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Issue 81, Jan 2019
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Genetic testing: Can it guide medication selection and improve outcomes?

Tanner JA et al. J Psychiatr Res. 2018 Sep; 104:157-162. doi.org:10. 1016/j.jpsychires.2018.07.012. Epub 2018 Jul 21. PMID: 30081389

Background

The treatment of major depression and other psychiatric disorders is limited by failed medication trials and tolerability issues. There has been an aggressive effort to use pharmacogenomics to guide medication selection and improve outcomes. The focus of this study was to evaluate the use of gene testing in primary care and psychiatric practices to assess outcomes.

Methods

This is a large naturalistic open label prospective study evaluating the effects of GeneSight pharmacogenomic-guided treatment (PGx) on clinical outcomes of depression (N=1871). The Beck Depression Inventory (BDI) was used in this study to quantify depression. All patients underwent gene testing, and medications were prescribed based on gene-drug interactions. Fifty percent reduction in the BDI was considered a response and BDI < 10 was defined as remission of depression. There was no control arm or a treatment as usual group (TAU). Information pertaining to prior medication trials and their effects was not described. Standardized rating scales in antidepressant trials, such as the Montgomery Asberg Rating Scale (MADRS), Hamilton Depression Rating Scale (HDRS), and Quick Inventory of Depressive Symptoms (QIDS) were not used in this study.

Results

The study reported a significant symptom reduction (27.9%) baseline-to-endpoint at 8-12 weeks. They reported a 25.7 % response rate and a 15.2% remission rates. Outcomes were significantly better among patients treated by primary care providers versus psychiatrists (response rate 30.1% versus 22.3%; remission rate 19.5% versus 12.0%).

Conclusions

The use of combinatorial pharmacogenomic testing improves patient outcomes in Major Depressive Disorder. This study with design limitations further concludes that pharmacogenomic testing should be used in a broader clinical testing.

Clinical Commentary

The use DNA to predict response (“tailored treatment”) and tolerability to certain antidepressants/psychotropics sounds like an excellent idea. However, the science currently is not supportive of widespread use of pharmacogenomic guided treatment (Rosenblat JD et al. J of Psychiatr Res 107 (2018).

  • This study was chosen to address this hot clinical issue for the readership as it is a burning question in the minds of several clinicians including myself. It is being touted to clinicians without FDA approval.
  • This study was flawed due to lack of a control arm or a treatment as usual group as well as standardized objective measures were lacking.
  •  Aggressive marketing for use of gene testing has resulted in the FDA taking a stance with recommendations to providers, patients, labs, and genetic test developers. “However, sufficient clinical evidence is not currently available for these genetic tests or software programs and, therefore, these claims are not supported for most medications.”
  • Contact FDA at: 1-888-INFO FDA (1-888-463-6332) or (301) 796-3400. You can also email   [email protected]. Additional information is available at the DDI Web page.
  • In my opinion as a clinician, I would not recommend routine genetic testing for all patients. At this time gene testing does not predict medication response for a particular patient. It may be appropriate in some cases where there are lot of tolerability issues.
  • The science still needs to catch up, and hence use is extremely limited.
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Concussion and associated risk of suicide. An important neuropsychiatric issue!

Fralick M et al. JAMA Neurol. 2018 Nov 12. doi:10.1001/jamaneurol.2018. 3487. Epub ahead of print PMID:30419085

Background

In the recent past increased attention has been paid to concussion, which is the most common form of traumatic brain injury (TBI). In the past concussion was neglected to a large extent. Now there are clinics that specialize in treating concussions. The field has realized the increasing complications of concussions, such as recurrent headaches (physical symptoms), cognitive symptoms, emotional lability, and mood problems. These symptoms can elevate the suicide risk. This study was designed to assess the suicide risk post-concussion.

Methods

This research focused on extracting data from studies conducted between 1963-2017 (54 year time frame). Databases such as Medline, Embase, PsycINFO, and Published International Literature on Traumatic Stress (PILOTS) were used. Studies that quantified risk of suicide, suicide attempt, or suicidal ideation after concussion were included in the meta-analyses. The primary exposure was concussion and the primary outcome was completed suicide. Secondary outcomes were suicide attempts and suicidal ideation. The sample included both military and nonmilitary personnel as well as children and adults.

Results

The study had a large sample size and  included 10 cohort studies (N=713706 individuals diagnosed and 6236010 individuals not diagnosed with concussion), five cross sectional studies (N=4420 individuals diagnosed and 11275 individuals not diagnosed with concussion), and two case-control studies (N=446 individuals diagnosed and 8267 individuals not diagnosed with concussion).

  • The risk of completed suicide is two-fold higher in those with a concussion history.
  • The risk of suicide attempts and suicidal ideation was also significantly elevated in those with a history of concussion.
  • The risk of suicide did not change based on being in the military.
Conclusions

This study suggests that a history on concussion increases suicide. Future studies are needed to better identify these high-risk individuals and develop strategies for risk reduction.

Clinical Commentary

Concussions are a lot more common than we think in the civilian world and are often missed in history gathering. A benign looking sport, such as cheerleading has a high rate of concussion, (we would not suspect and ask), while in football we expect concussions. Typically, the neurologic symptoms resolve; however, the psychiatric symptoms, such as depression and anxiety may persist long past the physical recovery.

  • I would suggest we ask routinely on all initial evaluations about concussion and seizure history. Patients often may relate to the question: “Have you ever had your bell rung?” We need to ask the question of a patient in a way that they are on the same page. Concussion history, with or without loss of consciousness informs us regarding the severity factor.
  • The suicide rates were elevated for all age groups, the highest being in the 16-20 year age group.
  • The history of concussion should be included in every suicide/ lethality assessment.
  • We should think about concussion as a “software malfunction” as there may not be any physical abnormality that is detectable on brain imaging.
  • Pseudobulbar affect (PBA) should be excluded as emotional symptoms can overlap with PBA symptoms. PBA also occurs as a result of repeated concussions.
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Antipsychotics, thyroid and weight gain: What is the deal?

Vidal TSJ et al. J Psychiatr Res 2018 Nov; 106:74-81. doi: 10.1016/j.jpsychires.2018.09.014. Epub 2018 Sep 25 PMID:30292780

Background

There is a complex relationship between thyroid disorders and psychiatric illnesses. Thyroid function is routinely assessed in treating psychiatric disorders. There has been a surge in the prescription of antipsychotic medications, and less is known about their effects on the thyroid. This study examined this very issue.

Methods

This naturalistic Norwegian study recruited patients between the ages of 18 and 65 in the Oslo area. The sample included (N= 1345) patients and (N=989) healthy controls as a comparison group. The patients underwent a thorough clinical investigation and medication assessment. Thyroid function was determined based on free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels. Statistical analyses were used to assess the relationship between thyroid parameters and antipsychotic usage. Additionally, monotherapy users of olanzapine, quetiapine, aripiprazole, or risperidone were investigated separately.

Results
  • 12.9% of the patient group had undiagnosed thyroid issues.
  • Statistically significantly lower fT4 levels were found in the patients compared to healthy controls.
  • Lower fT4 levels were associated with the use of antipsychotic drugs. This was especially statistically significant in the case of olanzapine and quetiapine.
  • There were no statistically significant associations with the TSH levels.
  • The fT4 was significantly lower, especially in those on a combination of psychotropic medications, compared to those on an antipsychotic alone. The issue was more significant in those using antidepressants and antipsychotic drugs in combination.
Conclusions

There is an association between the use of antipsychotic medication and lower fT4. Clinicians should be aware of this especially with use of quetiapine, olanzapine, and those on combination therapy especially antidepressant combinations.

Clinical Commentary

This study clearly suggests that clinicians should do a thyroid screen of patients on antipsychotics and combination psychopharmacology, especially involving antidepressants. A hypothyroid state with low fT4 and normal TSH is thought to be due to an underperforming pituitary gland, also called central hypothyroidism. This needs thyroid hormone replacement.

  • In individuals taking these medications especially olanzapine and quetiapine this lower fT4 may be an underrecognized mechanism of weight gain.
  • A double whammy, the antipsychotic drug alone or in combination with an antidepressant causing the weight gain and also via the mechanism of related hypothyroidism.
  • Bottom line: please screen for TSH and fT4.
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Oral and injectable extended release naltrexone. Is the Injectable worth it?

Sullivan MA et al. Am J Psychiatry 2018 Oct 19: doi: 10.1176/appi.ajp.2018.17070732. Epub 2018 Oct19 PMID 30336703

Background

Opiate addiction is a severe public health problem gripping the Unites States currently. Opiate and suicide related deaths have lowered the US life expectancy to 78.6 years. Medication noncompliance is a key issue in this population. The introduction of long acting injections (LAI) has been welcomed in psychiatry and substance abuse fields. This study aims to address this very key issue comparing LAI to oral therapy in the addicted patients with regard to retention in treatment.

Methods

This randomized six-month study included patients (N=60) with opiate addiction. They were stratified by severity of opiate use and randomly assigned (1:1) to oral naltrexone (N=32) or naltrexone-XR monthly (N=28) injection. Enrollment was over a five-year time frame. All these patients had undergone inpatient opioid detoxification. Prior to discharge they were given 380 mg IM naltrexone XR or oral naltrexone 50 mg daily. Both groups received behavior therapy.

Results

The retention rate in the program was statistically significant, two times higher in the naltrexone XR monthly injection group (57%) versus the oral naltrexone group (28%).

Conclusions

These results support using naltrexone XR Injection in those with opiate addiction preferentially over oral naltrexone for retention in treatment program and relapse prevention.

Clinical Commentary

As a field we continue to struggle with opiate addiction, which is complicated by noncompliance. The take home message being:

  • Opiate addiction needs to be addressed on a war footing and treated like a medical disease.
  • 45.5% of individuals failed to complete detoxification in this study. The investigators started with N=608 and finally had N=60 participants which illustrates the problems faced.
  • LAI naltrexone XR should probably be the cornerstone of management of opiate abuse and for retention of patients in the behavioral program for relapse prevention.
  • Relapse discourages patients, resulting in a vicious cycle with negative outcomes.
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Major depression and bipolar disorder: Are there differences in pattern of cannabis use?

Taub S et al. Compr Psychiatry. 2018 Jan; 80:89-96. :doi: 10.1016/j.comppsych.2017.09.004 [EPub 2017 Sep13]. PMID 29069624

Background

The use of cannabis has increased significantly, since recreational use is allowed in a number of states in the US. Medical use of cannabis has also been approved by many states. Patients with mental health issues often use cannabis with the hope of improving psychological symptoms. Prior reports have indicated that there is a high use of cannabis in patients with major depression (MDD) and bipolar disorder (BPD). There is a scarcity of studies comparing cannabis use patterns in bipolar disorder and major depression.    

Methods

The study sample was drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). The sample included cannabis users who qualified for a diagnosis in the past year of MDD (N=217) were compared to those with BPD (N=168) in frequency and daily cannabis use. The rates of comorbid psychiatric disorders as well as cannabis use disorders (CUD) was assessed. The rates of suicidality were also assessed.

Results

Amongst individuals (having MDD or BPD) who used cannabis in the past year, the BPD group had a higher prevalence of cannabis use disorders. The prevalence of CUD was 39% in the MDD group and 52% in the BPD group. The BPD group used cannabis more frequently as well as more joints per day. This included those with BPD also having a higher comorbidity with personality disorders as well as using cannabis in more hazardous situations. No significant differences were found in the rates of suicidality amongst the two groups.

Conclusions

This study indicates that individuals with bipolar disorder have a more intensive pattern of cannabis use compared to those with major depression. This pattern of cannabis abuse may affect  the course of bipolar disorder.

Clinical Commentary

There is common a belief amongst cannabis users that “it helps them relax and helps with anxiety”. Some individuals also have a perception that it improves their sleep. This is all anecdotal without any randomized controlled trials as needed for psychiatric medications. Cannabis is getting a free pass.

  • Patients with bipolar illness use cannabis more frequently as well as are likely to use in potentially hazardous situations.  
  • Patients with bipolar disorder, having limited response to medications should be screened for CUDs which may be affecting the treatment response.
  • These finding have important implications as now all of Canada is recreational and more states in the US are going recreational. This will alter the course of bipolar disorder leading to rapid cycling and also adding to diagnostic complexity.
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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 i[email protected]

To contact GME, email us at [email protected]


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