lamotrigine and lithium for patients who (per the inclusion criteria of this study) had a PHQ-9 ≥10 and the rate at which the PCPs followed those recommendations. Table 2. Adoption rate of consultants’ recommendations by providers in Collaborative Care Consultation for depressed patients (2015–19) Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Open in new tab Table 2. Adoption rate of consultants’ recommendations by providers in Collaborative Care Consultation for depressed patients (2015–19) Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Open in new tab The majority of prescriptions for lamotrigine and lithium were written for patients in whom either the CIDI or the consultant’s impression indicated bipolarity (depression with prior or concurrent hypomanic symptoms that fall shy of DSM thresholds for Bipolar II). For patients without such an indication, lithium was prescribed in 6% (21/359) and lamotrigine in 6% (20/359). The Supplement contains additional data on rates of bipolarity in those for whom lamotrigine and lithium were recommended (as opposed to prescribed); and preliminary data on efficacy of these medications among depressed referred patients (PHQ-9 and GAD-7 scores before and after consultation). Lithium dosages and levels PCPs’ lithium prescriptions were for small doses: 600 mg daily or less in 84% of prescriptions ordered, with an average lithium level of 0.43 mEq/l (range 0.1–1.0). The highest dose was 900 mg daily, except when follow-up was assumed by psychiatrists, for three patients, who had higher dosages and levels. Of the 54 study patients for whom lithium was prescribed, 33% (18/54) of patients did not start or did not continue for more than 2 months. Of those who continued longer, 92% (33/36) had a lithium level. Adverse effects Weight gain As shown in Table 3, weight gain was not greater for lithium than for lamotrigine or neither medication. Table 3. Treatment-emergent adverse effects within 6 months of baseline by medications prescribed in Collaborative Care Consultation of depressed patients, 2015–19 (percentages reflect the portion of the exposed group with the adverse effect) Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 aDenominators in the N/N columns reflect the number of patients with data available for each adverse effect. bmIU/l; including only patients with no previous history of elevated TSH. Open in new tab Table 3. Treatment-emergent adverse effects within 6 months of baseline by medications prescribed in Collaborative Care Consultation of depressed patients, 2015–19 (percentages reflect the portion of the exposed group with the adverse effect) Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 aDenominators in the N/N columns reflect the number of patients with data available for each adverse effect. bmIU/l; including only patients with no previous history of elevated TSH. Open in new tab Hypothyroidism The low doses of lithium received by patients in this sample were associated with increases of thyroid stimulating hormone (TSH) beyond the upper limit of normal (4.2 mIU/l in our laboratory). As shown in Table 3, the rate of this elevation was 12% for lithium (5/42; alone or with lamotrigine) versus 2% on lamotrigine. Manual chart review revealed that these five patients’ elevation occurred quickly: the average interval between a normal value before lithium and their elevated value after prescription was 32 days (range 18–52). Creatinine elevation Creatinine reached 1.2 mg/dl in two patients given lithium. In both cases the consultant had warned specifically about that patient’s renal risk, because creatinine was already at 1.0 or 1.1. Lithium was discontinued in both cases, and neither progressed further towards renal failure. Severe reactions There were no observed lithium levels over 1.0 mEq/l among patients whose management remained in primary care. Regarding lamotrigine, in the 6 months after consultation, none of the patients’ charts include diagnoses of severe allergic reactions (Stephens–Johnson syndrome, toxic epidermal necrolysis or hemophagocytic lymphohistiocytosis). Discussion In these results from one variation of the CoCM: (i) lamotrigine and lithium were widely recommended by consultants; (ii) PCPs often, but not always, followed these recommendations; (iii) dosages of lithium were very low and were not associated with weight gain but did induce hypothyroidism at rates similar to those seen with higher lithium doses. Feasibility of lamotrigine and lithium in primary care Based on our clinical experience, many clinicians in our primary care clinics would have preferred that patients with bipolar disorder be transferred to a psychiatrist for management. But when given a choice of a 6-month waiting list or immediate availability of an MHS and rapid remote psychiatric consultation, the CoCM program has been accepted and appreciated (13). Data shown here demonstrate that in this context, PCPs routinely prescribe lamotrigine and low-dose lithium. We did not quantify prescription of 2nd generation antipsychotics prior to or after the CoCM program so cannot determine whether increased use of mood stabilizers directly decreased use of the antipsychotics, countering the last decade’s trend (3). On the other hand, consultants’ recommendations for lithium led to PCP prescriptions in only 32% of the cases. The other 68% could reflect disinclination by PCPs or patients; our data do not indicate which. But even when lithium was prescribed, it was not started or not continued beyond 2 months by 33% of patients. Overall these results suggest that CoCM programs may need to offer systematic assistance with patient education and shared decision-making when low-dose lithium is recommended. Interestingly, a library of over 700 decision aids (27) includes 7 tools for depression but only one bipolar-related tool (a complex site about Bipolar II) (28). These results reflect the experience of a single CoCM program in the USA. CoCM programs have had very different experiences with detection and treatment of bipolar disorders, e.g. bipolar screening rates varying from 18% (29) to 97% (17). CoCM visits are now funded by Medicare (30) but despite dissemination efforts (31), CoCM programs are not yet prevalent. Thus our results cannot be widely generalized, but they do demonstrate that in at least one context, routine prescription and management of lamotrigine and lithium in primary care is feasible. Lithium dosages While use of lamotrigine is relatively straightforward, and familiar to PCPs from use as an anticonvulsant, lithium can be more intimidating. Guidelines for its use tend to be extensive (32). But in the CoCM, psychiatric assistance is close at hand. Our consultants often recommended very low initial doses and cautious titration, e.g. increasing all-at-bedtime dosing by 150 mg steps every 4–7 days until response, or any problems (decrease to the previous dose), or 600 mg nightly, followed by a blood level. Lithium efficacy Preliminary data on patient outcomes are presented in the Supplement. Small sample size prevents any conclusions but suggests study of the efficacy of lithium in primary care is warranted. In general, in mood disorders, lithium has three roles: (i) as an adjunct to an antidepressant; (ii) in bipolar depression and (iii) for suicide risk reduction. As an adjunct in the treatment of mood disorders, lithium is a first or second line option in ten recent guidelines (33). The dosage in this role is not fully established but trough levels of 0.5–0.8 mEq/l have been recommended (34), based largely on one review which found lower doses less effective (35). Given that many of the patients in this study were on an antidepressant at the time of consultation [per a previous study in the same population (36)], lithium was likely frequently used in an adjunctive role. For bipolar depression, efficacy of lithium (at any dose) is debated (37). In recently updated guidelines from the Canadian Network for Mood and Anxiety Treatments and the International Society for Bipolar Disorders, lithium is a first line option although a trough level of 0.8–1.2 mEq/l is recommended (15). To our knowledge, lithium has not been studied as mono- or adjunctive therapy for subthreshold bipolarity. Lithium has a specific anti-suicide effect at usual therapeutic doses not seen with other adjunctive options such as atypical antipsychotics or other mood stabilizers (38). Moreover, this effect of lithium has been observed even at levels found in some municipal water supplies (39). By extension it seems likely that even very low doses of lithium such as used by PCPs in this study can reduce suicide risk. Thus, the fact that 46% of our sample had suicidal ideation (PHQ-9 item 9 >0) may have contributed to consultants’ recommendations for lithium. Our data do not indicate which of these potential roles for lithium (antidepressant adjunct; for bipolar depression or for suicide risk reduction) drove consultants’ recommendations. Adverse effects Assessment of adverse effects in this study was limited to reactions posing significant risk to patients and documented in the medical record. Overall, we found that PCPs using medications they are sometimes hesitant to prescribe (4) did so safely. PHQ-9 and GAD-7 outcome data provide preliminary evidence that clinical benefit can be achieved despite the cautious dosages which kept adverse effects infrequent. Rate of obtaining serum lithium levels when warranted (92%) was superior to some psychiatrists’ rates (68%) (40), closer to that seen following a primary care quality improvement program (96%) (41). However, two concerns remain: first, though essentially case reports within this study, it appears that even low doses of lithium can quickly increase creatinine in patients who already have some evidence of renal compromise (e.g. a creatinine of 1.0 or 1.1). Second, though our sample is small, it appears that even low doses of lithium may cause increases in TSH in some patients, surprisingly quickly, exceeding the upper limit of normal in an average of 32 days after lithium was initiated. When should one be concerned if TSH is increasing on lithium? Certainly if depressive symptoms remain (i.e. not asymptomatic subclinical hypothyroidism), and especially if they are worsening after an initial positive response to lithium. Cohen et al. suggest a TSH >2.5 µIU/ml should trigger consideration of levothyroxine (42). Our results imply that obtaining a follow-up TSH earlier than some guidelines suggest [e.g. Up-to-Date, 6 months (43)] is warranted. In the 6 months after consultation, weight gain on low doses of lithium and low blood levels was not greater than on lamotrigine or neither medication, but this observation is limited by small sample sizes; it warrants replication. Limitations Limitations of this study include small sample size in some subgroups, which arise primarily from deliberate exclusions but also from missing data. Additional limitations include narrow ethnicity: though representative of our Pacific Northwest population, the sample is highly skewed, diminishing the generalizability of the reported findings. Conclusions (i) In a Collaborative Care program of psychiatric consultation, recommendations for lamotrigine and lithium were frequent. (ii) Adoption of these recommendations was far below 100%, warranting further investigation. (iii) Low doses of lithium were not associated with weight gain, but did rapidly induce hypothyroidism. These results suggest that a Collaborative Care program of psychiatric consultation in primary care can facilitate the use of lamotrigine and lithium, reversing recent trends towards other medications with more severe short- and long-term risks. Declaration Funding: our IRB approved this study as Exempt Research, which was supported in part by a grant from the John C Erkkila, MD, Endowment for Health and Human Performance, award # GN00456-16. Dr Phelps receives royalties from McGraw-Hill and W.W. Norton & Co. for books on bipolar disorders. Ethical approval: not applicable. Conflict of interest: none. Data availability The data underlying this article will be shared on reasonable request to the corresponding author. References 1. Kroenke K , Unutzer J. 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UpToDate . https://www.uptodate.com/contents/lithium-and-the-thyroid (accessed on 10 August 2020 ). © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Family Practice Oxford University Press

Lamotrigine and lithium in primary care psychiatric consultation: adoption and adverse effects

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Oxford University Press
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Copyright © 2021 Oxford University Press
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0263-2136
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10.1093/fampra/cmaa131
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Abstract

Abstract Background The Collaborative Care Model of psychiatric consultation in primary care has improved outcomes for unipolar depression, but bipolar depressions are challenging for providers and consultants. Although lamotrigine and lithium are both first line medications for bipolar depression, their use in primary care has been declining over the last decade. Objective Our project aimed to quantify the frequency of and adoption of recommendations for lamotrigine and lithium, and their adverse effects, in a Collaborative Care program. Methods Chart review. Results For 620 depressed adult patients (Public Health Questionnaire, 9-item ≥10), lamotrigine and lithium were recommended by psychiatric consultant for 35% and 26% of patients, respectively; and when recommended, were prescribed by primary care providers 50% and 32% of the time, respectively. Eighty-four percent of lithium dosages were 600 mg or less; average serum level 0.32 mEq/l. In follow-up up to 6 months, lithium was associated with no more weight gain than lamotrigine; but 12% of patients receiving lithium had thyroid stimulating hormone increases exceeding the upper limit of normal, occurring in an average of 32 days after the initial prescription. Conclusions (i) In a Collaborative Care program of psychiatric consultation, recommendations for lamotrigine and lithium were very frequent. (ii) Adoption of these recommendations is variable, warranting further investigation. (iii) Like higher doses, low doses of lithium induced hypothyroidism (rapidly)—but not weight gain. Collaborative Care, depression, lamotrigine, lithium, primary health care psychiatry, referral and consultation Key messages Systematic assessment of bipolarity guides psychiatrists’ recommendations. Lamotrigine was recommended in 35% of consultations, lithium in 26%. When recommended, providers actually prescribed: lamotrigine 50% and lithium 32%. Eighty-four percent of lithium prescriptions were for 600 mg daily or less, mean level 0.43 mEq/l. Weight gain on lithium < on lamotrigine but rapid increases in thyroid stimulating hormone seen in 12%. Introduction Primary care providers (PCPs) deliver more mental health care than psychiatrists and psychotherapists combined (1) and prescribe the majority of psychotropic medications (2). But use of lamotrigine and lithium by PCPs has decreased markedly in the last 10 years, with a corresponding increase in the use of 2nd generation antipsychotics (3). Many PCPs understandably regard bipolar disorders as beyond their scope of practice (4). They prefer to transfer patients with bipolar disorder to a specialist. But in the UK in 2019, 10% of psychiatrist posts were unfilled—double the rate in 2013 (5). Likewise, in the USA, most areas have too few psychiatric specialists, a problem forecast to worsen (6). Thus, PCPs are often managing bipolar disorders, even if not by preference. To help make psychiatric assistance more available in primary care, a system for remote psychiatric consultation in primary care was developed at the University of Washington: the Collaborative Care Model (CoCM) (7). This approach has been shown in multiple randomized trials to improve primary care of depression (8). Bipolar disorders, however, have proved challenging in the CoCM (9). Moreover, mood specialists around the world are increasingly suggesting that mood disorders be regarded as a spectrum from unipolar to bipolar, rather than separate conditions (10–12). This complicates identification and management of mood disorders in primary care: if there is no line between unipolar and bipolar disorders, there is no boundary for scope of practice and no clear indication to switch treatments, e.g. from antidepressants to mood stabilizers. In an Oregon (USA) variation of the CoCM (13), we include a system for identifying bipolarity, not just those bipolar disorder as defined by Diagnostic and Statistical Manual (DSM-5) criteria, as long advocated by bipolar experts (14). Consultants’ treatment recommendations are similarly nuanced, but often include lamotrigine and lithium, as these have been consistently recommended for bipolar depression in treatment guidelines from around the world (15). Can a CoCM program help PCPs ‘rediscover’ lamotrigine and lithium? Will PCPs accept a dimensional approach to depression that leads to these medications, without a formal bipolar diagnosis? Using data from our CoCM program, we set out to address these questions. Specifically, we sought to quantify the frequency of consultants’ recommendations for lamotrigine and lithium; the frequency with which these recommendations were implemented by PCPs; the doses of lithium used and adverse effects thereof. Methods Population Our Institutional Review Board approved this inquiry as Exempt Research. We reviewed consecutive CoCM referrals for patients with depression, as defined by a Public Health Questionnaire, 9-item (PHQ-9) ≥10 at the time of consultation or within 3 months prior; whose age was over 18; and who had at least one follow-up PHQ-9 in the 6 months after consultation; for consultations recorded between 1/1/15 and 5/1/19. Because new prescriptions of lamotrigine or low-dose lithium were our primary interest during the design of this study, patients who had received these medications prior to their consult, per 6-year electronic health record (EHR) data, were excluded. This reflects an initial research focus on clinical outcomes with these medications, and limited funding for manual chart review. [Further explanation of this exclusion is presented in the online supplement (16) of a previous publication (17).] Measures The structure of our CoCM variation including data gathered by our in-clinic psychiatric assistant (Mental Health Specialists, MHS) has been described previously (13,17). In brief, the MHS takes warm hand-offs from PCPs who have identified a possible mood or anxiety or other mental disorder. They then conduct a structured interview (same day or scheduled) and chart their findings in the patients’ EHR. Included in the interview are a series of standard measures: the PHQ-9, a widely used tool for quantifying depression; the Generalized Anxiety Disorder, 7-item (GAD-7), an analogous tool for anxiety symptoms (18); and the Composite International Diagnostic Interview (CIDI) version 3.0, a 9-point structured interview from the World Health Organization’s for detecting bipolar disorders (19). All referred patients also complete a questionnaire (with assistance from the MHS as needed) gathering information on variables that have been consistently associated with bipolar disorders, presence of which therefore increases the probability that a depression has bipolarity (20). These non-manic bipolar markers include: family history; age of onset of first depression; course of illness (highly recurrent depressions, post-partum onsets) and response to treatment (including highly overenergized experiences on antidepressants) (21). The CIDI 3.0 elicits a prior history of hypomanic or manic symptoms, serving a role similar to the more widely known Mood Disorder Questionnaire (MDQ), but with higher sensitivity, specificity and predictive values (22,23). Interpretation of the CIDI results in the context of data on non-manic bipolar markers can substantially increase the positive predictive value of CIDI results (24). The PHQ-9 is routinely used in primary care to quantify depression (25). In our program, as in most CoCM programs, all patients complete a PHQ-9 at the time of referral and serially thereafter to track and adjust treatment response. This questionnaire’s item 9 queries degree of suicidal ideation, from 0 to 4. For this study, all responses greater than 0 were regarded as indicating the presence of suicidal ideation. We also administer the GAD-7 initially and serially, for assessment of anxiety symptoms pertinent to a variety of anxiety disorders and also pertinent to bipolar mixed states, where anxiety can be a prominent symptom (26). Consultants’ treatment recommendations were assessed by manual chart review, noting whether a recommendation was made for lamotrigine and/or lithium or neither. PCPs’ prescriptions for lamotrigine and/or lithium were obtained from the EHR, also noting lithium dosages. Data regarding treatment-emergent adverse reactions were obtained from the EHR. Where warranted, individual charts were reviewed to confirm the timing of prescriptions and adverse events. Statistical analysis The primary outcome of interest was the use of lamotrigine and lithium in primary care, as reflected in consultants’ recommendations and PCP’s prescriptions. Linear regression models were used to determine whether three groups—patients receiving lamotrigine, lithium or neither—differed significantly in PHQ-9 or GAD-7 outcomes at 0–3 months and at 3–6 months, after adjusting for differences in baseline scores. All analyses were performed in R version 3.6.1. Results Study sample Medical record data were available for 1476 consultations on patients ≥18 years of age. We excluded 129 patients who had no PHQ-9 or GAD-7 data available within 3 months prior to their psych review; 246 patients whose PHQ-9 within 3 months of their consultation was <10; and 439 patients who had previously received lamotrigine and lithium. Forty-two additional patients were excluded as they did not complete a CIDI or the standard patient questionnaire in the consultation process. This left a study sample of 620 patients whose demographics and prior primary care diagnoses are shown in Table 1. We did not exclude patients with a prior primary care diagnosis of bipolar disorder. In this sample, patients’ average age is 45 (S.D. 16.5); 68% are female. Suicidal ideation was present (PHQ-9 item 9 >0) in 46% of these depressed patients. Table 1. Demographics and primary care psychiatric diagnoses on problem list in Collaborative Care Consultation of depressed patients (2015–19) . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 PTSD, Post-Traumatic Stress Disorder; ADHD/ADD, Attention-Deficit Hyperactivity Disorder/Attention Deficit Disorder. Open in new tab Table 1. Demographics and primary care psychiatric diagnoses on problem list in Collaborative Care Consultation of depressed patients (2015–19) . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 . % . N . Race  White or Caucasian 95 592  Other 3 18  Unknown or patient refused 2 10 Primary care problem list psychiatric diagnoses  Anxiety disorders 55 341  Depressive or dysthymia 40 249  Substance use disorder 19 119  PTSD 16 99  Bipolar disorder 12 72  ADHD/ADD 8 51  Adjustment disorder 4 23  Schizophrenia 1 7 PTSD, Post-Traumatic Stress Disorder; ADHD/ADD, Attention-Deficit Hyperactivity Disorder/Attention Deficit Disorder. Open in new tab Recommendations and prescriptions As in most CoCM programs, in our variation psychiatrists operating remotely make treatment recommendations for patients on whom they consult. With rare exceptions, they do not conduct patient interviews, provide patient education, assist in shared decision-making or write prescriptions. PCPs evaluate the psychiatrist’s recommendations and decide whether, how and when to implement them. Table 2 shows the rate at which psychiatrists recommended lamotrigine and lithium for patients who (per the inclusion criteria of this study) had a PHQ-9 ≥10 and the rate at which the PCPs followed those recommendations. Table 2. Adoption rate of consultants’ recommendations by providers in Collaborative Care Consultation for depressed patients (2015–19) Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Open in new tab Table 2. Adoption rate of consultants’ recommendations by providers in Collaborative Care Consultation for depressed patients (2015–19) Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Medication . Recommended by consultants, % of all study cases . N/N . Prescribed by PCPs when recommended, % . N/N . Lamotrigine 35 220/620 50 111/220 Lithium 26 161/620 32 51/161 Open in new tab The majority of prescriptions for lamotrigine and lithium were written for patients in whom either the CIDI or the consultant’s impression indicated bipolarity (depression with prior or concurrent hypomanic symptoms that fall shy of DSM thresholds for Bipolar II). For patients without such an indication, lithium was prescribed in 6% (21/359) and lamotrigine in 6% (20/359). The Supplement contains additional data on rates of bipolarity in those for whom lamotrigine and lithium were recommended (as opposed to prescribed); and preliminary data on efficacy of these medications among depressed referred patients (PHQ-9 and GAD-7 scores before and after consultation). Lithium dosages and levels PCPs’ lithium prescriptions were for small doses: 600 mg daily or less in 84% of prescriptions ordered, with an average lithium level of 0.43 mEq/l (range 0.1–1.0). The highest dose was 900 mg daily, except when follow-up was assumed by psychiatrists, for three patients, who had higher dosages and levels. Of the 54 study patients for whom lithium was prescribed, 33% (18/54) of patients did not start or did not continue for more than 2 months. Of those who continued longer, 92% (33/36) had a lithium level. Adverse effects Weight gain As shown in Table 3, weight gain was not greater for lithium than for lamotrigine or neither medication. Table 3. Treatment-emergent adverse effects within 6 months of baseline by medications prescribed in Collaborative Care Consultation of depressed patients, 2015–19 (percentages reflect the portion of the exposed group with the adverse effect) Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 aDenominators in the N/N columns reflect the number of patients with data available for each adverse effect. bmIU/l; including only patients with no previous history of elevated TSH. Open in new tab Table 3. Treatment-emergent adverse effects within 6 months of baseline by medications prescribed in Collaborative Care Consultation of depressed patients, 2015–19 (percentages reflect the portion of the exposed group with the adverse effect) Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 Medication group . ≥3% wt. gain, % . N/Na . ≥5% wt. gain, % . N/N . Follow-up TSH >4.2b, % . N/N . Lamotrigine 40 46/114 25 28/114 2 1/46 Lithium 38 20/52 21 11/52 8 3/39 Both 71 5/7 43 3/7 67 2/3 Neither 37 151/403 24 96/403 8 11/130 aDenominators in the N/N columns reflect the number of patients with data available for each adverse effect. bmIU/l; including only patients with no previous history of elevated TSH. Open in new tab Hypothyroidism The low doses of lithium received by patients in this sample were associated with increases of thyroid stimulating hormone (TSH) beyond the upper limit of normal (4.2 mIU/l in our laboratory). As shown in Table 3, the rate of this elevation was 12% for lithium (5/42; alone or with lamotrigine) versus 2% on lamotrigine. Manual chart review revealed that these five patients’ elevation occurred quickly: the average interval between a normal value before lithium and their elevated value after prescription was 32 days (range 18–52). Creatinine elevation Creatinine reached 1.2 mg/dl in two patients given lithium. In both cases the consultant had warned specifically about that patient’s renal risk, because creatinine was already at 1.0 or 1.1. Lithium was discontinued in both cases, and neither progressed further towards renal failure. Severe reactions There were no observed lithium levels over 1.0 mEq/l among patients whose management remained in primary care. Regarding lamotrigine, in the 6 months after consultation, none of the patients’ charts include diagnoses of severe allergic reactions (Stephens–Johnson syndrome, toxic epidermal necrolysis or hemophagocytic lymphohistiocytosis). Discussion In these results from one variation of the CoCM: (i) lamotrigine and lithium were widely recommended by consultants; (ii) PCPs often, but not always, followed these recommendations; (iii) dosages of lithium were very low and were not associated with weight gain but did induce hypothyroidism at rates similar to those seen with higher lithium doses. Feasibility of lamotrigine and lithium in primary care Based on our clinical experience, many clinicians in our primary care clinics would have preferred that patients with bipolar disorder be transferred to a psychiatrist for management. But when given a choice of a 6-month waiting list or immediate availability of an MHS and rapid remote psychiatric consultation, the CoCM program has been accepted and appreciated (13). Data shown here demonstrate that in this context, PCPs routinely prescribe lamotrigine and low-dose lithium. We did not quantify prescription of 2nd generation antipsychotics prior to or after the CoCM program so cannot determine whether increased use of mood stabilizers directly decreased use of the antipsychotics, countering the last decade’s trend (3). On the other hand, consultants’ recommendations for lithium led to PCP prescriptions in only 32% of the cases. The other 68% could reflect disinclination by PCPs or patients; our data do not indicate which. But even when lithium was prescribed, it was not started or not continued beyond 2 months by 33% of patients. Overall these results suggest that CoCM programs may need to offer systematic assistance with patient education and shared decision-making when low-dose lithium is recommended. Interestingly, a library of over 700 decision aids (27) includes 7 tools for depression but only one bipolar-related tool (a complex site about Bipolar II) (28). These results reflect the experience of a single CoCM program in the USA. CoCM programs have had very different experiences with detection and treatment of bipolar disorders, e.g. bipolar screening rates varying from 18% (29) to 97% (17). CoCM visits are now funded by Medicare (30) but despite dissemination efforts (31), CoCM programs are not yet prevalent. Thus our results cannot be widely generalized, but they do demonstrate that in at least one context, routine prescription and management of lamotrigine and lithium in primary care is feasible. Lithium dosages While use of lamotrigine is relatively straightforward, and familiar to PCPs from use as an anticonvulsant, lithium can be more intimidating. Guidelines for its use tend to be extensive (32). But in the CoCM, psychiatric assistance is close at hand. Our consultants often recommended very low initial doses and cautious titration, e.g. increasing all-at-bedtime dosing by 150 mg steps every 4–7 days until response, or any problems (decrease to the previous dose), or 600 mg nightly, followed by a blood level. Lithium efficacy Preliminary data on patient outcomes are presented in the Supplement. Small sample size prevents any conclusions but suggests study of the efficacy of lithium in primary care is warranted. In general, in mood disorders, lithium has three roles: (i) as an adjunct to an antidepressant; (ii) in bipolar depression and (iii) for suicide risk reduction. As an adjunct in the treatment of mood disorders, lithium is a first or second line option in ten recent guidelines (33). The dosage in this role is not fully established but trough levels of 0.5–0.8 mEq/l have been recommended (34), based largely on one review which found lower doses less effective (35). Given that many of the patients in this study were on an antidepressant at the time of consultation [per a previous study in the same population (36)], lithium was likely frequently used in an adjunctive role. For bipolar depression, efficacy of lithium (at any dose) is debated (37). In recently updated guidelines from the Canadian Network for Mood and Anxiety Treatments and the International Society for Bipolar Disorders, lithium is a first line option although a trough level of 0.8–1.2 mEq/l is recommended (15). To our knowledge, lithium has not been studied as mono- or adjunctive therapy for subthreshold bipolarity. Lithium has a specific anti-suicide effect at usual therapeutic doses not seen with other adjunctive options such as atypical antipsychotics or other mood stabilizers (38). Moreover, this effect of lithium has been observed even at levels found in some municipal water supplies (39). By extension it seems likely that even very low doses of lithium such as used by PCPs in this study can reduce suicide risk. Thus, the fact that 46% of our sample had suicidal ideation (PHQ-9 item 9 >0) may have contributed to consultants’ recommendations for lithium. Our data do not indicate which of these potential roles for lithium (antidepressant adjunct; for bipolar depression or for suicide risk reduction) drove consultants’ recommendations. Adverse effects Assessment of adverse effects in this study was limited to reactions posing significant risk to patients and documented in the medical record. Overall, we found that PCPs using medications they are sometimes hesitant to prescribe (4) did so safely. PHQ-9 and GAD-7 outcome data provide preliminary evidence that clinical benefit can be achieved despite the cautious dosages which kept adverse effects infrequent. Rate of obtaining serum lithium levels when warranted (92%) was superior to some psychiatrists’ rates (68%) (40), closer to that seen following a primary care quality improvement program (96%) (41). However, two concerns remain: first, though essentially case reports within this study, it appears that even low doses of lithium can quickly increase creatinine in patients who already have some evidence of renal compromise (e.g. a creatinine of 1.0 or 1.1). Second, though our sample is small, it appears that even low doses of lithium may cause increases in TSH in some patients, surprisingly quickly, exceeding the upper limit of normal in an average of 32 days after lithium was initiated. When should one be concerned if TSH is increasing on lithium? Certainly if depressive symptoms remain (i.e. not asymptomatic subclinical hypothyroidism), and especially if they are worsening after an initial positive response to lithium. Cohen et al. suggest a TSH >2.5 µIU/ml should trigger consideration of levothyroxine (42). Our results imply that obtaining a follow-up TSH earlier than some guidelines suggest [e.g. Up-to-Date, 6 months (43)] is warranted. In the 6 months after consultation, weight gain on low doses of lithium and low blood levels was not greater than on lamotrigine or neither medication, but this observation is limited by small sample sizes; it warrants replication. Limitations Limitations of this study include small sample size in some subgroups, which arise primarily from deliberate exclusions but also from missing data. Additional limitations include narrow ethnicity: though representative of our Pacific Northwest population, the sample is highly skewed, diminishing the generalizability of the reported findings. Conclusions (i) In a Collaborative Care program of psychiatric consultation, recommendations for lamotrigine and lithium were frequent. (ii) Adoption of these recommendations was far below 100%, warranting further investigation. (iii) Low doses of lithium were not associated with weight gain, but did rapidly induce hypothyroidism. These results suggest that a Collaborative Care program of psychiatric consultation in primary care can facilitate the use of lamotrigine and lithium, reversing recent trends towards other medications with more severe short- and long-term risks. Declaration Funding: our IRB approved this study as Exempt Research, which was supported in part by a grant from the John C Erkkila, MD, Endowment for Health and Human Performance, award # GN00456-16. Dr Phelps receives royalties from McGraw-Hill and W.W. Norton & Co. for books on bipolar disorders. Ethical approval: not applicable. Conflict of interest: none. Data availability The data underlying this article will be shared on reasonable request to the corresponding author. References 1. Kroenke K , Unutzer J. 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UpToDate . https://www.uptodate.com/contents/lithium-and-the-thyroid (accessed on 10 August 2020 ). © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Family Practice – Oxford University Press

Published: Dec 26, 2020

Keywords: primary health care; lithium; lamotrigine; depressive disorders; psychiatric consultation; psychiatry; collaborative care; consultants

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