Depression and antidepressants

(Back to my good ol' warning: don't use this blog as medical advice, go to a doctor instead. Kthxbai)

Mood Disorders

In this post we'll be focusing on depression (hence the title), but I'm going to run through the other mood disorders first:

• Major Depressive Disorder: At least two depressive episodes (I'll describe what these are in a bit).
• Dysthymic disorder: Like Major Depressive Disorder, but less severe and chronic (>2 years)
• Depressive disorder Not Otherwise Specified (NOS): You'll be seeing "NOS" a lot. It's just a way for the DSM (Diagnostic and Statistical Manual) to accommodate people that kind of fit the criteria by not really.
• Bipolar I: At least one manic episode in addition to depressive episodes.
• Bipolar II: Kind of like Bipolar I, but instead of mania, you have hypomania (nearly but not quite manic).
• Cyclothymic disorder: I think this is like bipolar disorder, but less extreme. It is defined as short periods of mild depression interspersed with short periods of hypomania and normal mood.
• Bipolar disorder NOS: Yup...
• Mood disorder due to General Medical Condition: So basically like being depressed because you have cancer
• Substance-induced mood disorder: Mood issues due to a drug or due to withdrawal effects from a drug
• Mood disorder NOS

At the risk of plagiarising the DSM, here are the diagnostic criteria for a major depressive episode in the DSM.

Firstly, you need at least five of the following symptoms (and at least one of the symptoms has to be either (1) or (2)).

1. Depressed mood most of the day, Nearly Every Day (NED)
2. Markedly diminished interest or pleasure in all, or almost all activities most of the day (anhedonia)
3. Significant weight loss or weight gain when not dieting
4. Insomnia or hypersomnia NED
5. Psychomotor agitation (i.e. being really restless or fidgety) or retardation (i.e. moving around less) NED
6. Fatigue or loss of energy NED
7. Feelings of worthlessness or guilt
8. Diminished ability to think or concentrate NED
9. Recurrent thoughts of death, suicidal ideation or a suicide attempt

Secondly, you also need to fit the "exclusion criteria":

1. No mania (because then you'd probably fit the criteria for bipolar disorder instead)
2. "Clinically significant" distress or impairment in social, occupational or other areas of function
3. Not due to effects of a substance (because then I guess that would be substance-induced mood disorder)
4. Symptoms not better accounted for by bereavement

Monoamine Oxidase Inhibitors (MAOIs)

The very first antidepressant, iproniazid, was an inhibitor of monoamine oxidase (an enzyme that breaks down monoamines, such as serotonin and noradrenaline). It was discovered pretty much by accident: iproniazid is actually a treatment for tuberculosis, but they found that it lifted the mood of depressed patients. The success of MAOIs gave rise to the monoamine depletion hypothesis of depression, which suggests that depression is due to a depletion of monoamines such as serotonin and noradrenaline. Interestingly enough, reserpine, an Indian herbal medicine used to treat hypertension, blocks transport of monoamines into vesicles and causes depression, lending support to this hypothesis.

One of the biggest issues with MAOIs was the possibility of causing a hypertensive crisis. You see, tyramine from the diet is usually metabolised by monoamine oxidase. When this is blocked by MAOIs, tyramine can build up. Tyramine can displace NA by reversing the direction of NA transporters that would otherwise take NA up into the nerve terminals. When NA is displaced, it can stimulate postsynaptic neurons, leading to an increase in heart rate, headaches and all kinds of fun symptoms. This effect is also known as the "cheese effect," probably because tyramine is found in cheese.

Recently, RIMAs, or Reversible Inhibitors of MonoAmine oxidase, have been produced. These reversibly inhibit only A-type MAO (yes, there are multiple types, imaginatively named A and B) and do not have the "cheese effect" problem of the earlier MAOIs. So far, only one (moclobemide) is available in Australia.

Tricyclics

The first tricyclic antidepressant, imipramine, was also discovered more or less by accident. Imipramine was created in an attempt to improve the antipsychotic properties of clorpromazine. It turns out that imipramine did jackshit as an antipsychotic, but helped with depression. Additionally, it was safer than MAOIs. Tricyclics work by blocking the re-uptake of serotonin and noradrenaline into presynaptic neurons, allowing these monoamines to stimulate the postsynaptic neuron for longer periods of time. Some tricyclics have a higher affinity for NA transporters, whereas others have a higher affinity for serotonin transporters.

One thing that the MAOIs and tricyclics have in common (as well as some of the newer drugs, but I'll get to them later) is that while they can act on monoamines really quickly, the actual therapeutic effects can take weeks to develop. It has since been found that these drugs can increase the subsensitivity ("tolerance") of certain receptors. One of these is adenylate cyclase- when subsensitivity to adenylate cyclase occurs, there is a reduction in cAMP following stimulation of β-receptors. Another is the α₂-autoreceptor, which as I mentioned earlier, would usually inhibit the further release of NA. All of this gave rise to a new hypothesis: the noradrenaline dysregulation hypothesis, which suggests that depression arises from dysregulation of noradrenaline levels in the brain.

New Generation Drugs

MAOIs and tricyclics are relatively uncommon these days. SSRIs (selective serotonin reuptake inhibitors, e.g. fluoxetine and escitalopram) and SNRIs (serotonin and noradrenaline reuptake inhibitors, e.g. venlafaxine) are probably some of the more common ones, but there are also RIMAs (as mentioned earlier), NRIs (noradrenaline reuptake inhibitors), NDRIs (noradrenaline and dopamine reuptake inhibitors), SARIs (serotonin-2 antagonist and 5-HT reuptake inhibitors) and SNDIs (serotonin and noradrenaline disinhibitors). A new class of drugs called melatonin receptor agonists is also being trialled.

Now for a couple more notes on SSRIs, because as I just said, they are probably some of the more commonly-prescribed antidepressants today. SSRIs, like MAOIs and tricyclics, can subsensitise α₂-autoreceptors, but they might not be able to subsensitise adenylate cyclase. On the other hand, they might be able to enhance serotonin transmission by causing subsensitivity of inhibitory autoreceptors, specifically dendritic 5HT-1A inhibitory autoreceptors and terminal inhibitory autoreceptors. Subsensitivity of dendritic receptors means that production of serotonin won't stop any more from being produced, and subsensitivity of terminal receptors means that release of serotonin won't stop any more from being released. The end result is an increase in production and release of serotonin.

One last thing to say! This is kind of out of place, but I don't know where else to put this. There's another theory about depression called the hippocampal neurogenesis theory. VEGF (vascular endothelial growth factor), aside from being able to stimulate the growth of new capillaries, can also stimulate the growth of brain cells, and it's been hypothesised that VEGF might be an intermediary in the antidepressant response.

Okay, I lied, that wasn't the last thing I had to say! This is also kind of randomly put in, but deal with it, okay? It's been suggested that antidepressants may not have much of an effect beyond placebo except in cases of severe depression. Is overprescription a problem? I don't know, but don't stop taking your meds without asking a doctor. Antidepressant discontinuation syndrome sucks.