Issue 92, Dec 2019
Share This
Cannabinoids for the treatment of mental disorders: Let the data speak!

Black N. et al. Lancet Psychiatry. 2019; Oct 25 pii S2215-0366 (19):30401-8. doi:10.1016/S2215-0366 (19) 30401-8. [Epub ahead of print]  PMID 31672337

Background

In recent years the use of medical cannabis has grown exponentially. This includes cannabis derivates such as tetrahydrocannabinol (THC) and cannabidiol (CBD). These agents have been suggested for anxiety and depression as well as post-traumatic stress disorder (PTSD). There are several concerns about cognitive impairment and psychosis with cannabis use. This study analyzed the available evidence to ascertain the effectiveness and safety of medicinal cannabinoids for the treatment of symptoms of various mental disorders.

Methods

The meta-analyses included studies over 38 years from 1980-2018. The search included MEDLINE, Embase, PsychINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews. The search also included unpublished data from Clinical Trials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry. Studies with participants at a minimum of 18 years of age looking at depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder (PTSD), or psychosis were included. The primary outcomes were remission or changes in symptoms from these mental disorders. The safety of medicinal cannabinoids for these mental disorders was also examined. The evidence from randomized controlled clinical trials was synthesized as odds ratios (ORs) for disorder remission, adverse events, and withdrawals. The evidence was also synthesized as standardized mean differences (SMD) for change in symptoms. The evidence quality was assessed using the Cochrane risk bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Results

There were 83 eligible studies for the various mental disorders included in the meta-analyses. The majority of the studies were for depression and anxiety. Pharmaceutical THC (with or without CBD) improved anxiety symptoms among individuals with other medical conditions (primarily noncancer pain and multiple sclerosis, although the evidence GRADE was low). Pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study.  Pharmaceutical THC (with or without CBD) did not significantly affect any other primary outcomes for mental disorders examined but did increase the number of subjects that had adverse events including withdrawals. In summary, the results did not provide significant evidence in support of the treatment of mental symptoms with medicinal cannabinoids.

Conclusions

The evidence is lacking that cannabinoids improve depressive disorders, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, PTSD, or psychosis. There is low-quality evidence regarding the improvement of anxiety symptoms in individuals with other medical conditions. There is a lack of evidence to provide guidance for using these agents for mental disorder symptoms. High-quality studies are needed to examine the effect of medicinal cannabinoids on treating mental disorders.

Clinical Commentary

The use of medical cannabis has evidence in limited areas in cases of chronic pain, chemotherapy-induced nausea and vomiting, certain kinds of epilepsy. Because cannabis has been recreationally and medically approved in many states, its use in treating mental illness may be getting legitimized in the eyes of patients and some providers. This is going to have serious consequences in the future. This study suggests a lack of evidence for cannabis in treating mental symptoms. It also suggests that there are significant side-effects. It is interesting to note that medical cannabis use is "fast-tracked" without objective data. The Federal warnings are largely ignored.

  • If a new antidepressant or antipsychotic was to come to market, we would need double-blind randomized placebo-controlled trials and FDA approval. I do not see any of that with medical cannabis?
  • Please be careful as it is not covered by insurance and some patients are getting medical cannabis card based on “chronic pain”. Subsequently, they find they cannot afford it and start using street cannabis with the explanation “it’s still the same and I can afford it”.
  • In the past, we asked patients if they used supplements while taking a medical history. Today we should be asking about cannabis, vaping products, supplements, and medications while taking a history. We must be aware of drug interactions related to cannabis which utilizes the cytochrome P450 3A4 substrate.
  • “Today’s cannabis is not the same as your parents' time". The concentration was a lot lower back then. With a greater profit motive, now cannabis is industrial grade and could contain other dangerous substances like opiates.
  • In summary: It is important to note the lack of evidence for medical cannabis as a treatment of mental symptoms. The side-effects are considerable which include psychosis, impaired attention span, and short-term memory. In adolescents, there is evidence for impaired brain development and also the precipitation of schizophrenia. Medical cannabis use is not recommended for the treatment of symptoms of mental illness based on the lack of current supportive evidence.
Expand Content
Share this Section:
Role of exercise in treating depression: Randomized controlled trial among youth with major depression

Nasstasia Y et al. J Affect Disorders. 2019; Dec 1;259: 413-423. doi: 10.1016/j.jad.2019.08.035. Epub 2019 Aug 19.  PMID 31610998

Background

Exercise is being increasingly recognized as an efficacious intervention for major depressive disorder (MDD). To our knowledge differential treatment effects on depressive symptoms (cognitive, affective, and psychological) and associated changes in psychological, physiological and behavioral factors have not been examined among youth with MDD.

Methods

The study included youth with a mean age of 21 years (N=68) who met DSM-IV diagnostic criteria for MDD. The participants were randomized to an immediate intervention or Control/delayed condition (N=34/group). The intervention comprised an initial session of motivational interviewing (MI) followed by a 12-week, multi-modal exercise program. Changes in depressive symptom profiles were assessed with the Beck Depression Inventory (BDI-II) total score and factorial symptom subscales.

Results

There were significant differential improvements in BDI-II total scores post-treatment among intervention participants, which were also observed across the cognitive and affective subscales. Improvement was noted in negative self-concept, (cognitive subscale), interest/activation (affective subscale), and energy (somatic subscale). Significant differential improvements were also observed in exercise participation, negative automatic thoughts, behavioral activation and bench press repetitions among participants. This correlated significantly with depression improvement.

Conclusions

Exercise differentially affects depressive symptom profiles with similar antidepressant effects as would be expected from psychological therapies improving negative cognition and emotional health.

Clinical Commentary

This is an extremely thoughtful study that has important findings. MDD is highly prevalent in youth and associated with comorbid eating, anxiety, substance use disorders, and increased risk of suicide completion. Established treatment approaches are limited for youth due to a lack of accessibility to psychological therapies and medication-related side-effects. Depressed patients have decreased motivation and the inclusion of a pre-study MI to help set the tone and maintain engagement was a great idea as part of the design. Another important feature of this study is the inclusion of both aerobic and resistance training exercise. 

  • It is interesting to note that exercise affected depressive symptom profiles similar to antidepressant effects from psychological therapies to improve negative cognitions. I think this is powerful.
  • The exercise intervention was delivered in a supervised group format, and potential social mediators of change cannot be excluded. This is a potential limitation of this study. On the other hand, a group format can also be viewed as maintaining motivation. 
  • The key is to get our patients in the real world motivated. We often have to be a cheerleader for a depressed individual.
  • Overall a holistic approach that includes: exercise, psychological and medication treatments, healthy structured lifestyle, good sleep hygiene, avoiding drugs and alcohol is likely to move things forward. Often patients are looking for one “magic pill/fix” and there is none.
  • In Summary: As a clinician, I suggest that we add exercise to our treatment plan. This study reveals the benefits of exercise in the cognitive, affective, and somatic areas of depressive symptomatology. Exercise has other benefits that include cardiovascular health, muscle tone, improved balance and fall prevention. Exercise can serve as an adjunct to psychotherapy and medication treatments. The key piece is building and sustaining the motivation to exercise.
Expand Content
Share this Section:
Antidepressant treatment in old age: Risk of dementia increased or decreased?

Kodesh A et al. Am J Geriatr Psychiatry. 2019 November 19; 27 (11):1177-1188. Doi: 10.1016/j.jagp.2019.05.019 Epub 2019 May 29.  PMID:31235427

Background

Depression is common in patients with dementia, with prevalence ranging between 10% and 62%. Major depressive disorder (MDD) has been reported to be a prodrome/or risk factor for dementia. Antidepressant medication appears to have limited efficacy in the treatment of MDD among older individuals in clinical trials. The study was designed to test competing hypotheses that antidepressant exposure was associated with an increased risk of dementia versus decreased risk.

Methods

This was a prospective national matched cohort study from Israel (N=71,515) that included patients without dementia (2002-2012) aged 60 and over. They were followed for incident dementia over four years. Exposure to antidepressant therapy was assessed. Hazard ratios (HR) were used to quantify the association of antidepressant therapy and the risk of incident dementia. The robustness of the results was tested using 24 sensitivity analyses.

Results

In the primary analysis, the risk of incident dementia for the group exposed to antidepressant monotherapy compared to the group unexposed to antidepressants was estimated with an adjusted HR=3.43. (The risk of dementia in the antidepressant exposed group was 3.43 times greater than the unexposed group).

Conclusions

This study suggests that monotherapy antidepressant exposure in old age was associated with increased incident dementia. Clinicians, caregivers, and patients may wish to consider the potentially negative consequence of antidepressant exposure and aim to balance the costs and benefits of treatment. 

Clinical Commentary
  • There are competing hypotheses regarding the association between antidepressant use and the risk of dementia in older adults. The first postulates that most antidepressants have anticholinergic properties which impairs cognitive function and increases the risk of dementia. The competing hypothesis postulates that antidepressant medications, owing to brain-derived neurotrophic factor levels, anti-inflammatory effects, hippocampal neurogenesis, and/or through the modulation of glial activation reduce dementia.
  • These findings suggest that the risk was associated with all classes of antidepressants. The risk was highest in the paroxetine group (HR=5.47) and low in the amitriptyline group (HR=1.99).
  • Most antidepressant use appears to be off-label suggesting that there were more illnesses in the exposed group rather than the unexposed group.
  • The subgroup of core psychological depressive symptoms in patients with dementia benefit from mirtazapine (Zuidersma M et. al 2019).
  • This study has limitations such as the confounding effects of familial and genetic factors.
  • In Summary: Clinicians should be careful in considering antidepressant therapy for depressed older adults. In my opinion, paroxetine should be avoided due to higher risk of dementia. Psychotherapies including problem-solving therapy, and cognitive behavioral therapy should be considered. Medical problems should also be addressed. 
Expand Content
Share this Section:
Obstructive sleep apnea (OSA) and risk of affective disorders

Kim JY et al. JAMA Otolaryngol Head and Neck Surg. 2019 Sep 12.; 70 (3):344-353. Doi: 10.1001/jamaoto.2019.2435. [Epub ahead of print] . PMID:31513273

Background

Sleeping difficulties are common in affective disorders. These patients are often prescribed sedatives to help them sleep with limited effects; however, the real issue might be OSA. This study was designed to assess the association between OSA and the development of affective disorders.

Methods

This study used a nationwide representative cohort sample from the Korea National Health Service database. The study included 197 patients with OSA diagnosed between January 2004 and December 2006 as well as 780 individuals without OSA. Both were matched using propensity score matching. The main outcomes and measures included affective disorder events over a 9-year follow-up period.  

Results

This population included 87 percent males. Fifty-five percent of the participants were under the age of 55 years. The incidence per 1,000 person-years of affective disorders was 49.57 and 27.18 in the OSA and comparison groups, respectively. After adjustment of sociodemographic factors (age, residential area, and household income), disability, and comorbidities, hazard ratios (HR) were calculated. The HR for patients with OSA developing affective disorder was 2.04. In further subgroup analyses, the HRs for patients with OSA who developed depressive and anxiety disorders were 2.9 and 1.75 respectively. Female patients with OSA had a significant likelihood of depression (HR 3.97) and anxiety (HR 2.42). In male patients with OSA the HR for depression was 2.74 and for anxiety was 1.64. In summary, the risk of affective disorders was increased in patients with OSA with associated sex differences of females displaying significantly greater risk than males.

Conclusions

The results indicate that OSA is associated with an increased incidence of affective disorders. Additional studies are needed to replicate these findings.   

Clinical Commentary

 This study which comes from ENT colleagues suggests that patients with OSA have an increased prevalence of depression and anxiety with females being at greater risk.  The sleep literature reveals that approximately 25% of sleep apnea patients have depressive disorders/or maybe on antidepressants.

  • The patients with depression and anxiety often have a Body Mass Index (BMI) in the obese range related to medications, disease state, and stress eating.
  • We as clinicians should ask questions related to OSA. These would include asking the significant other about snoring. This is especially important in patients complaining of sleep problems.
  • The severity of OSA is measured by the Apnea/hypopnea index as defined by the American Society of Sleep Medicine.  
  • The strength of this study is the nine-year follow up as well as having a comparison group. Limitations include a lack of availability of other data points such as obesity, lipid profile, alcohol, and smoking status. The lack of obesity data is a significant limitation.
  • In summary, we should be cognizant of the relationship between OSA and mood and anxiety disorders. Clinicians should consider this as a bidirectional relationship. In patients with sleep problems, we should consider a sleep study.
Expand Content
Share this Section:
Restless legs syndrome and suicide risk: Is there an association and should we pay more attention?

Zhuang S. et al. JAMA Netw Open. 2019 Aug 2;2 (8): e 199966. doi: 10.1001/jamanetworkopen. 2019. [Epub ahead of print]  PMID:31441941

Background

The suicide rate in the United States has been on the rise. Restless Legs Syndrome a common neurologic disorder is associated with higher odds of suicidal ideation.  The evidence for this association is limited. This study was conducted to assess the association between RLS and the risk of suicide and self-harm

Methods

This was a cohort study and was performed using Truven Health Market Scan national claims data from 2006 to 2014. The baseline data acquisition was from 2006 to 2008 and the follow-up data covered six years (2006-2014). The sample 24179 nonpregnant participants with RLS and 145194 age and sex-matched participants without RLS at baseline who were free of suicidal ideation, self-harm, cardiovascular disease, or cancer at study baseline. The diagnosis of RLS was identified by the International Classification of Disease, Ninth Revision code (ICD-9). The main outcomes of the study included incident suicide and self-harm event, identified by the ICD-9.

Results

The sample consisted of 32 percent males. The average age of the participants was 49 years. There were 119 incident suicide and self-harm cases identified. Individuals with RLS had a higher risk of suicide or self-harm compared to those without RLS (hazard ratio 2.66). Adjustments were made for lifestyle (e.g. alcohol and obesity), chronic diseases (depression, insomnia, diabetes, chronic kidney disease, peripheral neuropathy, anemia, and Parkinson’s disease), and use of medications. After excluding those with depression, insomnia, and obstructive sleep apnea the significant association between RLS and suicide or self-harm persisted (Adjusted hazard ratio 4.14)

Conclusions

This study revealed that RLS was associated with a high risk of suicide and self-harm, and the risk was independent of most identified diseases and conditions.

Clinical Commentary

This prospective study found elevated suicide/self-harm associations with RLS. The exact mechanisms remain unclear, although the contribution of depression has always been forwarded as an explanation. This finding has been reported in the literature previously with individuals with RLS having three times higher odds of suicidal ideation/behavior. Although depression prevalence has been reported to be higher in those with RLS, this study found elevated suicide/self-harm independent of depression.

  • There are several complexities to increased suicide association, such as sleep disturbance which may be multifactorial including obstructive sleep apnea (OSA).
  • Sleep disturbance is associated with a two-fold increase in the rate of completed suicide.
  • The associations of sleep, RLS, depression, and suicide are multidirectional and complex.
  • In summary: We clinicians should ask about RLS and treat the condition. The diagnosis is purely based on history and there is no laboratory test for detecting this condition.  The following questions are useful (National Sleep Foundation): 1) Do you have an urge to move your legs usually accompanied by uncomfortable sensations? 2) Are the symptoms relieved by movement? 3) Do the symptoms begin or worsen at rest such as lying down? 4) Are the symptoms worse at night? Commonly used FDA approved medications for the treatment of RLS are ropinirole, pramipexole, gabapentin, and rotigotine. There is also the Restless Leg Syndrome Foundation website, https://www.rls.org. We should always assess suicide risk and act to treat appropriately when a patient is noted to have an elevated risk.  
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]