Genetic researchers argue that genetic predisposition can partly explain depression. One of the main ways to investigate this is twin studies. In one of the largest studies to date, Kendler et al (2006) used 42,161 twins from the Swedish Twin Registry. They found that the concordance rate for female MZ twins was 44%, while for female DZ twins, only 16%.  In male MZ twins, the rate was 31% and for male DZ twins, the rate was 11%.   This seems to indicate that the disorder may be more genetic in origin for women than for men.

This is seen as support for the hypothesis that genetic factors might predispose people to depression. The fact that the concordance rate for MZ twins is far below 100 percent indicates that depression may be the result of a genetic predisposition—also called genetic vulnerability.

The fact that the concordance rate for MZ twins is below 100 % does not contradict the argument that depression is genetically inherited. It may mean that the gene is there, but both twins have not experienced the same level of stress and thus both twins have not "expressed their genes." The fact that some of the DZ twins also both had depression may also be explained by the fact that they do share some of the same genes as well as that they may not have experienced the same environmental stressors.

A meta-analysis by Sullivan et al. (2000) looked at twin and family studies of major depressive disorder. The research showed that genes may account for one-third of the cases of depression. Shared environmental factors provided only a negligible role in adults, but played a more significant role in the onset of depression in children. The researchers concluded that there is not a single gene that leads to depression, but rather that depression is the result of several genes that act together to produce a vulnerability to depression when other risk factors are present.

Since twin studies leave a lot of questions unanswered, modern research in genetics now focuses on genetic mapping. Recent research has used DNA markers to try and identify the gene or genes that are involved in depression. The Human Genome Project allowed us to see that there are up to 11 genetic markers - or variations - that seem to be correlated with Major Depressive Disorder. However, one of the difficulties in linking genes to the disorder is the nature of the diagnosis – the symptoms vary between individuals in both type and extent.  It could well be that there is no such single disorder as “depression” and therefore, psychiatrists are attempting to treat several different disorders under one diagnosis.

Cai et al (2015), however, may be moving us toward finding those specific genes. The researchers analysed DNA sequences from 5,303 Chinese women with depression and another 5,337 controls. In this GWAS, researchers found genetic sequences that seemed to be linked to depression.  One of those sequences was in the area of a gene which is important for energy-producing cell structures called mitochondria. The correlations were confirmed in another set of more than 3,000 depressed men and women and over 3,000 controls. Although the Human Genome Project indicates that several markers may be linked to the etiology of depression, it is only through research such as this that looks at large samples that psychologists can hope to understand more precisely the role of genetics and consider how this information could assist in treatment.

The role of serotonin and cortisol in depression

Even if genetics is the root of depression, the question is what do those expressed genes actually do? They don't just make you "feel depressed." They must lead to some physiological changes that in turn lead to us being depressed. What could those changes be?

Researchers have found that patients with major depressive disorder have an imbalance of several neurotransmitters, including noradrenaline, serotonin, dopamine, and acetylcholine. Why does this matter?  If psychologists are able to determine that a neurotransmitter is the cause of depression, then drugs could be made available that would effectively treat the disorder.   However, it is not that simple.  As we will see, it is difficult to know whether lower levels of certain neurotransmitters are the cause of the disorder, or whether they are actually one of the symptoms of the disorder.  Since most of the research is correlational in nature, we are left with the problem of bidirectional ambiguity – Do low levels of serotonin cause depression or does depression lead to low levels of serotonin?  Or both?  Or neither?

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. Low levels of serotonin appear to result in OCD-like symptoms including obsessive thoughts and compulsive behaviors. It also may result in impulsivity, suicidal thoughts, and aggressive behavior. Lower levels of serotonin are also linked to mood swings, worrying, insomnia, and sadness.  Caspi's research on the genetic origins of Major Depressive Disorder demonstrates a potential link to serotonin, as the genes that were studied were responsible for serotonin transmission.

Drugs like Prozac were created to restore chemical balance and solve the problem of depression once and for all. However, although Prozac increases serotonin levels within hours after the drug is taken, it usually takes 2 – 4 weeks before there is any effect.  And nearly half of all clinically depressed patients fail to respond to available antidepressant medications. In addition, reducing levels of serotonin in the brain does not lead to depression in all people.  This leaves the Serotonin Hypothesis with very little support. Yet, antidepressants based on the regulation of serotonin levels -  SSRIs - are commonly prescribed to people diagnosed with depression.   

However, there is plenty of evidence that SSRIs increase communication from neurons that release serotonin, as well as norepinephrine and dopamine, and that the consequences of the transmission of these neurochemicals, such as the creation of new neurons or gene expression, can alleviate depression.

 Teacher only box

The goal of this discussion is to get students to consider what would be an acceptable level of improvement for them to say that it is worth marketing the drug.  Drug testing is usually done compared to placebos in randomly allocated blind treatment conditions - and the goal is to have a p-value less than or equal to 0.05.  But statistical significance is fraught with controversy.

There is no correct answer to how they would make their decision, but it is a good discussion.  Obviously, when we hear that 9 out of 10 people recommend something, we think it is better than when 7 out of 10 recommend it - but does that mean that a 7 is "bad?"  Think about ratings of hotels on Tripadvisor.  The average is 7.9 vs. 9.0.  Does that make the 7.9 a bad choice?

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 major depressive disorder 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.

Malberg et al (2000) 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 monoamine oxidase inhibitor and an SSRI.  In addition, some rats received an 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.

Videbech and Ravnkilde (2004) 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 of 351 patients and 279 healthy controls. The analysis found up to a ten percent 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. A hippocampal reduction could explain the common symptom of memory problems in patients with depression.  However, the study was cross-sectional and the data correlational.  We cannot assume that a small hippocampus is the result of a lack of neurogenesis and the reason for depression.

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.

Checking for understanding

Cognitive approach to depression