Monday, 2 November 2015

Mental Health, Psychiatric Drugs and Metabolism


We are pleased to publicate this article about the effects of psychiatric medication on metabolism recently written by Catherine Clarke SRN, SCM, MSSCH, MBChA and Jan Evans MCSP. Grad Dip Phys. 
There is plenty of evidence about these type of studies and researches. Since the pharmaceutical industry has no interest in circulating them it is OUR responsibility, being at the receiving end, to share them and stay informed.
Previous articles by Clarke shedding light on the ill-effect of psychiatric drugs and consequential patient violence were publicised on the Asylum Magazine  ( Nos 17.2, 17.3 and 20.3). 
The fully referenced and detailed article can be obtained requesting it directly to the author : cclarke@post.com

Catherine Clarke SRN, SCM, MSSCH, MBChA.
Jan Evans MCSP. Grad Dip Phys
28th September 2015

 Mental health disorders are predominantly treated with psychiatric medications, which are licensed psychoactive drugs. This document focuses primarily on psychiatric drug induced mood changing side effects in relation to metabolisation. Metabolism is defined as an ability of the body to break down medications. Individual  inability to break down medications efficiently causes toxicity, resulting in side effects. This enlightening information falls outside the remit of mental health mainstream literature. Although ‘side effects’ is common terminology, Adverse Drug Reactions (ADRs) is the more accurate term as it reflects drug induced toxicities and is referred to throughout this document. The term antipsychotic is definitively replaced by neuroleptic, which means literally to ‘seize the nerve’.

Psychiatric Medications Adverse Drug Reactions

Many individuals treated with psychiatric medications experience severe ADRs, without any effective drug response. Whilst antidepressant and neuroleptic drugs can cause iatrogenic physical ADRs, it is not widely known that psychiatric medications can induce mood changing neurotoxic behavioural ADRs. SSRIs for depression can precipitate deepening depression, suicidal ideation, suicide, homicidal ideation, homicide, akathisia and agitation, mania and delirium, severe anxiety, bizarre thinking and reasoning psychosis, and hallucinations.  Neuroleptics, used to treat psychosis, are linked with violence, suicidal and homicidal behaviour leading to completed suicide  and  homicide.      

So why do some individuals respond well to drugs and others not?
 
A major factor for varied drug responses is due to individuals’ differing genetic makeup,  known as pharmacogenetics or drug metabolism. Although there are many metabolising systems in the body, the major metabolising systems for psychiatric medications are the CYP450 enzyme system, principally in the liver, and the serotonergic system. Both systems have an important role in the outcome of treatment, ADRs and efficacy.

  450CYP Enzyme System
 
75% of psychiatric drugs including antidepressant and neuroleptic medications, are metabolised through CYP2D6, which is one of the most variable metabolizing enzyme pathways known. Other pathways that metabolise antidepressants and neuroleptic drugs include CYPC19, CYPC9, CYP1A2, CYP 3A4 and CYPA5.Genetic variations, known as alleles, classify individuals as either being Poor Metaboliser (PM), Intermediate Metaboliser (IM), Extensive Metaboliser (EM) or Ultra Metaboliser (UM) genotypes. PMs have two non-functional alleles and IMs have one non-functional allele plus one diminished allele or two diminished alleles or two partially active alleles. UMs have more than two active gene copies on the same allele, or increased expression of a single allele. EMs have one or at the most two functional alleles with ‘normal ‘activity.Genetic variability affects psychiatric medication outcomes.  PMs and IMs incur neurotoxicities leading to violent acts, as do UMs with prodrug use. EM individuals are likely to have a therapeutic response without neurotoxic ADRs.EMs determine the window of opportunity for a drug therapeutic level and sets the recommended drug dosage. This is important, as drug companies do not specify drug dosage for UMs, IMs and PMs, which explains why these individuals do not respond well to standard drug doses.



Combined PM and IM frequency via CYP450 2D6:
·      26% Caucasians
·      40-50% African-Americans
·      50% Africans

Statistically, Black Minority and Ethnic (BME) populations have greater difficulty metabolising psychiatric medications compared with White and Asian population, due to the higher frequency of lower metabolism at CYP 2D6. BME groups are four times more likely to experience psychosis than Caucasians,  with African Caribbean people three to five times more likely than any other group, of being diagnosed with schizophrenia and admitted to hospital. 

Serotonergic System


Antidepressants and neuroleptics are regulated through the serotonergic system. The serotonin system consists of the Serotonin Transporter Gene and serotonin receptors (5-HT). As with the CYP450 system, the serotonergic system has genetic variations that affect outcomes.

Serotonin Transporter Gene and Antidepressants


Genetic variations in the promoter region of the Serotonin Transporter Gene (5HTT-LPR) are coded as L/L (2 long alleles), L/S (a long and a short allele) or S/S (2 short alleles). Those individuals with the L/L code have a ‘normal’ gene activity and respond well to antidepressant medications. In contrast individuals with the short allele have slower gene activity, resulting in a reduction of serotonin transmission. Both L/S and S/S individuals treated with antidepressants have poor outcomes, and a ‘powerfully predicted non response’. Emerging antidepressant ADRs are inevitable for individuals with the short allele. 
Individual response to neuroleptic medication is also affected by 5HTT-LPR variations. 50% of individuals coded L/L receiving neuroleptic treatment with haloperidol experienced parkinsonian side effects; however the incidence of parkinsonian side effects for L/S and S/S allele individuals rose to 62.2% and 83.1% respectively.

What is the frequency of 5HTT-LPR Gene Variants?



Population Frequency of 5HTT-LPR Variations

Individuals coded with (S/S) and (S/L) genotype: 
Caucasians S/S (39%)
Caucasians S/L (52%)
East Asians S/S (49–74%)
Native Americans S/S (42%)
African Americans S/S (7–17%)

Individuals coded with L/L genotype:  
Caucasians (29–43%)
African Americans (45–56%)
Native American (10–14%)
East Asian samples (1–13%)

Serotonin Receptors


There are 14 types of 5-HT receptors that can be targeted by antidepressants and neuroleptics. However the 5-HT 2A serotonin receptor variant, in particular, is associated with individual poor response and increased risk of ADRs when treated with antidepressant selective serotonin reuptake inhibitors. This same receptor variant has been linked to poor response from some individuals having neuroleptic treatment. 


Genotype Testing 


CYP450, 5HTT-LPR and 5-HT receptor genotype testing can determine individual status for metabolizing psychiatric medications. Prescribers do not currently conduct genotype testing prior to treatment and take no account of whether or not individuals are able to efficiently metabolise medication. The current practice is to work on a crude trial and error basis when treating individuals with psychiatric medication. 
Genotype testing of an individual prior psychiatric medication treatment would enable assessment and prediction of the potential for neurotoxic behavioural ADRs in line with genotype status as depicted in the table above. The genotype test is a simple blood or swab test and in 2013 the standard cost of a test was £30.  Retrospective genotyping for psychiatric drugs has demonstrated that there would have been a significant reduction in the financial outlay/cost based on the use of inappropriate medication and subsequent uneccessary healthcare costs.
           
Genotype testing is used by pharmaceutical companies during medication trials (stages II - 1V), to de-select individuals who are PMs and potentially liable to suffer severe ADRs. This practice includes trials with psychiatric medication and is done for reasons of safety, and also to show medication in its best light.

Discussion


Neurotoxic behavioural ADRs are not understood in psychiatry. When individuals respond violently to psychiatric medication the practice in psychiatry is to increase the dose and/or polypharmacy. This practice is completely futile as further medications increase neurotoxicities. Individuals are theoretically being overdosed, albeit unwittingly by prescribers. Prescribing of psychiatric medications is done on a crude trial end error basis. Individual suffering is immense. This needs to change.

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