In the previous article, I looked at the changes in the brain in depression. I discussed the theory (monoamine) of reduced serotonin and noradrenaline (norepinephrine), and dopamine in depression. In this article, I will discuss medication (psychopharmacological), treatment of depression. Serotonin (ST) and noradrenaline (NA) are made from proteins tryptophan, and tyrosine, in the brain. Dopamine (DA) is converted to noradrenaline. Noradrenaline, dopamine, and serotonin are called monoamine neurotransmitters (all related, like brother, sister, and cousin). Any of the three or all, may be deficient in depression. Depression with symptoms of low energy, reduced motivation, poor concentration, short term memory loss, and severe cases not able to talk and even walk (severe psychomotor retardation), is likely due to dopamine/noradrenaline deficiency. While depression with anxiety (like agitated depression), predominantly due serotonin deficiency.
Antidepressants, work by restoring these chemicals (monoamines) at brain receptors (postsynaptic).
ANTIDEPRESSANTS:
Tricyclic antidepressants (TCA’s)
These were discovered in 1950’s (examples being amitriptyline, imipramine, and clomipramine).
They work by blocking re-uptake of serotonin, noradrenaline, and in some cases dopamine, by increasing the deficient neurotransmitters in emotional brain (limbic) postsynaptic brain receptors.
They are none specific, affecting other neurotransmitters and receptors, accounting for side-effects from these drugs, some of which are desirable.
These include;
Dryness of mouth, constipation, blurred vision, urinary retention, short term memory (blocking cholinergic receptors).
Drop of blood pressure (postural hypotension) from lying/seating to standing (due to blocking of alpha 1 receptors which maintain tone in blood vessels).
Sedation/drowsiness (desirable effect, can help sleep, due to antihistamine, H1 effects in the brain).
May induce seizures in susceptible individuals (lower seizure threshold).
In overdose can cause serious abnormal heart irregularities (arrhythmias).
Monoamine Oxidase Inhibitors (MAOI’s)
Monoamine oxidase (MAO), is an enzyme which breaks down (metabolises) m0noamines (ST, NA, DA). Thus, after its function is over, the body gets rid of these monoamines. MAOIs prevents breakdown of these monoamines, in order to increase back the levels at the receptors (post synaptic), which are lowered in depression.
There are two types of MAO (monoamine oxidase), A and B. MAO A breaks down serotonin, noradrenaline, and dopamine, and MAO B, tyramine.
Drugs like, phenelzine, tranylcypromine, are examples MAOIs. They inhibit (prevent) breakdown of serotonin, noradrenaline, and dopamine, increasing their availability in their respective receptors (postsynaptic receptors). They also inhibit tyramine. They inhibit (prevent breakdown) of both MAO A and B (they irreversibly bind to MAO), until the drug is cleared from the body).
Tyramine is a substance found in certain foods especially fermented ones, like cheese (causing the cheese reaction), red wine, smoked fish, marmite, broad beans pods etc. Monoamine oxidase breaks down tyramine, and therefore MAOI’s like the ones above, prevent breakdown of tyramine outside the brain (tyramine does not cross blood brain barrier).
Tyramine releases adrenaline (epinephrine) and noradrenaline (norepinephrine) outside the brain which can cause very high rise in blood pressure (hypertensive crisis), leading to a stroke. Patient’s taking these antidepressants should avoid foods containing tyramine, to minimise this serious side effect.
MAOIs, may interact with some amine drugs, like pseudo ephedrine found in cough mixtures, and decongestants, by inhibiting breakdown of these drugs, causing rise in blood pressure. The person may experience a throbbing headache, due to the severe rise in blood pressure.
Other side effects are similar to TCI’s as above, like dryness of mouth, constipation, blurred vision, dropping of blood pressure from lying/seating to standing (postural hypotension).
Moclobemide acts by preventing breakdown (inhibition) of monoamine oxidase type A. (It is called Reversible Inhibition of Monoamine A; RIMA).
As it inhibits breakdown of serotonin, noradrenaline and dopamine (MAOA), but not tyramine (MAOB), it therefore less likely to cause the cheese reaction or interact with other medicines like cough mixtures or decongestants. It safer than phenelzine or tranylcypromine or similar drugs (as they inhibit both MAO A and B).
Selective Serotonin Reuptake Inhibitors (SSRIs)
These drugs selectively inhibit reuptake of serotonin, thus preventing it going back into the pre-synaptic (before the synapse) cells, and by doing so increases serotonin in the synapse to bind to the post synaptic (after the synapse) receptor. (Monoamine theory of depression, states serotonin and norepinephrine is reduced in the post synaptic receptors).
Examples of SSRIs include; fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, escitalopram.
Side effects include nausea, vomiting, and diarrhoea (due to initial stimulation of serotonin receptors in the gut). Other side effects include, irritability, headache, poor sleep (in a small percentage of people excessive sleep), agitation, anxiety.
Nausea and vomiting can be minimised by take the drug with food, insomnia (taking it in the morning) and other side effects by starting at a low dose, and gradually increasing to an effective (therapeutic) dose for the individual. These initial side effects like anxiety tend to settle after few days. (SSRIs are also effective treatment for anxiety as well, and again it is essential to start with a low dose, and gradually increase the dose over weeks).
The same principle should apply when coming off SSRIs. The dose should be reduced gradually over a number of weeks to minimise discontinuation (withdrawal symptoms).
SSRIs are relatively safe in overdose compared to TCAs, which can be fatal (cause death).
Noradrenaline Reuptake Inhibitors (NRIs)
These drugs block reuptake of noradrenaline into the presynaptic cells, increasing availability of noradrenaline in the synapse, to bind to postsynaptic receptors. (Monoamine hypotheses).
An example of this is Reboxetine. It is effective for treating depression. Side effects include effects anorexia, sweating, chills, headaches etc, (due to increase of noradrenaline).
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
These drugs block both reuptake of serotonin and noradrenaline (in high dose also block reuptake of dopamine). Thus, increasing serotonin, noradrenaline and dopamine, in postsynaptic receptors, reversing depression. Severe depression, which may be due to lack of more than one of these monoamine neurotransmitters, respond better to these dual-action antidepressants.
Examples of this group of drugs include, venlafaxine, duloxetine and milnacipran. Side effects similar to SSRIs and NRIs. They cause or worsen high blood pressure (hypertension) in high doses.
Noradrenaline Dopamine Reuptake Inhibitor (NDRIs)
These drugs block both reuptake pump of both noradrenaline and dopamine. Thus, increasing both noradrenaline and dopamine in postsynaptic receptors, reversing depression.
An example of this is bupropion. This drug can also be used for smoking cessation (by increasing dopamine in the reward Centre).
Side effects are due partly dopamine and noradrenaline effects which include sweating, tremor, agitation, dizziness, etc.
Serotonin Antagonist Reuptake Inhibitors (SARIs)
These drugs block reuptake of serotonin (like SSRIs, although not as strong), and also block serotonin receptors (2A postsynaptic receptors). Serotonin is increased to due to reuptake blocking effects, and is enhanced by receptor blocking effects, improving depression and anxiety.
The two examples are trazodone and nefazodone.
Trazodone can improve sleep (2A blocking effect, and antihistamine, H1 effect), drop in blood pressure from lying/seating to standing (postural hypotension due to alpha 1 blocking effects), dryness of mouth (antimuscarinic effects like TCAs).
Nefazodone is no longer available in the UK.
Noradrenaline and Specific Serotonergic Antidepressant (NaSSA).
Mirtazapine is an example of this. It increases serotonin and noradrenaline in their respective receptors (postsynaptic receptors), by a different mechanism (alpha2 adrenoreceptor antagonism), rather than blocking reuptake, like SNRIs. It also blocks serotonin (5HT2A, 5HT2C, and 5HT3) postsynaptic receptors. As outlined above, increasing serotonin and noradrenaline at the respective receptors (postsynaptic receptors), will improve symptoms of depression.
The blocking of the above receptors, will enhance serotonin antidepressant effects, improve anxiety, sleep, and has no gastrointestinal side effects (nausea, diarrhoea, like those caused by SSRIs), but also account for the main side effect of this drug, weight gain (through blocking 5HT2C receptors in the hypothalamus). Sedation is also a side effect (antihistamine, H1 effect).
Other Antidepressants
Melatonin Receptor Agonist
Agomelatine enhances melatonin receptors (MT1 and MT2 receptor agonist) and selectively block serotonin receptors (5HT2c antagonist). Agomelatine is said to work in depression by restoring biological rhythms (circadian rhythms), which are said to be disrupted in depression. It does not block reuptake of serotonin, noradrenaline or dopamine, like SSRIs, SNRIs or TCAs.
It will improve sleep, without causing drowsiness the next day. It does not usually have the side effects associated with other antidepressants, including weight gain (TCAs) and sexual side effects (SSRIs, SNRIs, and TCAs).
Agomelatine has been associated liver abnormalities, hence prior to starting it, liver tests need to be checked, and continue monitor after a number of weeks.
Vortioxetine is termed an atypical antidepressant. It inhibits reuptake of serotonin (like SSRIs), increasing serotonin at its receptors (postsynaptic receptors). It enhances (agonist at 5HT1A receptors), and blocks other serotonin receptors (5HT3 antagonist), improving depression, and anxiety. Side effects include nausea, vomiting, dizziness etc.
Supplements:
Omega-3 fatty acids play a role in development and functioning 0f the nervous system. There is clinical, and research evidence that low levels omega-3 fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) may be linked with emotional (mood) disorders like depression or depression in bipolar disorder.
Fish oil is rich in omega-3. Omega-3 fatty acids with EPA, have been shown to be beneficial in depression.
In my clinical practice, I recommend omega-3 with EPA 1 g up to three times a day for my patients with depression or bipolar depression, in addition to antidepressants or mood stabilisers.
Tryptophan: As outlined above, serotonin is made from the protein tryptophan. There is clinical and research evidence that tryptophan has antidepressant effects, and in particular this effect more evident when it is added to antidepressants.
In my clinical practice, for patients with severe depression who have not fully responded to antidepressant and cognitive behavioural therapy, I normally add L-Tryptophan, and obtain good results.
Lifestyle:
Exercise has shown be beneficial in depression. Exercise induces natural highs in reward Centre (My Brain is Out of Control; chasing the dopamine!).
In patients who are able to do this (patients who are severely depressed may not able to do this, as energy and motivation may be affected), this should be added to the treatment programme of depression, and this would also help with weight gain due to some of antidepressants like mirtazapine.
References:
British National Formulary (BNF). September 2016 – March 2017.
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Kaplan & Sadock’s. Comprehensive Textbook of Psychiatry. Seventh Edition Volume 1; 2000. Lippincott Williams & Wilkins.
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Dr Patrick Mbaya MD FRCPsych.
