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Issue 88, Aug 2019
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Highly processed food and mortality-What’s the association?

Rico-Campa A et al. BMJ. 2019 May 29; 365-: l1949. doi:10.1136/bmj.l1949. [Epub ahead of print] PMID:31142450

Background

We have knowledge that excessive consumption of processed food such as cheese, sugar, and soda are detrimental to health. Relationship between consumption of these foods and increased obesity, cardiovascular disease, irritable bowel syndrome, and cancer has been established. This study looked at the relationship between highly processed food intake and all-cause mortality. The study is relevant to mental health as our patients consume excessive amounts of highly processed food.

Methods

This is a prospective study conducted collaboratively by the University of Navarra Spain, Spanish Institute of Health Madrid Spain, Harvard School of Public Health Boston, and the Department of Nutrition and School of Nursing, University of Minas Gerais, Brazil. The sample (Spanish university graduates) included 19,899 subjects (12,113 females and 7,786 males) aged 20-91 years.  The participants were followed every 2 years, between December 1999 and February 2014. During these visits’ information regarding food and drink consumption was collected according to the degree of processing based on the NOVA classification. This was evaluated through a validated 136 item food frequency questionnaire. The consumption of energy adjusted-ultra-processed foods was categorized into 4 groups (low, low-medium, medium high, and high consumption) and all-cause mortality was assessed using hazard models.

Results

There were 335 deaths during the 200,432 person years of follow up. Participants in the high consumption group had a higher hazard of all-cause mortality compared to those in the lowest quarter of consumption of processed food. There was also a significant dose response relationship. For each additional serving of ultra-processed food, the all-cause mortality increased by 18%.

Conclusions

A higher consumption of ultra-processed foods (>4 servings daily) was independently associated with a 62% increased hazard for all-cause mortality.

Clinical Commentary

The consumption of processed foods has increased worldwide particularly in the west. This is a large prospective study adding to the current knowledge regarding the relationship between processed food and mortality in addition to the medical ailments that we already know about. The sample was followed over 15 years were Spanish university graduates. This study though not done in a population of psychiatric patients still applies to us in mental health, as there is a high consumption of processed foods in the severely ill psychiatric population.

  • We in psychiatry still do minimal, if at all anything, with a focus on food choices in our severely and persistently ill psychiatric patients. Our mentally ill population consumes a high amount of processed foods and so the problem may be worse in our patients.
  • The subjects in this study were Spanish University graduates. It is not clear how that would work for the US population with mental illness. I think we all have a good idea how that stands!
  • This study underscores the importance of paying attention to the food consumed by our patients as well as education with a focus on cooking at home using simple recipes. This would bring an overall change. The type of food consumed also affects the gut microbiome which is being linked to health problems both physical and psychiatric (see GME RR July 2019).
  • A simple example is the use of the sugar substitute high fructose corn syrup (HFCS) in the United States which is probably not assessed in this study as it is not consumed in Europe in the same way. HFCS increases the risk of obesity and also cardiovascular disease. It is sweeter than sugar and is also used to prolong shelf life of products.  
  • In summary these findings though not directly from a mentally ill population should sound the alarm for us in mental health, as our patients consume a high amount of processed foods. We also have knowledge that severe mental illnesses such as schizophrenia and mood disorders increase the incidence of diabetes and cardiovascular problems. Most psychiatric medications and a high prevalence of drug and alcohol abuse add fuel to the fire. This study is a call to action for each one of us to spend time on the dietary education of our patients. Community mental health centers (CMHC) are uniquely positioned to start education programs. My aim for reviewing this study is for us all to try and make a difference that will enhance outcomes for patients.
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Cariprazine treatment of bipolar depression: A randomized double-blind placebo-controlled phase 3 study

Early W et al. Am J Psychiatry. 2019 June 1;176 (6):439-448; doi: 10.1176/appi.ajp. 2018.18070824. Epub 2019 March 8. PMID:30845817

Background

There is growing awareness regarding the accurate diagnosis of bipolar depression in patients presenting with depressive symptoms because of focused education. There is also a paucity of FDA approved well tolerated treatments for bipolar depression. This phase 3 study assessed the efficacy, tolerability, and safety of cariprazine in bipolar I depression.

Methods

This 6-week study consisted of a double-blind placebo-controlled design having adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and were currently in a depressive episode. They were assigned randomly to receive placebo (N=158) or cariprazine 1.5 mg/day (N=157) or cariprazine 3.0 mg/day (N=165). Changes from baseline to week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score were assessed.

Results

Both dosages of cariprazine were significantly more effective than placebo. Common treatment-emergent side-effects (occurring in at least 5% of the participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable to the placebo group.

Conclusions

Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.

Clinical Commentary

The availability of carprazine for bipolar depression is welcome for us clinicians as this disorder has considerable morbidity and mortality. It was approved by the FDA for bipolar depression in May of 2019. It is already approved for the treatment of schizophrenia and manic or mixed episodes of bipolar I disorder. Cariprazine is a D3 receptor-preferring D3/D2 and 5HT1a receptor partial agonist. It exhibits a high affinity for D3 and D2 receptors. The D3 receptors are highly expressed in brain regions involved in cognition, motivation, and reward related behavior. Hence the engagement of the D3 receptor by cariprazine may have positive effects on cognition, mood, and measures of reward including reduction in anhedonia and addictive behavior.

  •  Cariprazine is effective for bipolar I depression at both the 1.5 mg dose as well as the 3 mg dose, findings replicated from a prior phase 2 study. The MADRS reduction of 2.5-3 points is consistent with other medications approved for bipolar I depression. Replication of results is a strength favoring the medication. The optimal dosage is 1.5 mg/day.
  • Clinicians should note there are some nuances to the pharmacokinetics of cariprazine which has 2 major active metabolites (Desmethyl cariprazine [DCAR] and Didesmethyl cariprazine [DDCAR]) both with long half-lives. These metabolites are equipotent to cariprazine. The implications being cariprazine and DCAR concentrations reach steady state at approximately week 1 to week 2 and DDCAR week 4 to week 8. Hence adverse reactions (EPS and akathisia) may occur several weeks after drug initiation.  The long half life may potentially be protective in non adherent patients.
  • In my opinion this medication should be titrated slowly based on the pharmacology and delayed side-effects kept in mind. After starting cariprazine we should wait two weeks and look for a 20% improvement before titrating to the next level. Based on this strategy side-effects may be lower compared with clinical trials where rapid dose escalation was done. It is important to note that in the bipolar depression trials the akathisia was not dose related unlike the schizophrenia and bipolar manic and mixed episode trials.
  • When using cariprazine we will be switching in most cases from another drug and the “SWITCH” strategy is commonly used (S-start new drug, W- withdraw old drug gradually, I- involve the patient and significant other/family in the process, T-titrate the new drug, C-challenge any side-effects e.g. insomnia, H-halt the old drug). In most cases it may be an antidepressant, mood stabilizer or another atypical antipsychotic.
  • In summary: being a new agent it may be difficult to get insurance authorization until one or two generic agents are tried.   We would be switching for lack of efficacy or tolerability issues (such as metabolic issues) to cariprazine,  a novel drug that engages the D3 receptor. The doses are 1.5 mg and 3 mg /daily using the start low and go- slow strategy.
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Remission and recovery associated with lurasidone in the treatment of major depressive disorder with mixed features: Post-hoc analysis of a randomized placebo-controlled study with longer-term extension.

Goldberg JF et al. CNS Spectr. 2017 Apr; 22(2):220-227. doi:10.1017/ S1092852917000025. Epub 2017 Mar 7. PMID 28264739

Background

Patients with major depressive disorder (MDD) with mixed features (subthreshold hypomanic symptoms) are not only tough to identify but also to difficult treat. In the past the field has focused on symptomatic remission but functional remission (getting to original level of functioning) is the key.  This post-hoc analysis was done to study recovery and remission associated with lurasidone in this group of patients.

Methods

The data for this analysis is derived from patients with MDD with mixed features (DSM-5). The subjects were randomly assigned to a flexible dose of lurasidone 20-60 mg/day (n=109), or placebo (n=100) for 6 weeks followed by a 3-month open-label, flexible dose extension study for US sites only (n=48). Cross-sectional recovery was defined as the presence of both symptomatic remission (Montgomery-Asberg Depression Rating Scale (MADRS) score ≤ 12) and functional remission (all Sheehan Disability Scale [SDS] domain scores ≤ 3) at week 6 and at both months 1 and 3 of the extension study (“sustained recovery”).     

Results

A significantly higher proportion of lurasidone-treated patients (31.3%) achieved recovery compared with placebo (12.2%) at week 6. The number of manic symptoms at baseline moderated the effect size of attaining cross-sectional recovery for lurasidone treated vs. placebo. Sustained recovery rates were higher in patients initially treated with lurasidone (20.8%) versus placebo (12.5%).

Conclusions

This post-hoc analysis of a placebo-controlled study with open-label extension found lurasidone to significantly improve the rate of recovery at 6 weeks (vs. placebo) that was sustained at month 3 of the extension study. The presence of two (as opposed to three) manic symptoms moderated recovery at the acute study endpoint.

Clinical Commentary

This is an interesting study pushing the field to another level.  In most studies the criteria for remission is absence of symptoms, however, functioning is a key issue that has been addressed in this study. The criteria of cross-sectional recovery have been used which includes symptomatic remission (MADRS≤12) and functional remission (SDS≤ 3) at week 6.

                                                               

  • This study has carved out a specific group of MDD patients with mixed specifier including those with 2-3 hypomanic symptoms. These included elevated or expansive mood, inflated self-esteem or grandiosity, more talkative or pressure to keep talking, flight of ideas or racing thoughts, increased energy, excessive involvement in activities for negative consequences, and decreased need for sleep. A novel approach, trying lurasidone, FDA approved for bipolar depression was tried in this sample.  
  • Using antidepressants alone may not lead to recovery. Presence of symptoms leads to recurrence. Antidepressants also promote rapid cycling or ultimately lead to a manic episode in depressed patients with hypomanic symptoms.  (antidepressant-induced mania)
  • The important point made by this study in a subset of individual with MDD who have hypomanic symptoms (mixed specifier) is that symptomatic and functional remission can be achieved. The group with 2 hypomanic symptoms achieved recovery with number needed to treat (NNT) of 4. This translates into one patient achieving recovery when lurasidone is administered to four such patients. The results were not as good for those with 3 hypomanic symptoms.
  • In summary this study suggests a novel and promising approach for us clinicians that is not FDA approved. When evaluating patients with MDD clinicians should look for two or more hypomanic symptoms. The chances of complete recovery in this patient group (those with 2 hypomanic symptoms) are enhanced with lurasidone treatment, dosage range 20-60 mg /day. Using antipsychotics in those with mood disorders increases the risk of tardive dyskinesia (TD) and metabolic issues. Lurasidone does have a lower risk of causing metabolic issues. We need to monitor for these side-effects and get informed consent. Overall psychological stability is the cornerstone of management. These findings need to be replicated in other studies. However, it is not possible to wait for studies for those of us who work in the trenches. This study offers a new way of thinking.
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Analysis of risk factors and outcomes in psychiatric inpatients with tardive dyskinesia: A nationwide case-control study.

Patel R et al. Heliyon. 2019 May 17;5 (5): e01745. doi: 10.1018/ j.heliyon 2019.e01745. Epub 2017 Jan 23  PMID 31193370

Background

Tardive dyskinesia (TD) is a debilitating and a permanent side-effect of long-term exposure to first and second-generation antipsychotics. There are two FDA approved treatments for TD: duetetrabenazine and valbenazine.  The aim of this study was to analyze the comorbidities and outcomes in patients with TD during inpatient management. 

Methods

This case-control study was conducted using a nationwide inpatient sample (NIS) (N=77,022). The sample included adult inpatient hospitalizations for mood disorders and schizophrenia. Each case had a secondary diagnosis of TD while age matched controls did not have TD. Multivariable logistic regression was used to generate odds ratio (OR).

Results

The patients with TD were older in age (50-64 years;40%). The odds of having TD was two-fold higher in the African American population. TD patients had a higher likelihood of cardiometabolic comorbidities-obesity, hypertension, and diabetes compared to controls. Participants with TD had a 1.5 fold increased risk of comorbid drug abuse. Patients with schizophrenia and bipolar disorder (depressive) had four-fold higher odds of having TD. TD patients had a much higher odds of having severe morbidity. Patients with TD had a higher likelihood of having extended hospitalization by 6 days.  The cost was also higher by $20,000 compared to controls.

Conclusions

This study revealed that patients with schizophrenia and bipolar disorder had the highest risk and those with TD had greater severity of illness.

Clinical Commentary

This large case-control study has important findings for the clinician. The sample was taken from the NIS database sponsored by the Agency for Healthcare Research and Quality (AHRQ). NIS is the largest data base of inpatient stays in the United States.

  • We need to consider these findings in the context of two FDA available treatments for TD. These agents treat TD but the movements come back when the medication is stopped. Hence screening and prevention remains the key. The Abnormal Involuntary Movement Scale (AIMS) is the standardized scale accepted universally for monitoring for TD.
  • We should still be judicious in using antipsychotic agents especially in those patients with mood disorders as they are prone to TD. In patients with schizophrenia we should use the second-generation antipsychotics (SGA) which have a lower propensity to cause TD.
  • The African American population has a higher susceptibility to TD (two-fold higher odds). We also know in the past that African Americans are more likely to be diagnosed with schizophrenia and also more likely to receive FGA (First Generation Agents). This fact also applies to long acting injectable agents (LAIs).   
  • When using antipsychotics for non-psychotic disorders the risk of TD should be considered and other relevant options tried first.

In summary the aim is to prevent TD, being cognizant of the risk factors, and screen and treat patients early. Patients with TD are more likely to have cardiometabolic abnormalities, diabetes, and have a higher risk of drug-use. Patients with TD stay longer in the hospital and cost more to treat.   

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Anorexia Nervosa and bone loss: Role of oral contraceptives in young women to protect from bone loss.

Maimoun L et al. Fertil Steril. 2019 May; 111(5): 1020-1029e2.doi: 10.1016/j.fertnstert.2019.01.008. Epub2019 Mar25

Background

Anorexia Nervosa (AN) is a complex and tough to treat psychiatric disorder with multiple comorbidities. Bone loss can result in spontaneous fractures and can cause significant comorbidity amongst patients with AN. This study was conducted to evaluate the protective effects of oral contraceptives (OC) on bone loss in young women with AN.

Methods

This was a cross-sectional study (N=305) conducted in a university hospital. The study had  99 patients with AN using OC and 121 aged matched control group. Areal bone mineral density (aBMD) was evaluated by dual energy X-ray absorptiometry and bone turnover markers, with concomitant evaluation of leptin. 

Results

This study revealed that patients with AN on OC had had higher aBMD values compared with AN patients’ not taking OC. Patients with the lowest body mass index showed the best bone tissue response to OC. Preservation of bone density improved with longer duration of OC therapy and shorter delays between disease onset and start of OC treatment.  These changes were noted in the whole body and lumbar spine, femoral neck, hip, and radius. Bone formation markers were lower in both patient groups compared with controls. Markers of bone resorption were normalized in AN patients’ using OC.

Conclusions

Although OC use does not provide total protection of aBMD, this study suggests that OC could be prescribed for young women with AN to limit bone loss. 

Clinical Commentary

This cross-sectional study suggests that OC may have a protective effect on bone loss in patients with AN. The literature also indicates that women using OC in the premenopausal period tend to enter menopause with a 2%-3% higher bone density than non-users. This may delay the time at which bone mineral density falls into the fracture-risk zone. Hence a case can be made for early OC therapy in this group of patients. 

  • Bone loss in the AN results in significantly elevated morbidity and mortality.  These patients have a higher mortality just by the nature of having AN and; therefore, the need for OC treatment. 
  • These studies can be hard to interpret due to the multiple confounding variables such as age, smoking, exercise, duration of use, menstrual function and endocrine disease. Prospective studies in which confounders are controlled would be ideal but are hard to conduct. These are the limitations of these cross-sectional studies.
  •  Peak bone mineral density is achieved in the first two decades of life. AN adversely affects this process and puts these patients on the path to osteoporosis.

In summary: Anorexia Nervosa is a complex illness to treat with significant associated mortality. Because of low estrogen and high cortisol levels these patients suffer bone loss that aggravates the issue of fractures. Hence the clinician should consider the use of OC in this group of patients early in the illness collaboratively with the gynecologist/pediatrician. It is important to note that adequate nutrition is the real medicine for the underlying illness along with cognitive behavioral therapy.

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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 [email protected]

To contact GME, email us at [email protected]


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