From the Editor

From the perspective of the treatment team, a rehospitalization is a failure – a patient returning to the system, unwell again. From the perspective of the patient and her or his family, a rehospitalization can be frightening and humiliating.

How best to keep people with bipolar affective disorder out of hospital? In a new JAMA Psychiatry paper, the University of Eastern Finland’s Markku Lähteenvuo and his co-authors attempt to answer this question – not by using a RCT, but instead by tapping Finnish national databases.

For the record, they find one medication works better than the others: lithium.

800px-central_hospital_of_central_finlandFinland’s Central Hospital: adequate architecture but good data

In this Reading, we consider the new paper by Lähteenvuo et al., and also consider their approach.



“Real-World Effectiveness of Pharmacologic Treatments for the Prevention of Rehospitalization in a Finnish Nationwide Cohort of Patients With Bipolar Disorder”

Markku Lähteenvuo, Antti Tanskanen, Heidi Taipale, Fabian Hoti, Pia Vattulainen, Eduard Vieta, Jari Tiihonen

JAMA Psychiatry, 28 February 2018 Online First

Bipolar disorder is a serious, often debilitating, and recurring chronic psychiatric disorder, although individual disease courses may vary. Bipolar disorder is rated as the sixth most common cause of disability in the world by the World Health Organization, accounting for more loss of disability-adjusted life years than all cancers combined. Long-term medication is often required to attain remission and prevent relapses, although, even with advanced treatment protocols, rates of remission remain low. Many randomized clinical trials and their meta-analyses have been performed to discover the most efficacious treatment forms for prevention of relapse; some more recent trials also included antipsychotics in long-acting injectable (LAI) form. However, these studies did not include oral antipsychotics, and the comparative effectiveness of LAI vs oral antipsychotics has remained unknown.

Some meta-analyses have shown clinically meaningful differences between pharmacotherapies in their comparative effectiveness of acute treatment, but treatment guidelines until recently did not recognize such differences. However, as has been noted in the field of depression research, randomized clinical trials often have stringent inclusion and exclusion criteria and limited follow-up times, which may impair their ability to reflect the real-world effectiveness of therapies in their actual clinical application. Randomized clinical trials usually exclude patients with the most comorbidities and the highest severity of illness (eg, propensity to suicide). Furthermore, many efficient medications might cause adverse effects on a very long time scale. Thus, the most efficient way to obtain a good estimate on the overall real-world effectiveness of therapies for bipolar disorder may be through observational studies. One such recent study by Hayes et al indicated that lithium appears to be more successful as monotherapy maintenance treatment for bipolar disorder than valproate sodium, olanzapine, or quetiapine fumarate. Similar findings on the superiority of lithium compared with other pharmacologic treatments in bipolar disorder have been reported by Kessing et al in a 2011 registry study from Denmark and by Simhandl et al in a 4-year naturalistic follow-up study from Austria in 2014. Joas et al suggested that lithium is more effective than both quetiapine and olanzapine in prevention of relapse in bipolar disorder, and a study by Song et al suggested that lithium is superior to valproate sodium in preventing suicidal behavior in bipolar patients.

However, these studies were limited to only a few pharmacologic agents… This investigation aimed to overcome these shortcomings in the largest and most complete register-based, real-world effectiveness study of pharmacotherapies for bipolar disorder to date.

e8e64d3e1e0f3390c6c4bb06fe982edd_xlMarkku Lähteenvuo

Here’s what they did:

  • The authors used Finnish databases “to conduct a population-based cohort study of patients hospitalized for bipolar disorder…”
  • Patients included were hospitalized between 1 January 1987 and 31 December 2012 for bipolar.
  • To determine drug use, the PRE2DUP method was used. “The PRE2DUP method calculates the current dose with a sliding mean, uses package information (eg, number of tablets and administration intervals for injections), and takes into account stockpiling when constructing time periods of continuous use.”
  • Statistical analyses were done, based on “within-individual Cox proportional hazards regression model in which each individual is assigned his or her own stratum and the follow-up time is reset at the initiation of a new treatment, thus eliminating selection bias.” Analyses considered rehospitalization due to mental disorders, all cause hospitalization, and hospitalization due to cardiovascular diseases.

Here’s what they found:

  • “The study cohort consisted of 18 018 individuals with a total observation time of 128 353 person-years, with a mean observation (follow-up) time of 7.2 years (range, 1 day-17.0 years).”
  • Demographically: there were more women than men (9558 and 8460), and the median age was 46.6.
  • 9721 patients (54.0%) had at least 1 psychiatric rehospitalization. “We observed a total of 82 858 hospitalizations (for any cause; approximately 4.6 per individual), of which 36 131 were psychiatric hospitalizations (approximately 2.0 per individual) and 4862 were for cardiovascular reasons (approximately 0.3 per individual).”
  • The lowest risk of psychiatric hospitalization: risperidone long-acting injection (HR, 0.58), gabapentin (0.58), perphenazine long-acting injection (0.60), and lithium carbonate (0.67). See figure below.
  • The lowest risk of all-cause hospitalization: lithium (HR, 0.71).
  • Apart from valproic acid (HR, 1.53) and carbamazepine (1.95), no other medications studied were associated with a significantly altered risk of cardiovascular hospitalization


A few thoughts:

  1. This is a good study.
  1. Surprise: new wasn’t necessarily better. The best medication was lithium. They write: “To our knowledge, this is the first study on the comparative real-world effectiveness of all widely used psychopharmacologic agents and routes of administration in bipolar disorder. The main results of our study indicate that lithium is superior to other mood stabilizers and that LAIs are markedly better than identical oral formulations of antipsychotics.” Or, perhaps, this result isn’t so surprising. Indeed, other studies considering psychiatric hospitalizations – with different methodologies – have found lithium advantageous for people with bipolar (including papers published in World Psychiatry and the British Journal of Psychiatry). The authors note that lithium’s benefits were not limited to psychiatric hospitalizations, though. “[L]ithium use was also associated with the lowest risk of hospitalization for any cause of all the compounds studied. The incidence of hospitalization owing to any physical illness was substantially lower during lithium treatment when compared with 2 of the other most frequently used medications, valproate and quetiapine.”
  1. On a slight tangent, the new CANMAT guidelines for bipolar have just been published, and consider medications for several things including tolerability, safety, and efficacy. Lithium is recommended (along with a handful of other agents) as a first-line medication for the treatment of bipolar depression and mania. (You can find the new guidelines here: so it is, seven decades after John Cade published his original work on this salt, lithium continues to have a big role.
  1. There are clear advantages to the approach used by the authors – consider: the cohort had over 18,000 people. BUT there are clear disadvantages, too. The paper is accompanied by an Editorial that considers both the paper and it’s methodology. Stefan Leucht (Technische Universität München) and John M. Davis (University of Illinois) penned: “Enthusiasm and Skepticism About Using National Registers to Analyze Psychotropic Drug Outcomes.” You can find it here:

dr-stefan-leuchtStefan Leucht

They note the attractiveness of reaching beyond RCTs:

While RCTs are considered to be the gold standard because only randomization can rule out both known and unknown confounders, their limitations include trial populations that are not representative of the real world, trials that are typically short term, and outcomes that, in RCTs focused on the maintenance of patients with chronic disease, include only worsening of symptoms rather than full-blown rehospitalization.

Still, they take issue with the approach of Lähteenvuo et al.

A major limitation is that analyses of national registers can never fully control for confounders. For example, classic mood stabilizers were more effective than antipsychotics for the prevention of rehospitalization. This could be an example for “confounding by indication,” as the authors nicely explain: “the fact that treatments for individual patients are not selected at random, but are rather products of comprehensive clinical decision-making, the reasons for which are not stored in basic registries.” In other words, a change in outcome might reflect something associated with the reason the drug was used. Thus, it could be that the more patients with milder cases of bipolar disorder received mood stabilizers, while severely ill patients received antipsychotic medications. Theoretically, if most patients had initially received lithium, and if antipsychotics had mainly been added to the medication regimens of patients with poor outcomes who had relapsed, this would be a disadvantage for antipsychotics.

They continue:

We would also caution against interpretation of findings without considering the events and years at risk. For example, for mood stabilizers, there were 21 054 events and 63 139 years at risk, whereas the long-acting injectable antipsychotic olanzapine had 6 events and 11 years at risk… Gabapentin, which had 176 events and 541 years at risk, does not have an official indication for bipolar disorder, but had a high effect size. It could be that gabapentin was used for general medical reasons and thus used selectively for patients who were doing well, whereas benzodiazepines, which had a poor outcome, were added during episodes of more severe illness for sedation.

After noting the problems of using one country to extrapolate a result, they conclude:

Without a doubt, these analyses of national registers are a major advance. But clarification of some of these issues may give them an even stronger role in the interpretation of psychotropic drug effectiveness.

  1. The Editorial raises good points though it seems somewhat heavy in its criticism. We shouldn’t forget that there are problems with RCTs, too. In a recent guest contribution, Dr. David Goldbloom wrote on clinical trials and the real clinical world. “It is impossible to stay current on the treatment research results that emerge daily, and we look to those randomized controlled trials published in high-impact peer-reviewed journals for evidence of what works for people with the diagnoses that we find ourselves addressing in the office, the clinic, the ER or the inpatient unit. But who are those patients who sign consent forms to take part in these studies, and how much do they resemble the people sitting across from us?” You can find his full comments here:


Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.