Issue 62, Jun 2017
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Can obesity and gender tell us which antidepressant to prescribe?

Green G, Goldstein-Piekarski AN, Schatzberg AF, Rush AJ, Mad J, Williams L. Personalizing antidepressant choice by sex, body mass index, and symptom profile: An iSPOT-D report. Personalized medicine in psychiatry 1–2 (2017) 65–73.  

Background

There is a great need to be able to choose particular medications for a particular person, which is a major part of the trend towards “Personalized Medicine”.

This analysis aimed to assess whether obesity and gender might predict a better response to a particular antidepressant medication.

This study has received some attention in the press, so it is important for us to discuss it.

Methods

These analyses were done on data already collected in a study called the iSPOT-D. This was a “practical” randomized, controlled clinical trial of the treatment of major depressive disorder. The term “practical” means that it was designed to be similar to clinical practice as follows:

     - The participants and the treating clinicians were not blinded to the treatment, though the persons assessing the outcome were

     - Also, clinicians adjusted doses of the medications according to clinical judgment rather than a predetermined protocol.  

Participants in the analyses presented in this paper were 659 outpatients with major depressive disorder who were 18 to 65 years of age.

They were randomly assigned to treatment with either escitalopram, sertraline or venlafaxine extended-release for eight weeks.

As is conventional, a Hamilton Depression Rating Scale score of 7 or less at the end of the trial was considered to be “remission” from the depression.

Based on their BMI, 42% of the participants were of normal weight, 28% were overweight, and 31% were obese.

Obesity was further subdivided into class I (15% of participants), II (10%), and III (6%).

Results

In the overall study (Saveanu et al., 2015), the three antidepressants—escitalopram, venlafaxine extended-release, and sertraline—worked equally well.

In the analyses in this paper, participants who were morbidly obese were more likely than those of normal weight to have remission from their depression after treatment with venlafaxine extended-release.

With escitalopram or sertraline, the chances of remission were the same with high or normal BMI.

However, in persons with a higher BMI, venlafaxine did better than escitalopram.

This differential improvement was mainly explained by improvement in particular symptoms like sleep disturbance, somatic anxiety and appetite. Thus, in participants with greater BMI, venlafaxine-XR particularly reduced physical symptoms (sleep, appetite/weight changes) and somatic symptoms (fatigue, headache, muscle aches).

How much of a difference was there? The number needed to treat to achieve remission with venlafaxine-XR in obese III participants was 6.

Female participants with higher BMI were more likely to remit regardless of the medication given. This improvement in females was explained by changes in cognitive symptoms (including suicidal ideation and guilt) and by psychomotor changes. On the other hand, male participants who had higher BMI were not more likely to remit.

The authors argue that the findings of this study are not explained by the use of higher doses of medications in obese patients. Higher doses were used for obese patients in both genders and with each of the medications. Also, antidepressant dose was statistically controlled for. However, I have some reservations about this, as discussed below.

Conclusions

Using BMI, gender, and presence of specific symptoms may help guide the choice of antidepressant.

Female patients with higher BMIs may have better outcomes after antidepressant treatment, regardless of medication.

Obese patients, both male and female, were more likely to remit after treatment with venlafaxine XR than an SSRI.  

Clinical Commentary

The issue of BMI and antidepressant outcome has been confusing in the literature and contradictory data has been published. What this study suggests is that this may be because the relationship between being obese and responding to an antidepressant is different for males versus for females.

In this study, the dose of the antidepressant could be adjusted by the clinicians. In fact, they did give higher doses to persons who were obese. The statistical analyses did take into account (“control for”) the dose but such post hoc adjustments have limitations. In the multivariate model, the dose of the antidepressant narrowly missed statistical significance as a predictor of remission (p=0.068). Instead of recommending that all of us preferentially use venlafaxine in obese patients, I view these results as suggestive and requiring confirmation in future studies.

Another major limitation of this study was that there were only 12 male and 27 female obese III patients. Future studies specifically focusing on testing the hypotheses generated by this study would preferentially recruit obese III patients.

We must also keep in mind that venlafaxine is associated with a slightly greater cardiovascular risk, including that of hypertension, which may be important in obese patients.

We should also note that these analyses were not part of the main purpose of the iSPOT study. Such “post hoc” analyses may be interesting but should be considered tentative until confirmed in a prospective study.

Lastly, in the research on antidepressant response and obesity, something to think about is whether the depression of different subgroups (e.g., morbidly obese males or males with normal BMI) is the same illness.  

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Which psychosocial interventions are most helpful for bipolar disorder?

Chatterton ML, Stockings E, Berk M, Barendregt JJ, Carter R, Mihalopoulos C. Psychosocial therapies for the adjunctive treatment of bipolar disorder in adults: network meta-analysis. Br J Psychiatry. 2017 May;210(5):333-341. PubMed PMID: 28209591.

Background

Psychosocial treatments have now been shown to be efficacious as adjunctive treatments for bipolar disorders but we don’t know how they compare to each other.

This study combined existing studies using a special type of meta-analysis called a “network meta-analysis”. Standard meta-analysis can compare only two treatments at a time, but a network meta-analysis can evaluate the relative efficacy of multiple interventions even if they have not been directly compared with each other.

This study is the first network meta-analysis of psychosocial interventions used as adjunctive treatments for bipolar disorder.

Methods

Relevant studies of psychosocial interventions as adjunctive treatments for bipolar disorders in adults were identified by a search of the literature.

Network meta-analysis was used to pool these studies.

The outcome measures included relapse to mania or depression, medication adherence, symptom scales for mania/depression, and the Global Assessment of Functioning scale.

Results

A total of 41 clinical trials with data on about 3100 patients were included in this meta-analysis.

The majority of trials included in this analysis had evaluated either cognitive-behavior therapy, psychoeducation, or a combination of the two.

Psychosocial interventions that focused on family members caring for the person with bipolar disorder were found to reduce the risk of relapse to mania or depression.

How much of a reduction in risk? Compared to “treatment as usual,” there was a 39% reduction in the risk of relapse.

Both psychoeducation alone and psychoeducation plus cognitive-behavior therapy reduced medication non-adherence. The relative risk of non-adherence decreased very significantly to 0.14, i.e., an 86% reduction.

Psychoeducation plus cognitive-behavior therapy reduced manic symptoms. The benefit was huge (standardized mean difference or effect size was 0.95)

Psychoeducation plus cognitive-behavior therapy had a huge effect on improving overall functioning (standardized mean difference 2.55).

Unfortunately, none of the psychosocial interventions led to reduction in symptoms of depression.

Conclusions

Only adjunctive psychosocial interventions aimed at family members caring for the person with bipolar disorder reduced relapse rates.

The mechanisms by which psychosocial interventions aimed at family members are helpful are probably complex. However, the finding itself is not new. Decades of research has shown that reduction of “expressed emotion” (critical comments and/or emotional overinvolvement) by families of persons with schizophrenia or bipolar disorder can improve long-term outcomes.

Adjunctive psychoeducation plus cognitive-behavior therapy was helpful for reducing medication non-adherence, reducing symptoms of mania, and improving overall functioning.

Adjunctive psychosocial interventions did not reduce depressive symptoms. New approaches should be developed for this.  

Clinical Commentary

Nearly half of the studies included in this meta-analysis required patients to be euthymic at the start of the study. This suggests to clinicians that the best time to introduce these psychosocial interventions is when the patient is doing well.

Based on these analyses, for best results it would be optimal to use a combination of psychoeducation, cognitive-behavior therapy, and involvement of the caregivers.  

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Is being lesbian, gay, or bisexual a risk factor for suicide attempts?

Miranda-Mendizábal A, Castellví P, Parés-Badell O, Almenara J, Alonso I, Blasco MJ, Cebrià A, Gabilondo A, Gili M, Lagares C, Piqueras JA, Roca M, Rodríguez-Marín J, Rodríguez T, Soto-Sanz V, Vilagut G, Alonso J. Sexual orientation and suicidal behaviour in adolescents and young adults: systematic review and meta-analysis. Br J Psychiatry. 2017 Mar 2. pii: bjp.bp.116.196345. [Epub ahead of print]. PubMed PMID: 28254960.

Background

Some previous studies have suggested that lesbian, gay and bisexual (LGB) adolescents and young adults are at higher risk of suicidal behaviors.

This paper aimed to combine all existing studies using meta-analysis.

Methods

A systematic search of the literature was done.

Longitudinal studies of lesbian, gay, or bisexual persons aged 12 to 26 years in non-clinical settings that evaluated their risk or risk factors for suicidal behavior were included.

Studies assessing only transsexual persons were not included.

All except one of the studies incorporated in this meta-analysis were prospective cohort studies. Prospective cohort studies are very important for us to be sure that the risk factors being assessed really did come before the outcome being analyzed.

The studies were combined using meta-analysis.  

Results

Fourteen articles were included in the meta-analysis.

Persons who were lesbian, gay, or bisexual were at increased risk of suicide attempts (odds ratio 2.3).

This was also found when only men (gay or bisexual) were considered (odds ratio 2.2), but the association was not statistically significant when only lesbian or bisexual women were considered.

The risk of suicide attempts was particularly high for gay men (odds ratio 8.3 compared to heterosexual men) and less so for bisexual men (odds ratio 2.4 compared to heterosexual men).  

Conclusions

Adolescents and young adults who are lesbian, gay, or bisexual are at higher risk of suicide attempts.

Further research is needed to evaluate whether or not these persons are also at higher risk of completed suicide and to identify specific risk factors affecting the LGB population.

Clinical Commentary

Clinicians are used to reviewing several demographic and clinical factors that indicate that a particular person is at higher risk of suicidal behavior. This paper suggests that sexual orientation should also be taken into consideration.

In particular, being a gay man makes it eight times more likely that the person will have a suicide attempt.

Further research should identify:

     1) What the risk factors for completed suicide by lesbian, gay, or bisexual persons are, and

     2) What factors lead to increased suicidal behavior in this population. We can all speculate on what these are, but systematic research is needed.

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Should CBT be added when medication alone is not enough for depression?

Nakagawa A, Mitsuda D, Sado M, Abe T, Fujisawa D, Kikuchi T, Iwashita S, Mimura M, Ono Y. Effectiveness of Supplementary Cognitive-Behavioral Therapy for Pharmacotherapy-Resistant Depression: A Randomized Controlled Trial. J Clin Psychiatry. 2017 Feb 28. [Epub ahead of print] PubMed PMID: 28252882.   

Background

Unfortunately, major depressive disorder often does not respond adequately to medications.

Is addition of cognitive-behavior therapy to the medication helpful in such situations?  

Methods

A 16-week randomized, controlled trial was done outpatient specialty care settings.

The patients and the clinicians were not blinded to which treatment group each participant was in, but the persons evaluating the response to treatment were.

Participants were aged 20 to 65 years old.

They had major depressive disorder and had taken an antidepressant for at least eight weeks prior to entering this study.

However, they still had at least moderate severity of depression (Hamilton Depression Rating Scale score of 16 or more).

The Maudsley Staging Method for treatment-resistant depression score was at least 3 or more, i.e., at least mild treatment-resistance. However, more than 60% of the patients included in the study had had three or more courses of antidepressants.

The participants were randomly assigned to continue “treatment as usual” or to receive “treatment as usual” plus cognitive-behavior therapy (CBT).

The CBT consisted of 16 sessions of 50 minutes each, held once weekly, with the option to add four more sessions if needed.

Results

A total of 80 patients were randomized at the start of the study, of whom 73 could be followed up for 12 months.

Those who received cognitive-behavior therapy in addition to “treatment as usual” showed greater reduction in the severity of depression after 16 weeks of treatment.

How much greater? The difference in the mean reduction in Hamilton Depression Rating Scale scores in the two groups was 5.4. Note that in psychopharmacology clinical trials, a difference between two groups of two points or greater is usually considered clinically meaningful, so this is a big difference.

Another way of describing how much a benefit there was is to note that participants who received CBT were 2.4 times more likely to have a treatment response than those who did not.

Was this improvement sustained? The group that received CBT had a greater reduction in the severity of depression at 3 months, 6 months, and 12 months. At 12 months, the difference in the mean reduction in Hamilton Depression Rating Scale scores in the two groups was 4.4 points, still a big difference.  

Conclusions

Persons with major depressive disorder who have not responded to antidepressant treatment may benefit from the addition of cognitive-behavior therapy.  

Clinical Commentary

This study should act as a reminder that addition of CBT (along with medication) should be considered as a treatment option for patients with major depressive disorder who have not responded adequately to medication alone.

Unfortunately, systematic, high-quality psychotherapy (rather than a non-specific, “supportive therapy”) is underutilized in the treatment of major depressive disorder and is not easily available to most patients.

In the STAR*D study, many patients were reluctant to participate in CBT perhaps because they had to pay for CBT sessions and had to travel to another site to receive CBT. Thus, availability and access may be important determinants of whether our patients receive CBT.

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A treatment for clozapine-induced sialorrhea

Man WH, Colen-de Koning JC, Schulte PF, Cahn W, van Haelst IM, Doodeman HJ, Egberts TC, Heerdink ER, Wilting I. The Effect of Glycopyrrolate on Nocturnal Sialorrhea in Patients Using Clozapine: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial. J Clin Psychopharmacol. 2017 Apr;37(2):155-161. PubMed PMID: 28129312.   

Background

Nocturnal sialorrhea is one of the most frequent adverse events of clozapine.

It is quite bothersome to patients who suffer from it.

This study aimed to evaluate the use of glycopyrrolate for the treatment of clozapine-induced sialorrhea.  

Methods

A double-blind, randomized, crossover trial was conducted. “Crossover” means that the same patients received glycopyrrolate for some time and placebo for some time. They were randomly allocated to receive either glycopyrrolate first and then placebo or the other way around.

Thirty-two patients with clozapine-induced nocturnal sialorrhea were randomized to treatment with either glycopyrrolate 1 mg or placebo at bedtime.

Patients were treated for six consecutive days and then had a one week washout before starting the other “treatment” (glycopyrrolate or placebo).

After the double-blind phase, an optional open label phase of treatment with glycopyrrolate at a higher dose of 2 mg/day was also offered.  

Results

In the double-blind phase, the percentage of patients rating themselves as improved was 19% with glycopyrrolate 1 mg/day and 6% with placebo. However, this difference was not statistically significant, i.e., could have occurred by chance.

When the dose of glycopyrrolate was increased to 2 mg/day, the percentage of patients who were improved after treatment with glycopyrrolate was 44%. There was no placebo group during this phase, but if we assume that patients on placebo would not have improved further, this 44% of patients improved was statistically significantly greater than the 6% improved on placebo.

Conclusions

Glycopyrrolate 1 mg was not superior to placebo, but 2 mg led to significant improvement in clozapine-induced sialorrhea.

Clinical Commentary

A previous study (Liang, 2010) found glycopyrrolate 1 mg twice daily efficacious for clozapine-induced sialorrhea. The present study suggests that for nocturnal sialorrhea, if a lower dose of 1 mg/day is not effective within a few days, we should not jump to the conclusion that glycopyrrolate will not work for this patient. Rather, we should try a higher dose (2 mg at bedtime).

Of course, the 2 mg dose was evaluated without comparison to a placebo. Given the importance of sialorrhea as an adverse effect of clozapine, I hope that a randomized, controlled trial of using 2 mg at bedtime will be conducted soon in order to confirm the findings of this study.  

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Rajnish Mago, MD
Medical Editor, GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is author of "The Latest Antidepressants" and "Side Effects of Psychiatric Medications: Prevention, Assessment, and Management." Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Mago the citation at [email protected].

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