Biological Etiology of MDD PDF

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Biological Etiology and Treatment of Major Depressive Disorder Genetic Explanation Genetic Researchers Argue That; • •Genetic Predisposition Can (Partly) Explain Depression • •Genetic Factors Within Families Are More Influential Than Environmental Factors • Our Dna Contributes To Depression But Realistically…. Genetic Variation Makes Up Only A Very Small Part Of The Risk Of Depression APRCx1 – Kendler et al (2006) – The Swedish national study of depression Essential understanding: Genetic heritability may be due to A=genetic inheritence, C=shared environment and E=individual environment. Conclusion: This shows that there is a significant difference between men and women in terms of genetic predisposition to depression. Aim: Researchers carried out a twin study of over 42.000 twins from the Swedish Twin Registry to determine the level of heritability of depression. Procedure: 42,161 twins located through the national Swedish Twin Registry (a mixture of MZ and DZ twins). This is a nearly complete registration of all twin births in the country. Birth cohorts spanned nearly 60 years, which enable researchers to compare results across generations (longitudinal study). In order to gather their data, the researchers used a team of trained interviewers with adequate medical background to carry out telephone interviews. The interviewers assessed lifetime major depression by using modified DSM-IV criteria. Informed consent was obtained prior to the interview. Efforts were made to reach both members of a pair within a month. Results: • The estimated heritability of major depression for the entire sample was 38% - very similar to prior results. • The result of Kendler et al showed that the heritability of MDD was significantly higher in women (A=42%) than men (A=29%). • These estimates did not differ significantly across age cohorts.

APRCx2 – Caspi et al. (2003) – The 5-HTT gene and gene-environment interaction in depression Aim: To investigate the relationship between stressful life events and depression in individuals with different alleles of the 5-HTT gene. Procedure: In this quasi experiment, a representative birth cohort of 1,037 children from New Zealand were followed longitudinally. The sample was divided into three groups based on their 5-HTT alleles: • Group 1 had two short alleles • Group 2 had one short and one long allele • Group 3 had two long alleles The participants were asked to fill in a "Stressful life events" questionnaire which asked them about the frequency of 14 different events - including financial, employment, health and relationship stressors between the ages of 21 and 26. They were also assessed for depression. Results: •

There were no differences between the three groups in the number of stressful life events they experienced.

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Pps with a short allele of 5-HTT (s/l and especially s/s) reacted to stressful life events with more depressive symptoms. E.g. pps who had a stressful life event at age 21 demonstrated an increase in their depressive symptoms by age 26, but only if they carried a short allele of 5-HTT (s/l or s/s). Conversely, depressive symptoms of pps in the l/l group stayed on the same level.

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The effect of additional stressful life events increased depressive symptoms at a greater rate amongst pps who had short alleles (see graph).

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Among pps suffering four or more stressful life events, 33% of individuals with a short allele of 5-HTT developed depression, compared to 17% of those having the long/long variant.

Conclusion: The researchers concluded that 5-HTT influences an individual’s reaction of stressful life events. The study demonstrated that genetic predisposition can moderate a person’s reactivity to stressful life events – an instance of gene-environment interaction (G x E). The study shows that specific alleles of 5-HTT increase the vulnerability to depression.

Biochemical Explanation

- The Serotonin Hypothesis. The Most Prominent Theory Of The 1990S Was The Serotonin Hypothesis. The Serotonin Hypothesis Of Depression Argues That A Reduction In Serotonin Leads To Increased Predisposition To Depression.

Evidence For Serotonin Hypothesis: Anti-Depressants (E.G. Prozac) Appear To Be Effective In Relieving The Symptoms Of Severe Depression By Increasing Levels Of Serotonin In The Synaptic Gap In Some Ways, The 'How' Or 'Why' Don't Matter: What Matters Is That Antidepressants Appear To Be Effective And That The Treatment Works. Evidence Against Serotonin Hypothesis: • There Is Problem With Bidirectional Ambiguity. Research On The Levels Of Serotonin Is Correlational In Nature No Cause And Effect Can Be Established Because True Experimental Research On Humans Cannot Be Carried Out So We Cannot Be Sure Whether: The Level Of The Serotonin Caused The Depression The Depression Caused The Lower Levels Of The Serotonin There Is No True Interaction Between The Two Variables • Although Prozac Increases Serotonin Levels Within Hours After The Drug Is Taken, It Usually Takes 2-4 Weeks Before There Is Any Effect. Also, Nearly Half Of All Clinically Depressed Patients Fail To Respond To Available Antidepressant Medications. • Antidepressant Drugs Are Very Popular, But The Theory They Are Based On Is At Least 20 Years Out Of Date According To Some Critics. E.G. Us National Institute Of Mental Health Discredited The Serotonin Hypothesis As Far Back As 1984, 4 Years Before Prozac Was Even On The Market. It Appears To Have Been A Product Of Marketing, Not Science.

- Cortisol (Neurogenesis) Hypothesis • • • • • •

Modern research is focusing on what is called the Neurogenesis theory of depression. This theory argues that depression is the result of the cessation of neuron birth in the hippocampus as well as in other neural networks related to serotonin, dopamine and norepinephrine. Cortisol appears to be the reason for this lack of neurogenesis. Patients with MDD display a symptom called HPA-axis hyperactivity that results in the over-secretion of cortisol. This over-secretion of cortisol leads to reduced serotonin and other neurotransmitters in the brain, including dopamine, which has been linked to depression. This demonstrates how complex the brain’s chemistry is, and why the treatment for depression remains problematic.

What is the evidence for the neurogenesis theory? • Depressed patients seem to have smaller hippocampi than the general population. Hippocampi are also smaller during periods of depression than periods of good mental health. • Glucocorticoids (stress hormones) are elevated in depression and appear to inhibit neurogenesis in the hippocampus in rodents and non-human primates. • Chronic administration of anti-depressants increases neurogenesis in the hippocampus in rodents. Evidencex1 for Cortisol (Neurogenesis) Hypothesis of Depression – Malberg et al (2000) Researchers first suggested the possibility that neurogenesis supports the effect of antidepressants in a rat model for depression. They first injected antidepressants into the rats – including a monamine oxidase inhibitor and an SSRI. In addition, some rats received electroconvulsive shock. All of these methods have been seen to be successful in the treatment of some depressed patients. The researchers found that all of the treatments increased neurogenesis in the hippocampus and proposed that this increase is a mechanism to fight depression. In spite of the strong evidence in rodents, we still do not have a lot of evidence that this is the case in humans.

Evidencex2 for Cortisol (Neurogenesis) Hypothesis of depression – Videbech and Ravnkilde (2004) Researchers performed a meta-analysis of 12 studies using brain scans to compare hippocampal volume in patients with a diagnosis of depression with healthy controls. The sample comprised 351 patients and 279 healthy controls. The analysis found up to a 10% reduction of the hippocampus in the brains of depressed patients. Furthermore, the shrinking of the hippocampus was significantly correlated to the number of depressive episodes. Research on the levels of neurotransmitters and/or cortisol is correlational in nature - that is, that no cause and effect can be established because true experimental research on humans cannot be carried out The researchers themselves argue that we don't know whether depression causes shrinkage of the hippocampus or if people with small hippocampi are more vulnerable to depression. However, this is a promising theory that needs longitudinal prospective studies before anything can be concluded.

BIOLOGICAL TREATMENT OF MDD If the problem is based on biological malfunctioning, drugs should be used to restore the biological system. • The goal of treatment for MDD with antidepressant medication is generally to provide symptom relief. • A positive response to drug treatment is defined as a clear improvement, and remission is defined by the near absence of symptoms. • However, even when remission is achieved, an individual may have a risk of relapse, that is, the symptoms return after medication is discontinued. APRCx1: KIRSCH ET AL (2002) Aim: To investigate how effective SSRIs are in treating MDD using published and unpublished data, so also an investigation into researcher/publication bias in psychopharmacology Procedure: Researchers replicated the meta-analysis with a different set of clinical trials (statistical analysis of many studies). For these purposes they used the Freedom of Information Act to ask the Food and Drug Administration (FDA) to send them data sets that had been submitted by pharmaceutical companies when obtaining approval for antidepressants. The FDA funds clinical trials and requires companies to send in results of all funded trials, so the analysis included both published and unpublished data. Results: • Researchers found that 80% of the effectiveness of SSRI antidepressants can be explained by the placebo effect (a placebo is a substance that has no therapeutic effect, and is used as a control in testing new drugs). • Of the studies funded by pharmaceutical companies, 57% failed to show a statistically significant difference between antidepressant and a neutral placebo. Conclusion: • The findings of this study do not support the biochemical explanation of disorder. • No significant clinical difference between SSRIs and placebo from a practical application point of view, meaning the advantage of taking drugs medication is so small that it is not “worth it”. • This study suggests a publication bias in pharmaceutical companies who only use data which finds positive results for drugs in order to make profits....