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GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, Associate Professor of Psychiatry at Thomas Jefferson University, who selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by Dr. Mago.


Issue 38, June 2015


What can we try after medications fail to work for bipolar depression?

Schoeyen et al. Treatment-resistant bipolar depression: a randomized controlled trial of electroconvulsive therapy versus algorithm-based pharmacological treatment. Am J Psychiatry. 2015;172(1):41-51. PubMed PMID: 25219389.

 

Why is this study important?

  • Bipolar depression is difficult to treat. Period.
  • “Treatment-resistant” bipolar depression is associated with considerable suffering, disability, and risk of suicide

 

Background

  • This is the first randomized, controlled trial of electroconvulsive therapy (ECT) for “treatment-resistant” bipolar depression
  • ECT was compared to algorithm-based pharmacological treatment in patients with “treatment-resistant” bipolar depression

 

Methods

  • This was multicenter, randomized controlled clinical trial carried out at seven acute-care psychiatric inpatient clinics throughout Norway
  • 73 patients with “treatment-resistant” bipolar I or II depression were included
  • Patients were currently at least moderately depressed
  • Here’s what I don’t like: the definition of treatment-resistant was “lack of response to two trials (lifetime) with antidepressants and/or mood stabilizers with documented efficacy in bipolar depression (lithium, lamotrigine, quetiapine, or olanzapine) in adequate doses for at least 6 weeks or until cessation of treatment due to side effects.” That doesn’t seem adequate to show treatment-resistance in the current episode. But anyway, let’s continue…
  • Patients with rapid cycling or high suicide risk were excluded. (This is important to know so that we don’t assume that the study can be generalized to these patients.)
  • The patients were randomized to receive either ECT or algorithm-based pharmacological treatment
  • ECT was done as follows: three sessions per week for up to 6 weeks, brief pulse stimulation, and right unilateral placement of electrodes. It should be noted that right unilateral placement of electrodes may be less effective than bilateral placement
  • The algorithm-based pharmacological treatment was based on the book by Goodwin and Jamison (Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd ed., 2007)
  • Now, this was not a double-blind trial. Both the patient and the investigators knew which treatment the patient was getting. To compensate for this potential source of bias, the rating scale interviews at Baseline and Week 6 (the most important times) were audiotaped and were scored by blinded raters

 

Results

  • ECT was statistically significantly more effective than algorithm-based pharmacological treatment for reducing severity of depression
  • From previous issues of GME Research Review, you may know that I recommend that you immediately ask what percentage of the subjects were improved, i.e., the response rate
  • The response rate was 74% for patients who received ECT versus 35% for patients who received pharmacological treatment. That is a BIG difference.
  • The remission rate did not differ between the groups (35% versus 30%)

 

Conclusions

  • The authors noted that, “remission rates remained modest regardless of treatment choice for this challenging clinical condition.”

 

Clinical Commentary

  • This study is a good step forward. Most importantly, it reminds us that we should keep ECT in mind as a potential option for patients with bipolar depression who have not responded to medication.
  • However, the study does have some limitations (small sample size, inclusion of both bipolar I and II, lack of blinding, limited standardization of treatment in the control group, etc). I hope that more clinical trials of ECT for bipolar depression are conducted soon.
  • Since patients with rapid cycling were excluded, the findings cannot be generalized to them. This is important because patients with rapid cycling are more likely to be treatment resistant.
  • As noted above, these patients may not be considered “treatment-resistant” for the current episode.
  • Letters to the Editor that followed publication of this article noted that response/remission rates could have been even better if bilateral ECT had been used. I think that at least in those patients who had a limited response to right unilateral ECT, it would have been appropriate to switch to bilateral ECT

 

 

 

A subgroup of patients with ADHD or Major Depression more likely to convert to Bipolar Disorder

Chen et al. Comorbidity of ADHD and subsequent bipolar disorder among adolescents and young adults with major depression: a nationwide longitudinal study. Bipolar Disord. 2015 May;17(3):315-22. PubMed PMID: 25295997.

 

Why is this study important?

  • A common diagnostic challenge is to differentiate between bipolar disorder and the hyperactivity, impulsivity, unstable mood, and sometimes-reckless behavior of a person with attention deficit hyperactivity disorder (ADHD).
  • However, it is very important to realize that a substantial minority of patients may have both ADHD and bipolar disorder
  • When younger patients present with major depression, it would be extremely useful to know which patients are more likely to turn out to have bipolar disorder

 

Background

  • Previous studies have found that ADHD in childhood and adolescence is associated with an increased risk of major depression and bipolar disorder in later life

 

Methods

  • This study used the Taiwan National Health Insurance Research Database
  • About 58,000 subjects < 30 years of age who had major depression with (n ~ 1,200) or without (n ~ 57,000) history of ADHD comorbidity were enrolled
  •  Subjects who developed bipolar disorder during the next few years were identified

 

Results

  • Adolescents and young adults who had major depression with ADHD had a statistically significantly greater incidence of subsequent bipolar disorder compared to those with major depression but no ADHD (about 19% versus about 11%)
  • Even after statistically controlling for demographics and co-morbidities other than ADHD, presence of ADHD remained an independent risk factor for subsequent diagnosis of bipolar disorder

 

Conclusions

  • Patients with comorbid diagnoses of major depression and ADHD had an increased risk of diagnostic conversion to bipolar disorder compared to those who had major depression alone

 

Clinical Commentary

  • About 15% of patients with bipolar disorder (especially males) have a history of ADHD prior to first episode of bipolar disorder. That is well established
  • This study confirms the findings of a previous small study (Biederman et al., 2009)
  • A very important clinical implication of this study is that if a patient with ADHD has a major depressive episode, we must keep in mind that there is a greater chance that this will turn out to be bipolar disorder.
  • Emergence of subsequent bipolar disorder in 19% may not seem to be a huge proportion, but keep in mind that this is the percentage in only a few years of follow up. I assume that if these patients are followed up for several decades, a greater percentage may turn out to have bipolar disorder

 

 

Combining two medications to get better results in geriatric depression 

Lavretsky et al. Citalopram, Methylphenidate, or Their Combination in Geriatric Depression: A Randomized, Double-Blind, Placebo-Controlled Trial. Am J Psychiatry. 2015 Feb 13. [Epub ahead of print] PubMed PMID: 25677354.

 

Why is this study important?

  • Stimulants are commonly used off label for treatment of major depressive disorder in elderly patients — either as monotherapy or in combination with an antidepressant
  • However, whether this combination really does help more than an antidepressant alone has not been tested
  • This is the first randomized trial to assess the addition of methylphenidate to an antidepressant to improve outcomes in geriatric depression

 

Background

  • Aim: To evaluate the combination of methylphenidate with citalopram to improve outcomes in elderly depressed patients

 

Methods

  • This was a 16-week randomized, double-blind, placebo-controlled trial
  • 143 older outpatients diagnosed with major depressive disorder were recruited
  • Mean age of the participants was about 70 years
  • 41% of the participants met the criteria for “treatment resistance” (had two adequate trials of antidepressants of two different classes)
  •  Patients were randomized to three groups: methylphenidate plus placebo (N=48), citalopram plus placebo (N=48), and citalopram plus methylphenidate (N=47)
  • Mean dose of citalopram was 32 mg/day (range 20 to 60 mg/day)
  • Note that the dose of citalopram in this study was greater than what we use now after the FDA guidance on the risk of QT prolongation
  • Mean dose of methylphenidate was 16 mg/day (range 5 to 40 mg/day)

 

Results

  • All three groups showed significant improvement in depression severity and in cognitive performance
  • However, the improvement in depression severity was greatest in the combination citalopram plus methylphenidate group
  • Also, the speed of improvement in the first four weeks was greater in the combination group than in the citalopram plus placebo group
  • At the end of the study, 42% in the citalopram plus placebo group, 29% in the methylphenidate plus placebo group, and 62% in the citalopram plus methylphenidate group had remission from the depression
  • The difference between citalopram plus methylphenidate and methylphenidate plus placebo was statistically significant
  • The 20% difference between citalopram plus methylphenidate and citalopram plus placebo was not statistically significant. This means, we can’t be sure it was not only due to chance
  •  All three groups improved equally in terms of cognition
  • All three groups had the same amount of adverse events

 

Conclusions

  • Adding methylphenidate to citalopram led to greater percentage of patients remitting from the depression and more rapid improvement in the first four weeks
  • Adding methylphenidate did not lead to more adverse events
  • However, adding methylphenidate did not lead to greater cognitive improvement either

 

Clinical Commentary

  • The results of this study are encouraging and lend some support to the common use of methylphenidate in depressed older patients
  • At this time, what we are more confident about is that adding methylphenidate to the citalopram leads to quicker improvement (which is good)
  • But whether this combination leads to better results in the longer run is not yet clear

 

 

Should we routinely be titrating the dose of an SSRI up? If so, in which patients is this particularly useful?

 

Olgiati P, Serretti A. Persistent benefits of slow titration of paroxetine in  a six-month follow-up. Hum Psychopharmacol. 2015 Apr 21. doi: 10.1002/hup.2478. [Epub ahead of print] PubMed PMID: 25900268.

 

Why is this study important?

  • Quite a few patients are unable to tolerate an SSRI in the first few weeks
  • If we could do something to improve the tolerability of SSRIs in the first few weeks, this could have a significant effect on improving the outcome of patients with major depressive disorder
  • Can such a simple thing as titrating the dose up have such a beneficial effect?

 

Background

  • Elderly patients may be more sensitive to side effects of paroxetine
  • These authors previously published a paper comparing slow versus standard titration of paroxetine in elderly patients
  • Slow titration: paroxetine was started at 2.5 mg/day and increased by 2.5 mg on alternate days to 10 mg/day
  • Standard titration: paroxetine was started at 10 mg/day
  • In both cases, the dose could be increased beyond 10 mg/day as clinically indicated
  • This paper extends their data to outcomes after 6 months of treatment

 

Methods

  • 47 subjects from the original sample with a diagnosis of major depressive disorder and/or generalized anxiety disorder and >60 years of age were included

 

Results

  • At the end of 6 months, patients in whom paroxetine was slowly up-titrated were statistically significantly more likely to remit (84.0% vs. 54.5%; a big difference) and had lower depression and psychic anxiety levels
  • Dropout rate was 20% in the slow titration group compared with 77% in the standard titration arm. What a big difference!
  • However, there was an interesting twist in these findings: these differences were found ONLY in patients with generalized anxiety disorder

 

Conclusions

  • Paroxetine should be started at lower doses slowly titrated up in older depressed patients  with more anxiety or generalized anxiety disorder
  • This is expected to reduce dropouts and improve outcomes

 

Clinical Commentary

  • This study shows that at least in elderly patients with significant anxiety, titrating the SSRI up slowly can have a huge impact on reducing dropouts
  • In my personal opinion as a clinician, we should ALWAYS titrate the SSRI up. The question in my mind is only how low to start and how slowly to go up

 

 

Which psychiatric medications should we focus on for reducing ER visits due to adverse effects?

Hampton et al. Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiatry. 2014 Sep;71(9):1006-14. PubMed PMID: 25006837.

 

Why is this study important?

  • This paper highlights a problem that we need to think more about: that psychiatric medications can lead to significant adverse effects that require an emergency room visit and even hospitalization
  • I think this helps us to realize which medications are more of a problem. Maybe we can be more careful with those particular medications?

 

Background

  • Aim: To estimate the numbers of emergency department visits by adults in the US due to adverse drug events involving psychiatric medications

 

Methods

  • Used different databases about emergency room visits and about medication prescriptions
  • A systematic sample of emergency room visits by 19 years or older were analyzed
  • Medications looked at were: antidepressants, antipsychotics, lithium, sedatives and anxiolytics, and stimulants

 

Results

  • There were an estimated 89,000 emergency room visits per year related to adverse drug events associated with psychiatric medications
  • Of these emergency room visits, 19% resulted in hospitalization
  • You may think that this occurs mainly in older patients. Well, think again. Of these emergency room visits, about half (49%) occurred in patients aged 19 to 44 years
  • Of the psychiatric medications looked at in this study, the offending medications were, in descending order of frequency: sedatives and anxiolytics (31,000 visits), antidepressants (25,000 visits), antipsychotics (22,000 visits), lithium (3,600 visits), and stimulants (2,800 visits)
  • Now, some of these medicines are prescribed more often than others. So how about per X number of 10,000 outpatient prescription visits?
  • In that case, the order changes completely: antipsychotics (11.7), lithium (16.4), sedatives and anxiolytics (3.6), stimulants (2.9), antidepressants (2.4)
  • Is there a big one we can focus on? Zolpidem was implicated in 11.5% of ALL the visits to the emergency room that were related to an adverse drug event from a psychiatric medication
  • For adults 65 years or older, it was responsible for 21% of these visits
  • In both cases, zolpidem was the culprit in more cases than any other psychiatric medication
  • In case we think all hypnotics are equally a problem — per 10,000 prescription visits, zolpidem led to more emergency room visits than alprazolam, lorazepam, or clonazepam
  • Now, what kind of adverse drug events are we talking about?
  • Sedatives and anxiolytics: altered mental status (eg, delirium), disturbances in consciousness (eg, somnolence)
  •  Sedatives and anxiolytics, but particularly zolpidem: falls or head injuries
  • Antidepressants: sensory abnormalities (e.g., vertigo) and hypersensitivity reactions (e.g., rash or urticaria)
  • Antipsychotics: movement disorders and spasticities (e.g., dystonia, trismus, extrapyramidal disorders)
  • Lithium: abnormal drug level
  • Stimulants: sensory abnormalities, cardiovascular symptoms (e.g., palpitations)

 

Conclusions

  • Psychiatric medications are implicated in many adverse drug events treated in emergency rooms in the US
  • Efforts to reduce adverse drug events should include adults of all ages, not only the elderly
  • We may prioritize medications that cause either high numbers overall or high rates (per prescription) of emergency room visits

 

Clinical Commentary

  • OK. This is clearly a big problem
  • Maybe we should focus on medications that cause more problems. Maybe starting with zolpidem? The change in prescribing (starting with 5 mg/day and increasing to 10 mg only if appropriate) should help
  • In what other ways do you think we should change our practices? Please send us your suggestions!

 

 

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