Presynaptic Depletion and Suicidal Exhaustion
Based on my own experience of having been a patient with severe depression, and also having some academic knowledge of neurophysiology and pharmacology, I would like to suggest that the dangerous psychological state of suicidal exhaustion, deservedly discussed at some length on the SANE website, may at least in some cases correspond to a physiological state where the quantity of monoamine neurotransmitter molecules stored in the presynaptic terminals within certain important neuronal pathways, has become severely reduced (presynaptic depletion). I am concerned that, if this is the case, then the types of drug usually first prescribed to patients considered to require anti-depressant medication, may not be the safest available in terms of suicide risk.
In children and adolescents especially, their frequent new experiences, extensive learning and rapid brain development, mainly in the cerebral cortex, seem likely to be associated with a high level of neuronal activity, in particular a high rate of firing in the sub-cortical parts of the brain which, via neural pathways ascending to the cortex, enable and maintain alertness, attention and concentration, and awareness of mental functioning and well-being. This high rate of firing of the relatively small numbers of neurons in specific sub-cortical areas will tend to lead to some degree of neurotransmitter depletion in the presynaptic terminals of their axons. This would be consistent with the longer sleep requirements of these younger people, to enable learning to be consolidated and the neurotransmitter stores to be replenished. Similar presynaptic depletion may also arise in adults experiencing prolonged stressful and demanding situations, and/or working excessively long hours and/or getting insufficient sleep. At any age, such presynaptic depletion would be exacerbated if for any reason there were a below-normal amount of neurotransmitter available in the first place e.g. due to having sub-optimal gene variants or fewer of the relevant presynaptic neurons.
The effects of presynaptic depletion could be an important factor in at least some cases of clinical depression, and the increased mental effort involved in living with depression may, in turn, worsen the presynaptic depletion, causing a downward spiral towards extreme depletion and suicidal exhaustion. In such circumstances, starting treatment with drugs such as the selective serotonin reuptake inhibitors (SSRIs) and tricyclics, which inhibit reuptake of monoamine neurotransmitters into the presynaptic terminals and thereby exacerbate presynaptic depletion, will tend to make the depression worse, before the longer-term potentially therapeutic effects such as increased neurotransmitter biosynthesis and re-adaptation of the synaptic receptors, start to kick in. Such worsened depression may well involve an increased tendency towards suicidal thoughts, leading, in some more severe cases, to actual suicide attempts, especially during the first week or two of medication. I have observed this in the case of myself and understand that this clinical pattern is documented in the psychiatric literature.
Based on the above, it seems to me that it would probably be safer for the first line of treatment with antidepressant medication, especially in the more severe cases, and with younger or sleep-deprived people, to be a drug of a type which does not tend to exacerbate presynaptic depletion. The most obvious class of drug for this purpose would be the monoamine oxidase inhibitors (MAOIs), especially the more recently developed reversible types which do not require dietary restrictions to avoid tyramine reactions. MAOIs do not inhibit reuptake of monoamines into the presynaptic terminals and will tend to relieve presynaptic depletion by blocking the breakdown of monoamines within the presynaptic neurons, as well as possibly in the synaptic clefts. Mirtazapine and similar drugs also do not inhibit monoamine reuptake but do block the presynaptic receptors which would otherwise limit monoamine release, so these drugs will tend to increase monoamine release and may thereby worsen presynaptic depletion. Among the SSRIs, fluoxetine (Prozac) is widely recognized as the safest, especially for children and adolescents, probably due to its exceptionally large distribution volume and long half-life in the body, which cause a natural buffering and tapering of drug concentration, upwards on commencement and downwards on cessation.
I do not know whether there have been any clinical trials, or reviews of clinical data, comparing rates of suicides, or suicidal thoughts, among patients receiving the different classes of antidepressant drugs, and appreciate that for ethical and practical reasons such data, despite its potential importance, may be difficult to obtain.