The risk of treatment-emergent mania with methylphenidate in bipolar disorder

Abstract

Objective:

To determine the risk of treatment-emergent mania associated with methylphenidate, used in monotherapy or with a concomitant mood-stabilizing medication, in patients with bipolar disorder.

Method:

Linking Swedish national registries, we identified 2,307 adults with bipolar disorder who initiated therapy with methylphenidate between 2006 and 2014. The cohort was divided into two groups: with or without concomitant mood-stabilizing treatment. To adjust for individual-specific confounds including disorder severity, genetic make-up, and early environmental factors, we used Cox regression analyses conditioning on individual to compare the rate of mania (defined as hospitalization for mania or a new dispensation of stabilizing medication) 0–3, and 3–6 months after medication start with preceding non-treated periods.

Results:

Patients on methylphenidate monotherapy displayed an increased rate of manic episodes within three months of medication initiation (hazard ratio 6.7, 95% confidence interval: 2.0–22.4), with similar results for the subsequent three months. By contrast, in those taking mood-stabilizers, the risk of mania was lower after starting methylphenidate (hazard ratio 0.6, 95% confidence interval: 0.4–0.9). Comparable results were observed when only hospitalizations for mania were counted.

Conclusions:

No evidence was found for a positive association between of methylphenidate and treatment-emergent mania among bipolar disorder patients who were concomitantly receiving a mood-stabilizing medication. This is clinically important given that up to 20% of people with bipolar disorder suffer from comorbid ADHD. Given the markedly increased hazard ratio of mania following methylphenidate in bipolar patients not taking mood-stabilizers, careful assessment to rule out bipolar disorder is indicated before initiating monotherapy with psychostimulants.

INTRODUCTION

Bipolar disorder - a mood disorder with an estimated prevalence of 2.4%(1) - is characterized by episodes of mania (pathologically elevated mood) and depression (pathologically lowered mood) interspersed with euthymic (normal) mood.(2,3) Bipolar disorder has been ranked as the second leading cause of “days out of role” worldwide,(4) with ensuing high societal costs due to lost productivity.(5) Attention deficit hyperactive disorder (ADHD) is a neurodevelopmental disorder that affects between 1–5% of the population,(6,7) which is characterized by inattention, hyperactivity, and impulsivity; symptoms that may partially overlap with those of bipolar disorder.(3,8)

Bipolar disorder and ADHD not uncommonly co-occur. Comorbid ADHD has been observed in up to 20% of people with bipolar disorder and there is evidence that these co-occurring disorders are associated with a worse illness course than either disorder alone.(4,9–11) Research indicate that these disorders share common genetic etiologies,(11) but comorbid ADHD in bipolar disorder could still represent co-occurrence of two distinct pathophysiologies. Studies have, for example, suggested that patients with bipolar disorder who also have a history of childhood ADHD may represent a distinct early-onset subtype with specific neurobiological underpinnings.(9,12)

In current practice guidelines, pharmacotherapy is a cornerstone of management for bipolar disorder and ADHD.(3) The foundation of pharmacological treatment of bipolar disorder often involves one or more medications classified as mood-stabilizer, which can attenuate acute mood episodes and prophylax against recurrent episodes and/or cycling. Although there is some debate about which medications should be classified as mood-stabilizers, most experts agree that at least two medications – lithium salts, and valproate – are indicated for both acute-phase therapy and prophylaxis of bipolar I disorder and several second generation antipsychotic drugs are increasingly used as mood-stabilizers.(13) The therapeutics of ADHD differ considerably and most patients will at some point be treated with central stimulants, which are presumed to increase neuronal signaling by marked elevation of the extracellular concentration of neurotransmitters in the prefrontal cortex of the brain.(14) The psychostimulant methylphenidate is one of the most widely used medications for ADHD in both the US and the EU and its use to treat adults with ADHD has increased in recent years.(15,16)

There is a high rate of non-response and residual functional impairment in comorbid ADHD bipolar disorder,(17) and the pharmacological treatment of comorbid ADHD in bipolar disorder presents a challenge. Not only may the treatment for bipolar disorder worsen ADHD,(18) clinicians have long worried that methylphenidate and related medications might also induce mania or even provoke psychosis.^19–22 Some physicians even consider the use of psychostimulants to be contraindicated in bipolar disorder.(18) An analogous debate has centered on the use of antidepressants in bipolar disorder (e.g., both for treatment of depressive episodes and co-occurring anxiety disorders),(19–23) although recent research indicates that this risk is reduced or eliminated by the use of a concomitant mood-stabilizing treatment.(21,23)

A recent review of studies concerning the efficacy and safety of psychostimulants in adults with comorbid ADHD and bipolar disorder concluded that controlled studies and treatment guidelines were substantially lacking.(18) Only a handful of randomized controlled trials have studied stimulant use in comorbid ADHD and bipolar disorder,(24–27) and all had small sizes and half of them focused on adolescents only.(26,27) Nonetheless, these studies suggest that stimulants are effective in treating ADHD symptoms in bipolar disorder and produce no adverse mood elevation when used together with a mood-stabilizer. In addition, open reports and case series suggest that the response to stimulants in comorbid ADHD and bipolar disorder appears similar to those reported for adult ADHD.(18) Even though this is encouraging, the risk of treatment emergent-mania when psychostimulants are used in bipolar disorder needs to be further evaluated, both in larger studies and in real life settings before stimulant treatment can be recommended in bipolar disorder.

Large-scale observational datasets may be utilized to investigate combination therapies that are difficult or too costly to survey in a randomized controlled setting. But observational studies are hampered by confounding by indication, i.e., subjects prescribed a medication are inherently different from those who are not. However, several recent pharmacoepidemiological studies have employed within-individual study designs that better account for genetic and environmental confounds.(23,28–30) This design will automatically adjust for individual-specific confounds that normally restrict the usefulness of observational studies including disorder liability, genetics, and stable environmental factors (e.g. family environment, early trauma, and so on).

The aim of this study was to study the risk of treatment-emergent mania when methylphenidate is used in adults with bipolar disorder. We linked national Swedish registers and assessed the risk of manic events in the 3 months and the 3 to 6 months following initiation of methylphenidate therapy as compared with non-treated periods of equal length. We stratified the cohort by presence or absence of concomitant mood-stabilizing medication to explore if mood-stabilizing drugs influence the risk of treatment-emergent mania. By applying a within-individual design, we controlled for individual-specific confounds like mania liability, genetic make-up, and environmental factors.

METHODS

Subjects

Swedish national registries was linked with high accuracy using the unique individual Swedish national registration number.(31) A search algorithm that has been demonstrated to yield a high positive predictive value was used to identify bipolar disorder patients in the National Patient Register,(32) which includes all Swedish inpatient admissions since 1973 and all outpatient specialist admissions since 2001,(33) and provides admission dates along with the main and 8 secondary diagnosis codes in accordance with the International Classification of Disease (ICD). Individuals suffering from bipolar disorder were identified based on having at least two in- or outpatient admissions with a discharge diagnosis of bipolar disorder (ICD-8 296.00, 296.1, 296.3, 296.88, and 296.99; ICD-9 296.0, 296.1, 296.3, 296.4, 296.8, and 296.9; ICD-10 F30 and F31). For the purposes of the current project, we required that the diagnosis of bipolar disorder must preceded methylphenidate therapy. Additionally, to diminish the potential risk of misclassification the included individuals were allowed a maximum of one in- or outpatient diagnosis of schizophrenia (ICD-8 295; ICD-9 295; ICD-10 F25), and had to be 18 years of age at least 6 months prior to beginning methylphenidate treatment.

Exposure

Due to being essentially the only psychostimulant used to treat comorbid ADHD in bipolar disorder in Sweden, only methylphenidate was studied. The period of exposure to methylphenidate was from July 2005 through 2013. Exposure status was ascertained using data from the Swedish Prescribed Drug Register, which provides data on all Swedish dispensed prescription drugs.(34) The register provides prescription and dispensation dates, medication name, dose, package size, and a code in accordance with the Anatomical Therapeutic Chemical Classification System (ATC). Using this register, we identified dispensations of methylphenidate (N06BA04). To be included, an individual was required to have been dispensed methylphenidate without any other methylphenidate dispenses the preceding 9 months (period A in Figure 1), thereby ensuring that initiation of therapy occurred during that particular time interval.

Figure 1. Design of the study*.

* The design permits within-individuai comparisons of mania after initiation of methylphenidate treatment with a preceding nontreatment period. The follow-up time is divided into 0–3 months and 3–6 months to assess both acute (switch) and longer-term effects.

The cohort was next divided depending on whether or not patients were prescribed mood-stabilizers - medications approved for either treatment of mania or prevention of recurrent bipolar episodes including aripiprazole (N05AX12), lithium (N05AN01), olanzapine (N05AH03), quetiapine (N05AH04), and valproate semisodium (N03AG01). To be classified as being on continuous mood-stabilizing treatment, an individual had to have at least two dispenses of a mood-stabilizer in the 9 months preceding the methylphenidate medication start (period A in Figure 1), of which at least one had to occur within 6 months before the treatment (period B in Figure 1). To be classified as not using a mood-stabilizer, an individual could not have had any dispenses of stabilizing medication (aripiprazole, olanzapine, quetiapine, lamotrigine, lithium, valproate semisodium, carbamazepine, haloperidol, or risperidone) during the 6 months preceding the methylphenidate treatment (period B in Figure 1), nor at the date of methylphenidate dispensation. Patients in neither of these groups were excluded.

Outcome

The occurrence of mania among the patients was ascertained using discharge diagnosis codes for mania (ICD-10 codes F30.0, F30.1, F30.2, F30.8, F30.9, F31.0, F30.1, and F30.2). A dispensation of an antipsychotic, lithium, or valproate semisodium after methylphenidate treatment could indicate treatment for a manic relapse, or a late safety measure. In analysis 1 (Table 2), dispensations of atypical and typical antipsychotics (aripiprazole, olanzapine, quetiapine, haloperidol, or risperidone), lithium, or valproate semisodium among individuals without any dispensations of these drugs 9 months preceding methylphenidate medication (i.e., new dispensations) was interpreted as treatment for elevated mood, and counted towards a treatment-emergent mania. Doses of aripiprazole below 5mg, olanzapine below 5mg, and quetiapine below 100mg were not considered. In a supplemental analysis, new dispensations of lithium and valproate semisodium were not counted towards elevated mood (Supplement SA1). In analysis 2, only a diagnosis of mania counted as treatment-emergent mania (Table 3).

Table 2.

Risk of mania following methylphenidate medication based on mania diagnoses and new prescriptions of antipsychotics and stabilizers^*

Group	Number	Period	Hazard Ratio	P-value	95% Confidence Interval	Number of mania events (rate****)
No stabilizer**	718	0–3 months 3–6 months	6.67 9.67	0.002 <0.001	1.98–22.4 2.94–31.7	61 (0.08)
Stabilizer***	1103	0–3 months 3–6 months	0.56 0.91	0.010 0.758	0.36 – 0.87 0.50 –1.67	195(0.18)

^*486 individuals presented with uncertain mood stabilizer status and was excluded from the analysis. If no dispensation of an antipsychotic (aripiprazole, olanzapine, quetiapine, haloperidol, and risperidone), lithum, or valproate semisodium was observed in the nine months prior methylphenidate medication (period A in Figure 1), a dispensation after the methylphenidate medication (period C in Figure 1) was considered an indication of elevated mood. This definition was applied to both groups, and doses of aripiprazole, olanzapine, and quetiapine below 5mg, 5mg, and 100mg respectively were not considered.

^**Cannot have any type of of stabilizer medication during the 6 months prior the dispensation of methylphenidate (period B in Figure 1), nor at the date of dispensation of methylphenidate. This includes lithium, valproic acid, lamotrigine, olanzapine, quetiapine, aripiprazolam, risperidone, haloperidol, and carbamazepine.

^***Must have at least two dispensations of stabilizing drugs (lithium, valproic acid, olanzapine, quetiapine, or aripiprazolam) within the 9 months prior methylphenidate dispensation (period A in Figure 1). At least one dispensation of a stabilizing drug has to be within 6 months prior methylphenidate treatment (period B in figure 1).

^****Rate denotes number of identified mania events divided by total number of subjects in the group.

Table 3.

Risk of mania following methylphenidate medication based on mania diagnoses only^*

Group	Number	Period	Hazard Ratio	P-value	95% Confidence Interval	Number of mania events (rate****)
No stabilizer**	718	0–3 months 3–6 months	3.33 1.00	0.067 1.000	0.92–12.11 0.20 – 4.95	24 (0.03)
Stabilizer***	1103	0–3 months 3–6 months	0.48 0.86	0.002 0.640	0.30 – 0.77 0.47 –1.60	144(0.13)

^*486 individuals presented with uncertain mood stabilizer status and was excluded from the analysis.

^**Cannot have any type of of stabilizer medication during the 6 months prior the dispensation of methylphenidate (period B in Figure 1), nor at the date of dispensation of methylphenidate. This includes lithium, valproic acid, lamotrigine, olanzapine, quetiapine, aripiprazolam, risperidone, haloperidol, and carbamazepine.

^***Must have at least two dispensations of stabilizing drugs (lithium, valproic acid, olanzapine, quetiapine, or aripiprazolam) within the 9 months prior methylphenidate dispensation (period A in Figure 1). At least one dispensation of a stabilizing drug has to be within 6 months prior methylphenidate treatment (period B in figure 1).

^****Rate denotes number of identified mania events divided by total number of subjects in the group.

Statistical analysis

In total, 65,683 individuals with bipolar disorder were identified in the Swedish National Patient Register, of which 5,506 (8.4%) had at least one dispensation of methylphenidate between July 1, 2005 and December 31, 2013. Among these, 2,307 (41.9%) met the criteria of having a period of 9 months without receiving any other doses of methylphenidate prior the medication initiation and being over 18 years of age.

Similar to a previous study of antidepressant induced manic switch,(23) the effects of methylphenidate treatment on the rate of mania was estimated by cox proportional hazards regression analyses using the STCOX statement in STATA/IC 13. By conditioning on individual in the analyses (strata=individual), all subjects serve as their own control. This reduces confounding caused by differences between patients including disorder severity (e.g. proneness to mania), genetic makeup, and environmental factors. We compared the rate of mania during a six-month period prior methylphenidate treatment started (period B in Figure 1) with a six-month time period following methylphenidate treatment initiation (period C in Figure 1). To allow for assessment of both acute and more long-term effects,(20) interaction terms with split follow-up time (0–3 months, 3–6 months) was included in the statistical model. To account for deaths and migrations, we utilized the Cause of Death and Migration registries. If the patient died, emigrated, or was diagnosed with schizophrenia during the treatment period (period C in Figure 1), the follow-up was censored at this time. In a supplemental analysis, a diagnosis of schizophrenia after methylphenidate treatment was counted towards mania (Supplement SA2).

RESULTS

Table 1 presents descriptive statistics for the 2,307 subjects included in this study. Males made up 36.8% (N=848) of the cohort and the distribution among the age groups 18–25, 25–40, and 40+ were 15.4%, 46.8%, and 37.8%, respectively. Among the 2,307 subjects in the study, 718 (31.1%) received no mood-stabilizing treatment, 1,103 (47.8%) met the criteria for being on mood-stabilizing treatment, while 486 (21.1%) did not meet either criteria and was not included in subsequent analyses. Supplement SA3 presents the types of stabilizing drugs dispensed.

Table 1.

Descriptive statistics of the cohort

	Mono-therapy N=718		Stabilized N=1,103		Full sample* N=2,307
Characteristic
	N	%	N	%	N	%
Gender
Males	234	32.6	443	40.2	848	36.8
Females	484	67.4	660	59.8	1,459	63.2
Age group
18–25 years	122	17.0	161	14.6	356	15.4
25–40 years	322	44.9	523	47.4	1,079	46.8
40+ years	274	38.2	419	38.0	872	37.8
Civil status
Unmarried	476	66.3	691	62.7	1,462	63.4
Married	109	15.2	204	18.5	415	18.0
Divorced	128	17.8	201	18.2	415	18.0
Widowed	5	0.7	7	0.6	14	0.6
Employed	217	30.2	413	37.4	814	35.3
In school	99	13.8	133	12.1	303	13.1
	Mean	SD	Mean	SD	Mean	SD
Age at first bipolar disorder diagnosis	32.2	10.9	32.8	10.5	32.8	10.6
Family yearly income in US $	31,324	24,793	35,092	28,088	34,743	47,124

Abbreviations: N, Number. SD, standard deviation.

^*The full sample includes a group of 486 subjects with uncertain stabilizer exposure that were excluded from the analyses.

Methylphenidate and the risk of mania events derived from diagnoses and dispensations of stabilizing medication

When we defined treatment-emergent mania as a diagnosis of mania or a new dispensation of an antipsychotic or stabilizing drug, there were 61 mania events during the complete 12 months of follow-up among the 718 patients treated with a methylphenidate monotherapy (mania rate=0.08), and 195 mania events among the 1,103 patients with a concurrent mood-stabilizer treatment (mania rate=0.18). The risk of mania following methylphenidate treatment among subjects treated with methylphenidate monotherapy was increased in the first three months after treatment (hazard ratio (HR) 7.7, 95% Confidence Interval (CI): 2.0–22.4), and in the subsequent three to six months after treatment (HR 9.7, 95% CI: 2.9–31.7). By contrast, the risk of mania was reduced in the initial three months (HR 0.6, 95% CI: 0.4–0.9), and slightly reduced in the subsequent three to six months (HR 0.9, 95% CI: 0.5–1.7) among patients treated with a concurrent mood-stabilizer (Table 2).

Methylphenidate and the risk of mania derived from diagnoses only

When treatment-emergent mania was defined using diagnoses of mania only, the total number mania events was reduced but maintained a similar distribution (24 events in the monotherapy group, and 144 events in the concomitant mood-stabilizer group). The risk of mania following methylphenidate medication among the subjects on a monotherapy was elevated, although not statistically significantly, in the initial three months after treatment (HR 3.3, 95% CI: 0.9–12.1), and unchanged in the subsequent three to six months after treatment (HR 1.0, 95% CI 0.2–5.0). Similar to the first analysis, among the subjects treated with a concurrent mood-stabilizer the risk of mania was reduced in the initial three months (HR 0.5, 95% CI 0.3–0.8), and slightly reduced in the subsequent three to six months, although not statistically significant (HR 0.9, 95% CI 0.5–1.6) (Table 3).

Treatment-associated mania: methylphenidate and antidepressants

In a previous study published in the Journal,(23) we used similar data and methodologies to assess the risk of treatment-emergent mania due to antidepressant therapy in bipolar disorder. Table 4 contrasts the results from the previous study with results from the current study and suggests that concomitant stabilizing treatment attenuates the risk of medication-induced mania by methylphenidate and antidepressants in a similar fashion. In supplemental analyses we found no link between concomitant antidepressant treatment and the current study’s findings (Supplement SA4).

Table 4.

The results of the current study contrasted to those in a previously published study on antidepressants utilzing a similar methodology

Abbreviations: CI, Confidence Interval.

^*Results from the current study. The distribution of antidepressant treatment prior and after methylphenidate treatment was similar in both groups (stabilized and non-stabilized), with no apparent changes correlated with the initiation of methylphenidate treatment, and thus does not support that the increased risk of mania after methylphenidate treatment is attributable to antidepressant treatment (see Supplement SA5).

^**Results from the previously published article: The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry. 2014 Oct;171 (10):1067–73. doi: 10.1176/appi.ajp.2014.13111501.

DISCUSSION

In the largest study to date (N=2,307), we studied the risk of treatment-emergent mania in bipolar disorder patients when methylphenidate is taken alone or in combination with mood-stabilizing medication. We found that methylphenidate may be associated with treatment-emergent mania in patients on methylphenidate monotherapy, but no evidence was found for a positive association between of methylphenidate and treatment-emergent mania among bipolar disorder patients who were concomitantly receiving a mood-stabilizing medication.

Previous research on the effectiveness and tolerability of stimulant medication in bipolar disorder patients with comorbid ADHD is limited, both in number of studies and number of participants.(18,24–27) Furthermore, these studies are restricted to combinations of stabilizers and stimulants, and survey different types of stimulants and different populations (adults or children). Nevertheless, our finding that methylphenidate in combination with a stabilizing medication is not associated with a risk of treatment-emergent mania is in line with previous studies. For example, an open-label study of 14 adult patients with bipolar disorder and stabilizing medication reported no incidences of adverse elevated mood after methylphenidate treatment initiation.(25) Similarly, a 4-week placebo-controlled trial of methylphenidate in 16 stabilized bipolar disorder patients aged 5–17 with comorbid ADHD found methylphenidate to be well tolerated, and reported improved ADHD symptoms at the end of the study.(26) In another open-label study, 40 adult patients with comorbid ADHD-bipolar disorder were studied during 4 weeks of combination treatment with a mood-stabilizer and the stimulant lisdexamphetamine.(24) This study found improved ADHD- and depressive symptoms, and no increased risk of treatment-emergent mania, which echo findings in previous studies of methylphenidate.(25,26) Finally, in a 4-week randomized controlled trial of 40 subjects aged 6–17 with comorbid ADHD bipolar disorder, treatment with divalproex and amphetamine was found more effective to treat ADHD symptoms than divalproex and placebo,(27) with only one participant on stimulants experiencing mania.

Although there are no randomized studies of methylphenidate monotherapy in bipolar disorder to which our findings can be contrasted, an earlier study of the risk of treatment-emergent mania due to antidepressant monotherapy in bipolar disorder, using similar methodology, found analogous results as the current study (Table 4).

Given that up to 20% of bipolar disorder patients may suffer from comorbid ADHD,(4,9,35) it is not surprising that 8.4% of all identified Swedish bipolar disorder patients dispensed at least one prescription for methylphenidate during an 8-year period. Stabilizing medications effectively prevent mood episodes but risk worsening attention and concentration, which might impair everyday functioning in this subgroup of patients. Although previous studies suggest that stimulant use in comorbid ADHD bipolar disorder improve ADHD symptoms,(24–27) a remaining concern has been whether stimulants are safe in bipolar disorder, particularly in terms of treatment-emergent mania. Our large-scale study indicating no increased risk of treatment-emergent mania when methylphenidate is used in combination with a mood-stabilizer is thus reassuring, and suggest that this combination may provide a welcome treatment option for this complicated patient group.(4,9)

Strengths of this study include surveying a large number of subjects in a naturalistic setting. The study includes individuals that for various reasons would have been excluded or not volunteered for a clinical trial. Moreover, the use of a within-individual design automatically adjusts for a large number of individual-specific factors, including prior disorder severity, genetic makeup, and environmental factors, which would not be possible to adjust for in a conventional epidemiological approach. This provides an improved strategy in handling the hurdle of selection effects and confounding by indication in pharmacoepidemiological studies, which is exemplified by the difference in overall mania between the monotherapy and the stabilized group.

A limitation of this study is that - although the design allows for extensive adjustment of otherwise unmeasured confounds - it does not adjust for changes that might have occurred during the 12-month follow-up. Due to the observational nature of the study, it cannot be ruled out that potential unmeasured factors may be specific for each group. As such, the increased risk of mania in the monotherapy group may be attributable to untreated bipolarity, rather than the methylphenidate treatment per se. It is thus important to confirm the findings in other samples, and with other study designs.

It should be noted that the elevated risk of treatment emergent mania in the monotherapy group was not statistically significant when only mania diagnoses were taken into account (P=0.067). Even though this is likely to be due to the small sample size of the monotherapy group, it highlights that the number needed to harm is high (i.e., the risk of treatment emergent mania is low). Nonetheless, patients in the monotherapy group likely lacked a mood-stabilizing treatment precisely because they had a history of lower rate of mania than those that were on a mood-stabilizer (see mania rate in Table 2 and Table 3). This is important to consider because if the patients treated with a mood-stabilizer (with a higher underlying risk of mania) would be put on methylphenidate monotherapy, they may present a lower number needed to harm.

Whereas the diagnoses of bipolar disorder in the Swedish National Patient Register have been validated,(32) the diagnoses of acute mania have not. The diagnosis of acute mania in a patient with known bipolar disorder is, however, likely to be valid. It should be noted though, that even though this study is likely to have accurately captured the severe end of the mania spectrum, it might have failed to capture hypomania and elated mood that did not lead to a hospitalization. This is why we combined diagnoses of mania and new dispensations of antipsychotic medication at doses that correspond with an anti-manic treatment. In doing so, 37 additional mania events (5.2%) were observed in the monotherapy group (N=718), whereas 51 additional mania events (4.6%) were observed in the stabilized group (N=1,103). It is further possible that changes in type of stabilizing drug, or dosage, also indicate elevated mood. However, this was not considered due to the ambiguity of such changes. It should also be noted that new adjunctive stabilizing treatment might not represent a manic relapse but rather a late safety measure by a treating clinician. Furthermore, the diagnoses in the National Patient Register can only identify bipolar disorder as a whole, but cannot distinguish between bipolar 1 and bipolar 2 disorder. It is possible that patients with these two different presentations of bipolar disorder respond differently to methylphenidate treatment, which warrants further research.

Our study only focused on treatment-emergent mania. We did not assess the effectiveness of the stimulant medication on ADHD-symptoms. The study can thus neither inform us about the risk-benefit ratio of using stimulants in bipolar disorder, nor elucidate potential synergistic effects of the combination of methylphenidate and mood-stabilizer treatment. Lastly, because of the large number of different drugs used in the treatment of bipolar disorder, specific stabilizing medications could not be studied individually.

CONCLUSION

This study suggests that methylphenidate may increase the risk of treatment-emergent mania in patients suffering from bipolar disorder when it is used without a concomitant mood-stabilizing treatment. On the basis of this finding, we recommend careful assessment to rule out bipolar disorder before initiating methylphenidate as a monotherapy. As no association to treatment-emergent mania was observed among bipolar disorder patients who were concomitantly receiving a mood-stabilizing medication, it would appear that concomitant therapy of ADHD is both safe and feasible in the context of ongoing preventive therapy. Although this study utilized within-individual design to better handle confounding, the study used observational data and all potential confounding cannot be ruled out. Therefore more research is warranted in this important area to further elucidate the potential mania inducing properties of methylphenidate, and to what capacity stabilizing drugs hamper this adverse reaction.