Depression: a disease neuroscientist and author, Robert Sapolsky, calls the “bread and butter of human misery,” and what psychologist, Martin Seligman, has referred to as “the common cold of psychopathology.” Common being the operative word, as it is estimated that 5 to 20 per cent of us will suffer a major, life threatening, depression at least once during our lives. Indeed, by the year 2020, depression is forecast to become the second leading cause of medical disability on earth. In order to gauge how miserable this disease must be, one only needs to look at the statistics: over 50 per cent of all people who’ve died by suicide had been clinically diagnosed with depression. This disease is a killer, just as cancer is a killer and heart disease is a killer.
Depression won’t immediately kill you, however, it’s more like neurotoxic snake venom in that way: it’ll paralyse you first and then kill you. Depression is known to, first-and-foremost, induce anhedonia, or, “the inability to feel pleasure.” This will surround the suffers mind’s eye with feelings of a great sense of guilt and sadness (the paralysis, taking our snake venom analogy). Appetite and sexual drive will decrease, insomnia will impede one’s life and anxiety will cripple them with worry. These symptoms will consume everything, until one hits a plateau, and either the venom is removed, or suicide is thought to be the only relief.
Just as snake venom high-jacks many of your internally circulating chemicals and inhibits them, causing a painful paralysis and then death, so too does depression. Depression is thought to mechanise an enzyme, known as monoamine oxidase (MAO), that breaks down neurotransmitters such as serotonin and noradrenalin (NA) (chemicals associated with functions of wakefulness, motivation and appropriate mood). This enzyme, when hyperactive, jumps around within cells located in your brain (neurons) at an accelerated rate, degrading these neurotransmitters, rendering them inapplicable.
This particular mechanism of depression was found, in the 1960’s, when a drug called reserpine inadvertently seemed to cause depression in 20 per cent of the patients that were prescribed it. The active chemical substrate of this drug was shown to interfere with the initial cell storage of serotonin and NA leading to the inference, concluding that, depression is caused by the elevated depletion of these chemicals. Neuroscientists, in addition, noted that the drug imipramine, purposely introduced as an antidepressant, actually inhibits serotonin, once initially released, from being taken back into the cell that liberated it — leaving the chemical to linger. As neurotransmitters initiate their effects by travelling from one cell and latching on to another, the more numerously this can happen, the greater the effect a chemical can have; a mechanism imipramine achieves. Researchers of clinical depression quickly incorporated these observations, showing that a depletion of serotonin and NA seemingly contributes to depression, into what’s known as the monoamine hypothesis of mood disorders.
Yet, when a patient is prescribed something like a selective serotonin reuptake inhibitor (an agent that accentuates serotonins neuronal lingering), the depressed symptoms a patient expresses seem to take a couple of weeks to evaporate. This is despite the drug making serotonin more available almost immediately. Depression, therefore, cannot only be caused by an imbalance of a particular set of neurotransmitters, but, also, by structural changes within the brain. Depression functions in a manner more sinister and longer-lasting than even snake venom, as it changes chemical function and the structural integrity of our most endearing organ, the brain.
Selective serotonin reuptake inhibitors (SSRIs), researchers have found, provoke long-lasting structural changes in a brain region known as the hippocampus. The hippocampus, as well as being an integral piece of hardware for memory storage and integration, plays a role in regulating the hormone cortisol.
Cortisol circulates within the blood stream and “talks” to many of our bodies organs, including the brain. This hormone, in the main, prepares our body for an instance of stress, or fight-or-flight and can enhance mental faculties, such as attention and memory. When this circulating hormone reaches a certain blood-to-cortisol ratio the hippocampus realises this and communicates with the hypothalamus; issuing a command which inhibits the further release of cortisol. The hippocampus, unfortunately, can be inflamed and its cells destroyed by a toxic amount of cortisol, which will inhibit its function of down-regulating the blood-to-cortisol ratio. In short, too much stress will make cortisol King, ruler and executioner (of hippocampal cells at least). It is what the venom of depression hijacks in order to cause a slow death with feelings of anhedonia being the mechanism.
Everyone is, in their life experience, exposed to severe stressors that cause this kind of up-regulation of cortisol, yet not everyone experiences a major depression. But why? The answer is genetic predispositions. Studies have suggested that a change (or, a polymorphism) of the gene that codes for the serotonin receptor protein is more common among depressed individuals. Indeed, when lab mice have the gene that codes for serotonin receptors “knocked out” early on in life, their behaviour expresses an elevated sensitivity to stress. Even when the gene, later, is genetically restored, the behavioural markers of stress stay apparent. This suggests these sensitivities to stress are programmed into our behaviour and biological mapping at an early age. It also infers that SSRI may act by inhibiting the toxic effects of cortisol on the hippocampus by restoring some of the regions matter density and, thus, its ability to inhibit the release of cortisol.
That’s it then, if you’re unlucky enough to have this genetic predisposition it’s inevitable that the venom of depression will infect you, right? Well, there’s one more thing to take into account: not everyone with these genetic predispositions does get infected with depression. The venom is not innate, it needs to first be injected into your bodily systems through highly stressful life experiences.
In order to understand how life experience can either be the venom of depression, or the inoculation to it, we need to come back to the hippocampus. To “realise” the level of circulating cortisol, the hippocampus must express receptors for the cortisol to latch onto, thus creating a cascade within the hippocampal cells causing a signal to ascend to the hypothalamus. This signal “tells” this region to stop releasing cortisol. However, too much binding of cortisol onto these hippocampal receptors and cell death commences.
Studies using the mammalian rats, who share these same brain regions and hormonal mechanisms, show that if the pup is well groomed by its mother it’ll express more glucocorticoid receptors on the hippocampus; this allows the hippocampus to register the amount of cortisol currently circulating at a quicker rate and inhibit accordingly. Rat pups also exhibit less cortisol in their experimentally extracted spinal fluid and a reduction of anxiety-like behaviour as adults. This stress inoculator only appears to be effective when administered during early-life, as rats, when solitarily nurtured during adulthood, express fewer glucocorticoid receptors and more anxiolytic symptoms.
Studies researching early life-stressors–corroborating such evidence derived from the humble rat–document emotional abuse, sexual abuse and severe family conflict to all be independent predictors of depression in adulthood. As well as predicting depression, these factors also predicted decreased cortical thickness, a reduced hippocampus volume and a decline in overall cognitive performance.
Depression, then, mechanises internal chemicals just like snake venom to cause destruction within the body. This brand of venom destroys brain volume, cognitive performance and one’s capacity to feel pleasure itself. The cure to strain this vociferous poison from a suffers body is yet to be found. But recent developments in genetic and neuroscience research have provided some hope.