Evidence-Based Reviews

Dissecting melancholia with evidence-based biomarker tools

Current Psychiatry. 2014 February;13(2):41-48, 57

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Regrettably, these chemical compounds are not receptor-selective, but small structural modifications of these NMDA receptors have been found and lead to significant changes in potency and selectivity. This should serve as a unique starting point for developing highly specific NMDA receptor modulator agents for a variety of neuropsychiatric and neurological conditions. GLYX-13, a derivative of ketamine (an NMDA receptor antagonist), has been implicated for use in treating depression. It has been tested on 2 large phase-II study groups.²⁵

Neuronal circuitry of depression is altered by prolonged stress

Symptoms of depression can be explained by the anatomical circuit shown in Figure 6.^15,20 Impaired concentration, diminished ability to process new information, and decline in memory function are associated with decreased nerve density in the hippocampus, which plays a key role in learning, memory, and encoding of emotionally relevant data into memory.²⁶ The hippocampus interacts with the amygdala to provide input about the context in which stimuli occur.

Depressed people often demonstrate impulsivity and have difficulty controlling expression of emotions—traits that are attributed to increased neuronal density in the amygdala and insula, which has been illustrated in PET scans and voxel-based morphometry in depressed patients.²⁷ These brain areas are implicated in subjective emotional experience, processing of emotional reactions, and impulsive decision-making. The amygdala is normally highly regulated by the prefrontal cortex, which uses rational judgment to interpret stimuli and regulate the expression of emotion.

A study involving a facial expression processing task demonstrated reduced connectivity between the amygdala and prefrontal cortex and increased functional connectivity among the amygdala, hippocampus, and caudate-putamen in depressed patients.²⁴ And in a study that measured white matter conduction in various brain areas in depressed patients, the greatest reduction was found in areas connecting the limbic system to the prefrontal cortex and hippocampus—believed to be caused by stress response-induced ischemic glutaminergic neuroapoptosis.²¹ Such neuroapoptosis might lead to irrational interpretation of stimuli, unchecked expression of emotion, and impulsive thoughts and behavior that are often present in depression and other mood disorders.

Deep brain stimulation (DBS), in which electrodes are implanted in the brain, has proved effective at increasing synaptic connections between the prefrontal cortex and the limbic system when electrodes are placed appropriately.²⁸ Patients with refractory depression who are treated with DBS show increased gray-matter density and functional activity in the prefrontal cortex, hippocampus, and fronto-limbic connections.²⁹ DBS also increases neurotransmission of dopamine, serotonin, and norepinephrine within the fronto-limbic circuitry.³⁰

Identifying risk factors for depression

Genetic risk factors. Forty percent of patients with depression have a first-degree relative with depression, suggesting a strong genetic component.¹⁰ Inherited differences in hippocampal volume, synaptic connections between the prefrontal cortex and amygdala, γ-aminobutyric acid (GABA)/glutamate balance, BDNF neurotransmitter receptors, and anatomic positioning of the limbic system in relation to other brain structures might account for the heritability of psychiatric disorders such as depression.

Evidence has been consistent that hippocampal volume is diminished in the brain of depressed persons. However, there is no prospective cohort study to determine whether people who have lower gray-matter hippocampal density or volume, or both, before depression onset develop symptoms later in life. There also is no study to determine the percentage of people who have lower-than-average hippocampal gray-matter density or volume and who have a first-degree relative with depression. Such studies would yield valuable information about anatomic variables that increase the risk of depression.

It has been proposed that low GABA function is an inherited biomarker for depression. Bjork and co-workers found a lower plasma level of GABA in depressed subjects and in their first-degree relatives, confirming that GABAergic tone might be under genetic control.¹¹ Genetic loci studies in mice have linked depressive-like behavior to GABAergic loci on chromosomes 8 and 11, encoding alpha 1, alpha 6, and gamma subunits of GABA_A receptors.²³

A recent study in humans showed that severe, treatment-resistant depression with anxiety was linked to a mutation in the B1 subunit of the GABA_A receptor. Positive genetic associations were found between polymorphism in human GABA_A receptor subunit genes.¹¹

GABA metabolizing enzymes also can be considered biological modifiers of depression. For example:

GABA uptake and metabolism is controlled by the enzyme glutamic acid decarboxylase (GAD); depression has been found to be associated with a polymorphism in the GAD67 gene encoding an isoform of GAD.¹¹

GABA transaminase (GABA-T) is another key enzyme in GABA turnover.³¹ It catabolizes GABA.

We can conclude that, to a high degree, depression depends on GABA production and metabolism.

A variant in the human BDNF gene, in which valine is substituted for methionine in position 66 of the pro-domain of the BDNF protein, is associated with