Overview of Biological Predispositions and Risk Factors Associated with Depression

One of the most dominant mental illnesses of the modern era is depression; 2.1 million people reported to be suffering from depression in the 2015 National Health Survey of Australia. Depression is a common mental illness that severely limits psychosocial functioning, and is characterised by interpersonal issues such as dependency, helplessness, self-criticism, and feelings of failure and guilt. It is commonly believed that a combination of genetics, early life stressors, and ongoing stress largely determine vulnerability to psychiatric disorders like depression, however family, twin and adoptive studies have repeatedly demonstrated that mood disorders are a result of biological factors. Although the biology of depression has not yet been deciphered, it has been speculated that deregulation of molecular and cellular signalling pathways might play a significant role in the initiation and progression of depression. Biological mechanisms and genetic factors, such as the underactivity of neurotransmissions, are thought to be the primary cause of depression. A more comprehensive understanding of the biological predispositions and risk factors associated with depression may inform the development of more effective intervention or even preventions.

Brain imaging studies and post-mortem results of patients suffering from depression have shown a highly significant reduction in hippocampal and prefrontal cortex volume, playing an important role in emotion and mood disorders. Biologically, depression is characterised by an enduring decrease in the synaptic effectiveness that follows some types of electrical stimulation, most commonly in the hippocampus. The limbic brain structure, the hippocampus, is responsible for a variety of functions ensuring the survival, development and well-being of an individual. The hippocampus plays a specific and important role in central memory functions that mediate both dysregulated mood and cognitive dysfunction found in depressive disorder. It is crucial that the hippocampus functions correctly in order to modulate the hypothalamic-pituitary axis and regulate responses to stress. The activated hypothalamic-pituitary axis not only controls body peripheral functions, but also has profound effects on the brain. If the correct function of the hypothalamic-pituitary axis is impeded, it will be unable to produce the hormones necessary to prevent depressive symptoms.

Dysregulation in hippocampal functions has been observed in almost half of all depressed patients. A contributing factor to the decreased functionality of the hippocampus is high levels of stress. Elevated stress levels or exposure to exogenous glucocorticoid decreases hippocampal cell proliferation, which may induce hippocampal dendritic atrophy, suppressed neurogenesis in the dentate gyrus granule neurons, and decrease cognitive performance. These mechanisms, at a fundamental level, affect the response and adaptation of an organism to its environment, and malfunction resulting from stress can lead to harmful effects such as impaired learning and memory, reduction in long-term potentiation and other measures of synaptic plasticity.

Altered hippocampal function may also influence the activity of the neural circuitry in brain structures such as the prefrontal cortex, amygdala and nucleus accumbens, as these structures receive inputs from the hippocampus and are associated with emotionality.

As well as the hippocampus, several brain neurotransmitter systems have been linked with depression. Most primary brain functions depend on the presence and action of various monoamine neurotransmitters. A significant theory surrounding the biological basis of depression is the monoamine hypothesis, which stipulates that depression is caused by an alteration in levels of one or more of the centrally available monoamine neurotransmitters. Monoamines such as dopamine, serotonin, and norepinephrine produce their effect by inducing complex biochemical changes in postsynaptic neurons in the central nervous system through interaction with signalling proteins inside the postsynaptic cell membrane. Serotonin stimulates all areas of the brain and is its largest cohesive neurotransmitter system, while dopamine modulates reward and motivation functions, working memory and attention. Monoamine deficiency can result from decreased synthesis or early degradation of neurotransmitters, altered expression or function of the neurotransmitter receptors and degrading effects of the monoamine oxidases in the synaptic cleft. It is postulated the monoamine systems may create depressive symptoms by directly affecting the threshold or diathesis for self-directed and externally directed aggressive behaviour, or by influencing the severity of depression, hopelessness, or suicidal ideation. Deficiency of monoamines seen in depression could also result from decreased protein transporter functions and abnormalities in the neurotransmitter receptor function.

Underactivity of serotonergic neurotransmission has long been recognised as an important factor in the pathophysiology of depression. Serotonin is a monoamine neurotransmitter synthesised in the central nervous system plays a critical role in the function of the emotional system including regulation of mood, sleep, vomiting, sexuality and appetite. It is suggested that the diminished activity of serotonergic pathways plays a causal role in the pathophysiology of depression, as selective serotonin reuptake inhibitors are found to alleviate the symptoms of depression. Disturbance to the reward pathway, specifically the distribution of serotonin and other monoamines, can result in a loss of the ability to feel pleasure and accomplishment – symptoms characteristic of depression.

Serotonin is a simple monoamine synthesised from tryptophan. Depletion of tryptophan, an essential amino acid needed for serotonin synthesis, has been shown to induce depressive symptoms with patients who were successfully treated for depression with antidepressants. Tryptophan competes with branched-chain amino acids for transport across the blood-brain barrier and therefore the ratio of tryptophan to branched-chain amino acids in plasma is a critical determinant of the availability for tryptophan for brain serotonin synthesis. The dysfunction of tryptophan conversion to serotonin will in turn reduce the brain serotonergic activity, causing depressive symptoms. Tryptophan depletion is brought about by specific diets that diminish amino acid precursors of serotonin in the body, giving rise to mood changes. The minimum level of tryptophan is required to assist serotonin levels, which helps the body control appetite, sleep pattern and mood changes, which are all depressive symptoms.

Psychology research of depression should be driven to identify the main causes of depression in order to create more effective forms of treatment. More importantly, the associations between biological factors and depression must be further studied. While underlying biological mechanisms involved in depression remain unclear, but abnormalities in molecular and signalling pathways lead to depressive disorders. It is of considerable importance that the pathways capable of revealing possible targets for the diagnosis of depression and the treatment options of the disease.