GME Logo

User login

User menu



Issue 84, Apr 2019
Share This
The addition of risperidone to lithium or divalproex during maintenance treatment of bipolar I disorder: What do the data suggest?

Valdes M et al. J Affect Disord. 2019 Mar 1; 246:861-866. Doi: 10.1016/j.jad.2019.01.003. Epub 2019 Jan5 PMID: 30795492

Background

In patients with bipolar disorder recurrence of the illness is common, despite stabilization with mood stabilizers such as lithium and divalproex at therapeutic blood levels. Risperidone is used in combination with these agents for controlling manic episodes rapidly. This study was designed to answer the question regarding recurrence of manic or depressive episodes when risperidone and mood stabilizer therapy was continued long-term.

Methods

The trial included 93 patients treated with oral risperidone (dosage 1-6 mg) as adjunctive therapy to a mood stabilizer, randomized to one of three arms: 0-week, 24-week, 52 weeks. The patients in the 0-week arm (N=30) had risperidone tapered within 2 weeks of randomization. For the remaining 52 weeks they were on placebo. The 24-week arm patients had risperidone tapered and stopped over 2 weeks at the 24-week time point. Placebo was substituted for the remaining 26 weeks. The patients in the 52-week arm (N=33) were continued on risperidone for 52 weeks. All study personnel were blinded to the treatment arm allocation.  The patients were continued on the same mood stabilizer prescribed at study entry maintaining therapeutic levels (0.6-1.2 mmol/l for lithium and 350-830 μmol/l for divalproex). Time to any episode, manic episode, and depressive episode was compared between arms.

Results

The time to any episode was longer in the 24-week arm versus the 0-week arm but was not statistically significant. The time to relapse into a manic episode was statistically significantly longer in the 24-week arm. No other significant differences were noted between arms.  

Conclusions

The use of adjunctive risperidone in bipolar I disorder with lithium/divalproex reduced the risk of a manic episode during the first 24 weeks, but not after that time frame. This strategy did not reduce the risk of a depressive episode. 

Clinical Commentary

Long term management of bipolar illness remains a tough task, but important, as this is a life-long illness. Long-term studies are expensive and hard to conduct methodologically. Hence, we adopt secondary /post hoc analyses to gain insight.

  • This study suggests that adjunctive risperidone reduces the risk of relapse of manic but not depressive episodes when continued for 24 weeks but not at the 52-week time point. Hence, we should use risperidone adjunctively for 24 weeks. Weight gain was the most reported adverse event (N=8). No significant extrapyramidal side-effects were reported. The Abnormal Involuntary Movement Scale was not done to assess for tardive dyskinesia. 
  • No benefit was observed for preventing relapse of depressive episodes which cause greater morbidity in bipolar illness. Most of the relapses in the 52-week arm were due to depressive episodes, which also accounts for the non-significant results at the 52-week time point in this study.
  • Limitations: This study had a small sample size and also is a post hoc analysis. A study with a larger sample size and prospective design would be more informational.
  • Lurasidone (Latuda) in conjunction with lithium and divalproex has the FDA indication for acute treatment of bipolar depression but there are no long-term studies.  There remains an unmet need to develop long term treatments for preventing relapse in bipolar I disorder. Lamotrigine is one option with greater effect on depressive rather than manic symptoms. Thus, in psychiatry we try combinations which may not have been formally studied/FDA approved, such as the combination of risperidone and lamotrigine.
  • In summary risperidone is an effective generic medication in multiple dosage forms (tablet, liquid, long-acting injectable form) which has shown efficacy in prevention of manic symptoms in combination with lithium/divalproex at 24- week time point. 
Expand Content
Share this Section:
Alopecia and Depression: Is it a bidirectional relationship?

Vallerand IA et al. JAMA Dermatology. 2019 Jan16. Doi: 10.1001/jamadermatol.2018.4398 [Epub ahead of print] PMID:30649133

Background

Alopecia areata (AA) is an autoimmune disease characterized by hair loss that can impose substantial psychological burden on patients including major depressive disorder (MDD). Mental health issues have been reported to be present in these patients prior to the onset of AA. This raises the question of a bidirectional relationship, which was assessed in this study.

Methods

This was a large population based retrospective study conducted in the United Kingdom which included patients between the ages of 10 to 90 years of age. The study included the time frame between January 1986 and April 2018 (26-year period). To assess the risk of AA two cohorts were defined: Patients with a diagnosis of MDD and a reference general population cohort. To assess the risk of MDD the cohorts included: patients with a diagnosis of AA and a reference general population cohort. The development of MDD in the AA group was the primary outcome measure and the development of AA was the main outcome measure.  

Results

Patients with MDD had twice the risk of developing AA versus the reference general population cohort. Antidepressants had a significant protective effect. AA increased the risk of MDD by 30%. The results suggest a bidirectional relationship.

Conclusions

This study suggests that while patients with AA are at risk for MDD those having MDD are also at a significant risk for developing AA, suggesting a bidirectional relationship. Antidepressant use confounds the risk in MDD patients.

Clinical Commentary
  • The bidirectional relationship between MDD and AA was news to me as a clinician and I will be putting this in my practice right away. The idea is to screen AA patients for depression (dermatologist and PCP to be aware). Psychiatrists should ask MDD patients about hair loss in round patches on the scalp or other parts of the body. My patients have at times complained of hair loss and I have thought it may be due to divalproex or other medications. In retrospect I should have asked about AA.
  • There are several other conditions which have a bidirectional relationship with MDD. These include vitiligo, heart disease, irritable bowel syndrome, and hip fracture.
  • In summary I suggest that we screen for depression, and aim to treat to remission. We should ask about hair loss and further about bald patches. When we think of hair loss due to medications, we should also think of AA and ask a couple screening questions.

--Is the hair falling intact?

--Is the hair falling in round patches in the scalp or elsewhere in the body?

Labs: Measurement of hormone levels suggested include DHEAS (Dehydroepiandrosterone), testosterone, prolactin, FSH (Follicle Stimulating Hormone), LH (Luteinizing Hormone)

Serum iron, ferritin and Total Iron Binding Capacity (TIBC)

TSH, VDRL (Venereal Disease Research Laboratory), CBC

Refer to a dermatologist.

Expand Content
Share this Section:
Effective treatments for bipolar depression: Randomized double-blind placebo-controlled trial of cariprazine

Earley W. et al. Am J Psychiatry. 2019; 0:1-10; doi:10.1176/appi. ajp2018.18070824. [Pub ahead of print] . PMID:30845817

Background

The majority of individuals with bipolar I disorder present with depression as the index episode. There is significant morbidity during the depressive phase and also a high risk of substance abuse and suicide. There is a significant unmet need for the development of treatments for bipolar depression. This study investigates the efficacy of cariprazine in the treatment of bipolar depression.    

Methods

The 6-week study included patients (18-65 years old) with a DSM-5 diagnosis of bipolar 1 disorder currently in a depressive episode. The design was double-blind placebo controlled randomized clinical trial. This trial included three randomized groups; placebo (N=158), cariprazine 1.5 mg/day (N=157), and cariprazine 3 mg/day (N=165). The primary efficacy measure was change from baseline in Montgomery-Aberg Depression Rating Scale (MADRS). Change in Clinical Global Impressions severity (CGI-S) from baseline was the secondary efficacy measure.  

Results

Both cariprazine dosages were significantly more effective than placebo on the MADRS (primary efficacy measure) but there was no statistical difference on CGI-S (secondary efficacy measure). The adverse events twice the placebo rate included nausea, akathisia, dizziness, and sedation. Metabolic changes were small across groups.

Conclusions

Cariprazine at both dosages,1.5 mg and 3 mg/day was efficacious in reducing depression in Bipolar I disorder. It was also well tolerated.

Clinical Commentary

Cariprazine is already available with indications for schizophrenia acute and maintenance treatment, and Bipolar I manic and mixed episodes. Cariprazine is a partial D3/D2 and 5HT1A partial agonist. It has a favorable metabolic profile and no significant cardiac issues. The use of this drug has certain nuances. This drug has two metabolites desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), both being active moieties.

The parent drug cariprazine and DCAR reach steady state in 1-2 weeks while DDCAR reaches steady state in 4-8 weeks.  This has implications for titration.

  •  Suggested titration: Rapid titration may result in side-effects which are delayed due to time taken to reach steady state and multiple active metabolites. Clinicians should be aware of this nuance. I would suggest we titrate slowly (2-week intervals) for good tolerability and giving the patient a chance to have an adequate trial on cariprazine.  
  • Bottom line: Cariprazine shows efficacy for bipolar depression and may get FDA approval in the near future. The key is to keep the pharmacokinetics in mind and titrate gradually. Akathisia a noted side-effect, is treated with propranolol, clonazepam, and mirtazapine in that order of preference.
Expand Content
Share this Section:
Aspirin and N-Acetylcysteine as adjunctive treatments for bipolar depression

Bauer IE et al. J Clin Psychiatry 2018 Dec4;80(1). Pii:18m12200. doi:10.4088/JCP.18m12200. PMID 30549489

Background

Neuroinflammation has been implicated in the pathophysiology of mood disorders, including bipolar disorder. The treatment of bipolar depression remains difficult due to limited choices having FDA approval.  In this study both aspirin a nonsteroidal anti-inflammatory drug (NSAIDs) and the antioxidant N-acetylcysteine (NAC) were studied in a double-blind design.

Methods

This double-blind randomized placebo-controlled study included 24 medicated patients (age 18-65) with DSM-IV-TR diagnosis of bipolar 1 disorder. The patients were randomly assigned to receive either ASA (1000 mg), NAC (1000 mg), or combined NAC and Aspirin (1000 mg of each), or placebo. Data collection was between 2013 and 2017. The efficacy measure was a 50% or greater reduction in the MADRS score. C-reactive protein and interleukin levels were measured.

Results

At the 8-week time point there was no difference between placebo and any of the groups. At the 16-week time frame there was statistically significant difference between the placebo group and the combination group (NAC+aspirin) favoring the combination group.  There was no effect on the C-reactive protein and interleukin-6 levels (inflammation biomarkers) at 8 or 16 weeks.

Conclusions

This study suggests that co-administration of NAC and aspirin during a period of 16 weeks is associated with reduction in depressive symptoms. This study serves as a starting point for further research with a larger sample size. NAC and aspirin were well tolerated.

Clinical Commentary

This is the first study testing the effects of the NAC and aspirin combination. Based on the findings of this study we could carefully begin to use NAC and aspirin in our practice. Both agents do not need prescription.  Patients with bipolar depression who have tried other FDA approved treatments, or are partial responders to current treatment may be good candidates for this combination to enhance response.

  • In this study the NAC and aspirin combination were added to treatment as usual for bipolar 1 disorder. Treatment as usual was defined as the group taking psychiatric medications resulting in a partial response.  
  • This study also suggests that the responses are delayed noted at the 16-week assessment but not at the 8-week assessment. As no assessments were reported between 8 and 16-weeks, improvement could have started after 8 weeks. It is clear that the response to this combination is a delayed one
  • One needs to be careful using aspirin 1000 mg in patients especially those with bleeding risk/on blood thinners. I would not try this combination in older adults at this point.
  • This is not a frontline treatment.  We need to inform the patient that it is not FDA approved and hence is considered off-label. The patient needs to give a 16-week commitment.
Expand Content
Share this Section:
Suicide after discharge from inpatient psychiatric unit: How do data from 2.9 million discharges enlighten us?

Haglund A et al. J Clin Psychiatry. 2019 Feb 12; 80(2). pii:18m12172. : doi: 10. 4088/JCP.18m12172. PMID 30758922

Background

Suicide is a negative outcome that every clinician and administrator would like to prevent. The suicide risk is elevated post discharge from the inpatient unit irrespective of the diagnosis. Male patients who have depression and reaction to a crisis are at a higher risk post discharge. Psychotic patients who have had recent suicidal behavior also have an elevated risk of suicide post hospital discharge. This study investigated how recent suicidal behavior affects the suicide risk immediately post hospital discharge in a large sample.

Methods

This Swedish study created a cohort including all individuals discharged from psychiatric hospitals in Sweden from 1973 through 2009. Hazard ratios for discharge diagnoses were calculated. The risk of suicide within 30 days after discharge in each diagnostic category when suicidal behavior had been registered within 30 days before admission was estimated. 

Results

A total of 3,695 suicides occurred after approximately 2.9 million discharges over this 36 -year time frame. The results revealed that if there was recent suicidal behavior the risk of completed suicide increased prominently in all diagnostic categories. The risk of completed suicide was higher in schizophrenia (9 times higher) and other psychoses (7 times higher). The risk of suicide was highest in patients with depression especially male patients and those reacting to a crisis.

Conclusions

There was a distinct elevation in suicide risk across all diagnostic groups if recent self-harm had occurred. The suicide risk was even higher in psychotic patients. Overall, the suicide risk was high regardless of recent suicidal behavior. These findings have implications for treatment teams, psychiatrists, and hospital administrators.

Clinical Commentary

This study was very enlightening regarding inpatient work and discharges from the hospital. Hospital decisions are made by a treatment team and sometimes people lose sight of the patient history and these important issues get overlooked. Most hospitalizations are due to suicidal ideation/attempt. Being familiar with inpatient work I would estimate 70% of hospital discharges are high risk.

  • The inpatients units should have access to this data which is practical and clinically oriented. Use the zero-suicide approach. This is a system wide effort to fill the gaps through which a patient may fall through.
  • WWW.zerosuicide.com
  • As psychotic patients with schizophrenia and nonorganic psychosis have a higher risk, use long acting injectable (LAI) to control psychosis and enhance compliance. The LAI should be used early in treatment and the inpatient setting is a perfect location for getting started on a LAI.
  • Prior to discharge use the Columbia Suicide Severity Rating Scale (CSSRS). Multiple levels of staff should be trained in suicide risk assessment. Ask about access to firearms.
  • Screen for substance abuse and address it in treatment along with mental health issues. This aspect is often missed.
  • Use the “warm handoff” to transition to outpatient. Have the patient meet the outpatient clinician in person or via video. The outpatient appointment should be within 5 days of discharge or sooner. There should be a post discharge F/U of the patient to know that they went to the outpatient clinic.
  •  At discharge give a limited supply of medication 1-2 weeks supply.
  • Do not use “no suicide contracts”. They are not clinically helpful and also do not stand in the court of law.
Expand Content
Share this Section:

Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta 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. Gupta the citation at [email protected]

To contact GME, email us at [email protected]


GME does not provide medical advice. The website and articles are intended for informational purposes only. They are not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the GME Website. If you think you may have a medical emergency, immediately call your doctor or dial 911.

Log In

Join GME For Free

Become a GME subscriber and gain full access to our extensive library of 700+ psychiatric medical education videos, free CME webcasts, latest research updates, and more. To sample our content, watch the featured videos below.
Join Today!