Biological explanations of depression

Family studies - having a first-degree relative with depression appears to be a risk factor for depression. Family studies select people who already have depression - probands, and examine whether other members of their family have been or might be diagnosed with depression. If there is a genetic link for this disorder, the probands' relatives should show higher rates of depression than the rest of the population. Harrington et al. found that around 20% of such relatives have depression compared to a figure of around 10% for the population at large 

Adoption studies - Wender et al. studied the biological relatives of adopted individuals who had been hospitalised for severe depression. They foudn a much higher incidence of sevre depression in the biological relatives of the depressed group than in the biological relatives of a non-depressed group.

Genes as diatheses - Genetic factors are though to act as a diatheses in a diathesis-stress relationship. This suggests a genetic predisposition for depression interacting with environmental stressors to produce a depressive reaction. Therefore, expect such environmental stressors to affect those with the genetic predisposition differently to those without it. Kendler et al. found that women who were the co-twin of a depressed sibling were more likely to become depressed than thode without this presumedgenetic vulnerability. The highest levels of depression were found in the group who were exposed to significant negative life events and were most genetically at risk for depression. 

There is research support by Zhang et al. a mutant gene that starves the brain of serotonin has been found to be 10x more prevalent in depressed patients than in control individuals. The mutant gene results in an 80% reduction of normal serotonin levels in the brain. Caron et al found that this version of the gene was carried by 9/87 depressed patients, but only 3/219 healthy controls. Patients with the mutation failed to respond well to SSRI medications, which work via serotonin, suggesting that the mutation may underline a treatment-resistant subtype of depression.

The relatively low genetic comcordance rates for depression can be explained in terms of combordity, when 2 or more mental illness occur together and pherhaps have some common cause. People coul inherit a vulnerability for a wider range of disorders than depression alone. if this was the case we would expect to see higher concordance when looking at a range of disorders in related individuals. Kendler et al. found a higher incidence of mental disorders in twins when looking at depression and generalised anxiety disorder, than when looking at depression alone. Sugessting that some disorders such as depression are a product of genes that underline a number of different disorders. Actual symptoms that develop could be related to environmental triggers, so genes are a diathesis in a diathesis-stress relationship. 

Understanding of the genetics of depression among adolescents is limited. In adults about 40% of the risk of major depressive disorder is attributable tto genetic factors, but little data exists on the heritability of adolescents MDD. Glowinski et al. sampled 3416 female adolescent twins for MDD using structured telephone interviews that included a DSMV-IV based section for assessment of MDD. Lifetime occurrence of self-reported MDD ranged from 1% for girls under 12 to over 17% aged 19+older. Proportion of risk for MDD due to genetic factor was approximately 40% with remaing risk attributable to environmental factors. However, any conclusion about the heritability of MDD among adolescents can only be tentative as male twins were not included in sample - lacks population validity, also issues of social desirability bias as it was done over the phone can easily lie. 

Noradrenaline - first is was proposed that depression results froma deficiency of neurotranmitter noradrenaline in certain brain circuits. Among the findings linking low levels of noradrenaline to depression was the discovery that indirect markers of noradrenaline levels in the brain were often low in depressed individuals. Post-mortem studies revealed increased densities of certain noradrenaline receptors in brains of depressed suicide victims. Transmitter molecules become unusually scare in synapses, postsynaptic cell often expand receptor numbers in as compensatory attempt to pick up whatever signals available. 

Serotonin - Among findings supporting a link between low synaptic serotonin levels and depression is that cerebrospinal fluid in depressed and suicidal, patients contains reduced amounts of a mojor serotonin by-product, signifying reduced levels of serotonin in brain. Intro of prozac that selectively block serotonin re-uptake confirmed the association between low serontonin and depression. Delgado et al. gave depressed patients who were receiving antidepressants a diet that lowered their levels of one of the precursors of serotonin - tryptophan. Majority of the patients experienced a return of their depressive symptoms, which disappeared again when their diet was returned to normal. 

Research support for link between noradrenaline + depression - Kraft et al. studied 96 patients with MDD wo were treated for 6 weeks with a dual serotonin-noradrenaline re-uptake inhibitor (SNRI). Patients showed a significantly more positive response that those treated witha placebo, thus strengthening the link between the depletion of these neurotransmitters and development of depressive symptoms. 

Link between serotonin and depression is not straightforward. Some studies have used patients whose depression is in remission. These patients were given tryptophan-deficient amino acid that temporarily decreased serotonin levels in brain. They experienced brief relapse of symptoms during tryptophan depletion, suggesting that lowering of serotonin levels=depression.   However, individuals who never had depression nor a family history of depression tended not to show any mood changes following tryptophan depletion, despite the fact that a depletion in this alters the activity of the same mood-regulating regions of the brain - amygdala. Thus lowering, serotoinin levels does not induce depression in all individuals. Aan het Rot et al. suggests that it is possible that a depressive episode alters the serotonin system in such a way that a person becomes more vulnerable to the effects of future changes in serotonin levels.

Depression does have a genetic basis is supported by the evolutionary theory. The fact that depression is so widespread among humans suggests that it may have some evolutionary significance i.e. it may be adaptive. E.g. Buist-Bouwman et al. found that individuals reported higher levels of psychological functioning after their depression than beforehand. Evolutionary explanation suggests that as depression is costly both to the individual and their close social partners, it serves as an 'honest' signal of need with the result that others in the social network are more likely to provide much needed help and support which strengthens the individual. 

These drugs are used to treat moderate-severe depressive illnesses. They are typically taken for at least 4-6 months. 

How they work - depression is though to be due to insufficient amounts of neurotransmitters such as noradrenaline/serotonin being produced in nerve endings to activate neighbouring cells. Normal brains, neurotransmitters are constantly being released from nerve-endings. To terminate their action, neurotransmitter are reabsorbed into nerve endings or broken down by an enzyme. Drug works by either reducing the rate of re-absorption or by blocking the enzyme that breaks down the neurotranmitters. Both of these increase the amoutn of neurotransmitter avaible to excite neighbouring cells.

Tricyclics - blocks transporter mechanism that re-absorbs both serotonin+noradrenaline into the presynaptic cell. As a result more of these neurotransmitters are left in synapse, prolonging their activity and making transmission of next impulse easier.

Selective serotonin re-uptake inhibitors (SSRIs) - block mainly serotonin and so increase the quantity available to excite neighbouring brain cells, thus reducing the symptoms of depression. 

Phases of treatment - 3 distinct phases. Treatmens of current symptoms take place during acute phas eof treatment. once symptoms have gone, treatment enters continuation phase for about 4-6 months, after which medication is slowly withdrawn to prevent relapse. 3rd phase is maintenance phase for individuals with a history of recurrent depressive episodes.

Effectiveness: Severity of depression - Kirsch et al. reviewed clinical trials of SSRI and concluded that only in cases of most severe depression was there any significant advantage to using SSRIs. However, they also found that only for the most severely depressed group was there a difference between drug treatment and placebo. So even the placebo appeared to benefit moderately depressed individuals presumably because it offered them hope which contributed to a lessening of their symtpoms. For most severely depressed the expectation of anything working was lessened deminishing the any placebo effects and increasing apparent difference between treatment adn control conditions. SSRIs Vs non-SSRIs - some patients who fail to repsond to treatment with an SSRI antidepressant there may be some advantage in switching to alternative non-SSRI. However, in a meta-analysis of studies which compared the effectiveness of SSRIs Vs non-SSRIs there was no significant difference in outcomes for the 2 treatment groups. 

Appropriatness: Children+adolescents - antidepressants appear less useful when given to children and adolescents. Double-blind studies have consistently failed to demonstrate the superiority of antidepressants medications over placebo conditions. Ryan, suggests that this may have something to do with the developmental differences in brain neurochemistry. Risk of suicide - possibility that SSRIs may increase suicidal thoughts in vulnerable people. A review of studies comparing SSRIs and   with other treatments or a placebo condition, found that those treated with SSRIs were twice as likely to attempt suicide. A later review of studies found that although the use of SSRIs among adolescents increased risk of suicide, this risk was decreased among adults. Among adults aged 65 or older exposure to SSRIs appeared to have a protective effect against suicide attempts. 

Turner at al claimed that there is evidence of publication bias towards studies which show a positve outcome of antidepressant treatments, thus exaggerating the benifits of these drugs. Not were were positve results more likely to be published, but studies that were not positve were often published in a way that conveyed a positive outcome. Such selective publication can lead to doctors making inappropriate treatment decisions. 

Used in severely depressed patients for whom psychotherapy and medication have proved in effective. Used when there is a risk of suicide, as ECT often has quicker results than drugs. National Institute for Clinical Excellence suggests that ECT should only be used in cases where all other treatments have failed or when condition is considered to be life-threatening. 

Use of ECT - electrode is place above temple of non-dominant side of brain, a second is place in middle of forehead=unilateral ECT. Or one electrode is placed above each temples=bilateral. Patient is first injected with a short-acting general anaesthetic so they are unconscious. Oxygen is given to compensate for their inability to breath. Small amount of electric current, lasting about 1/2 sec, is passed thorugh brain. Current produces a seizure lasting up to 1 min, which affects the entire brain. Given 3x a week, with patient requiring between 3-15 treatments.

Mechanism of ECT - it is not understood how or why it completely works, but what is clear is that it is the seizure rather than the electrical stimulus that generates improvement in depressive symptoms. Seizure appears to restore the brain's ability to regulate mood, may do this by enhancing the transmission of neurochemical or by improving blood flow in the brain.

Effectiveness: ECT vs sham ECT - Studies that have compared ECT with sham ECT have found a significant difference in outcome in favour of real ECT. ECT has also been found to be effective in cases of treatment-resistant depression. Thus supporting th effective of ECT.

ECT vs antidepressants - review of 18 studies with 1114 patients comparing ECT with drug therapy showed that ECT was more effective than drug therapy in short-term depression. However, non of these trials compared ECT with newer antidepressants such as SSRIs. 

Appropriatness:

Side effects - physical side effects include impaired memory, cardiovascular changes and headaches. In a review of research, Rose et al. concluded that at leats 1/3 of patients complained of persistent memory loss after ECT. Weiner found a general slowing of cognition following ECT that takes weeks to disappear. It was also found that it had resulted in permanent fear and anxiety. 

Unilateral vs Bilateral ECT - one way of minimising the cognitive problems associated with ECT is to use unilateral ECT, rather than bilateral. Studies have found that unilateral ECT is less likely to cause cognitive problems than bilateral ECT, but may be just as effective.