Depression (Long) Notes

DEPRESSION

The molecular neurobiology of depression

Core symptoms of “clinical depression” include depressed mood, anhedonia (reduced ability to experience pleasure from natural rewards), irritability, difficulties in concentrating and abnormalities in appetite and sleep. Depressed patients are also more likely to develop coronary artery disease and type 2 diabetes. Depression also complicates the prognosis of a host of other chronic medical conditions.

There are several explanations for the comparatively rudimentary knowledge of depression’s pathophysiology:

1. Observing pathological changes within the brain remains markedly more difficult than for al other organs. Post-mortems are relied upon which have numerous limitations, as do neuroimaging techniques (rely upon changes in neuronal activity by using indirect markers of activation). Several animal models have also informed knowledge of the neural circuitry of depression but there are important challenges to how information gained from these models should be interpreted

2. Most depression occurs idiopathically and the limited understanding of its aetiology is reflected as a list of risk factors such as stressful life events, endocrine abnormalities, cancers and side effects of drugs, among many others. Genetic association studies have not uncovered strong and consistent genetic risk modifiers perhaps because of the sheer heterogeneity of depressive syndromes. Thus, genuine “depression genes” have not yet been identified.

The official diagnosis of depression is subjective and rests on the documentation of a certain number of symptoms that significantly impair functioning for a certain duration. These diagnostic criteria overlap with other conditions such as anxiety disorders, which have a substantial co-morbidity with depression.

Neural circuitry of depression

Several brain regions and circuits regulate emotion, reward and executive function, and dysfunctional changes within these highly interconnected “limbic” regions have been implicated in depression and antidepressant action. Studies of depressed patients show reductions in grey-matter volume and glial density in the prefrontal cortex and the hippocampus, regions thought to mediate the cognitive aspects of depression, such as feelings of worthlessness and guilt. However, the published findings are not consistent and are often complicated by co-morbid diagnoses.

In contrast to structural studies, experiments assessing brain function, such as fMRI or PET show that activity within the amygdala and subgenual cingulate cortex is strongly correlated with dysphoric emotions: indices of neuronal activity within these regions are increased by transient sadness in healthy volunteers and are chronically increased in depressed individuals, reverting to normal levels with successful treatment.

Inspired by these findings, it was shown that DBs applied to the white matter tracts surrounding Cg25 produced a sustained remission of depressive symptoms in a small cohort of treatment-resistant patients.

These forebrain networks are significantly modulated by monoamine projections from midbrain and brainstem nuclei (dopamine from the ventral tegmental area (VTA), serotonin from the dorsal raphe located in the PAG area and NO from the locus coeruleus). In addition to controlling alertness and awareness these NTs modulate the salience of emotional stimuli.

The role of monoamines

The “monoamine hypothesis” of depression, which posits that depression is caused by decreased monoamine function in the brain, originated from early clinical observations. Two structurally unrelated compounds developed for non-psychiatric conditions, namely iproniazid and imipramine, had potent antidepressant effects in humans and were later shown to enhance central serotonin or NA transmission. Reserpine, an old antihypertensive agent that depletes monoamine stores, produced depressive symptoms in a subset of patients. Today’s antidepressant agesnt offer a better therapeutic index and lower rates of side effects for most patients but they are still designed to increase monoamine transmission acutely either by inhibiting neuronal reuptake (e.g. SSRIs – e.g. fluoxetine) or by inhibiting degradation 9e.g. MAO inhibitors - e.g. tranylcypromine). However, the cause of depression is far from being a simple deficiency of central monoamines. MAO inhibitors and SSRIs produce immediate increases in monoamine transmission, whereas their mood-enhancing properties require weeks of treatment. Conversely, experimental depletion of monoamines can produce a mild reduction in mood in unmedicated depressed patients, but such manipulations do not alter mood in healthy controls.

It is now thought that acute increases in the amount of synaptic monoamines induced by antidepressants produce secondary neuroplastic changes that are on a longer timescale and involve transcription and translational changes that mediate molecular and cellular plasticity. As one example, the serotonin 5-HT_1B receptor interacts with a calcium binding protein named p11, which was upregulated in cerebral cortex on chronic treatment with SSRIs and was also found to be downregulated in post-mortem cingulate cortex samples from depressed individuals.

Monoamine-based antidepressants remain the first line of therapy for depression but their long therapeutic delays and low (about 30%) remission rates have encouraged the search for more effective agents. The serotonin receptors involved in the action of SSRIs remain unknown, although selective agonists of the serotonin 5-HT₄ receptor produce rapid antidepressant effects in rodents (3-4 days).

Experiments on mice deficient in P-glycoprotein, a molecule in the BBB that transports numerous drugs back into the bloodstream, have shown that several antidepressant agents, including the SSRI citalopram, are substrates for P-glycoprotein. Human polymorphisms in the gene encoding P-glycoprotein significantly alter antidepressant efficacy in...

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