Depression

Depression

Most common mood disorder

Symptoms include:

- persistent low mood with excessive rumination of negative thought, apathy and pessimism

- low self-esteem, e.g. feelings of guilt and inadequacy

- loss of motivation

- anhedonia

- sleep, libido and appetite disturbance

What are the two main forms of depression?

-Unipolar (mood changes and stays low)

-Bipolar (mood swings between periods of depression and mania), which is the opposite of depression, i.e. excessive self-confidence, exuberance and sometimes grandiose delusions).

Unipolar depression

Most cases are unipolar depression (~75% of cases) show no familial pattern, occurring at times of extreme stress, often associated with anxiety

Bipolar depression

While (~25% of cases) display a familial pattern, which appears unconnected with life events.

monoamine theory

To treat depression modulate levels of the monoamine neurotransmitters 5- hydroxytryptamine (5-HT) and noradrenaline (NA).

In particular:

- VMAT inhibitor reserpine prevents 5-HT/NA storage, used as antihypertensive, decreases mood

- α-methyltyrosine (inhibits tyrosine hydroxylase), and methyldopa (DOPA decarboxylase inhibitor), decrease NA production (used as anti-hypertensives) decreases mood

- MAO inhibitors, inhibit NA/5-HT breakdown increases mood

Iproniazid

MAO inhibitor so Increases mood

Antidepressant targets

-promote adaptive changes in monoamine transporter/receptor expression

-promote positive processing of emotional info.

MAO inhibitors

Phenelzine

Moclobemide

Increase the cytoplasmic concentration of 5-HT/NA.

No great effect upon vesicular stores and neurotransmitter release to nerve stimulation does not really change, but the rate of spontaneous leak increases.

Phenelzine

Inhibits MAO-A and MAO-B

Non-selective

Inhibits MAO irreversibly

Long washout required as new MAO needs to be synthesised

Moclobemide

MAO-A selective inhibitor

Reversible

Competitive inhibitor

What are the two main functions of MAO?

1) To regulate free NA/5-HT concentration in the presynaptic terminal (remember that reuptake determines NA/5-HT inactivation following release)

2) In the gut wall it acts to inactivate both endogenous and ingested amines, such as tyramine.

Cheese effect

tyramine would usually be broken down by MAO in the gut, but in people taking non-selective MAOIs it enters neurones via NET and into vesicles via VMAT where it displaces NA which leaks from pre-synaptic nerve terminals; for this reason, people taking MAOIs should avoid tyramine rich foods as it can induce severe hypertension, the cheese effect – not observed with moclobemide (MAO-A selective) because MAO-B can still break down tyramine.

What are side effects of MAO inhibtors?

-hypotension (possibly because of DA accumulating and replacing NA in sympathetic nerve terminals leading to decreased NA release)

-tremor and excitement due to CNS overstimulation and MAOIs containing a hydrazine moiety like phenelzine can cause hepatotoxicity.

-MAOIs are dangerous in combination with serotonin selective reuptake inhibitors (SSRIs) (excessive build up of 5-HT)

– serotonin syndrome -confusion, dizziness and/or hyperthermia, which can be fatal (similar to ecstasy poisoning).

Drugs for depression

-MAOI

-TCA

-SSRI

-SNRI

-Monoamine receptor antagonist

-Anxiolytics

TCA

These compounds are tertiary amines and inhibit NET and SERT, i.e. NA and 5-HT reuptake and some are metabolised to compounds

Imipramine

desipramine

amitriptyline

nortriptyline

What is the difference between NET and SERT inhibition?

NET inhibition is thought to relieve the biological symptoms of depression, whereas SERT inhibition relieves the emotional symptoms.

What is an issue with the TCA’s?

They affect other receptors contributing to the therapeutic effect, almost certainly produce side effects:

-block of histamine H1 receptors causes sedation (can be of benefit in patients with insomnia),

-block of ACh muscarinic receptors leads to a variety of side effects including a dry mouth, constipation and urinary retention

-acute toxicity such that TCAs were in the past often used in suicide attempts, initial delirium and excitement being followed by coma and respiratory depression

-metabolised in the liver by cytochrome P450 enzymes and thus drugs that inhibit these enzymes will affect TCA function

-potentiate the effects of both alcohol and anaesthetics

SSRI

Less side effects than for TCA and related to elevated 5-HT

e.g nausea, insomnia and loss of libido/failure of orgasm

e.g. simulation of 5-HT3 receptors in the CTZ could lead to feelings of nausea.

Well absorbed when taken orally and most have half-lives in excess of 18 hours, which is advantageous when being taken chronically (once daily tablet).

FIRST LINE TREATMENT:

-fluoxetine

-citalopram

Fluoxetine

not recommended for those under 18 years

Lack of efficacy, but also due to adverse effects including increased suicidal ideation

What does activation of 5-HT-1A

activation of somatodendritic 5-HT1A receptors (Gi- coupled) produces inhibition of 5-HT release

What does chronic SSRI use do

Following chronic SSRI use elevated [5- HT] causes desensitisation of somatodendritic 5-HT1A receptors, thus relieving their inhibition of 5-HT release and overall causing greater 5- HT signalling.

SNRIs

Venlafaxine

Duloxetine

Bupropion

have fewer side effects than TCAs due to fewer receptor-blocking actions

non-selective between inhibition of NET and SERT

side effects are sometimes less to SSRI as inhibition of 5-HT2A and 5-HT3 receptors results in less sexual dysfunction and nausea respectively – may also improve antidepressant/anxiolytic activity

Bupropion

Inhibits the reuptake of NA and DA, but not 5-HT, (used as an add on therapy for patients on SSRIs) however, it does not cause the euphoria associated with either cocaine or amphetamine, and is used as an antidepressant, as well as to treat nicotine dependence (Zyban).

Monoamine receptor antagonists

Mirtazapine

Trazodone

Vortioxetine

agomelatine

Mirtazapine

noradrenaline and specific serotonin antidepressant (NASSA) because of its combined antagonist properties at α2 adrenoceptors and certain 5-HT receptors (5-HT2A/C and 5- HT3).

Blockade of presynaptic α2 adrenoceptors causes increased NA release but also enhances 5-HT release

presence of increased NA there is greater stimulation of somatodendritic α1 adrenoceptors whilst there being a simultaneous decrease in α2 adrenoceptor-mediated presynaptic inhibition.

Trazodone

5HT2A/2C antagonist & weak SERT inhibitor (also used to treat insomnia)

Vortioxetine

SSRI with 5-HT1A agonist, 5-HT1B partial and 5-HT3 antagonist activity.

agomelatine

melatonin receptor agonist

used to treat severe depression

work by correcting disturbances in circadian rhythm that commonly occur in depression.

Ketamine (Esketamine the S(+) enantiomer)

Recent studies suggest Ketamine (Esketamine the S(+) enantiomer) may act as a rapidly acting antidepressant drug (RAAD). The mechanism is unclear as other NMDA antagonists ie memantine do not replicate this action, with selective effects at GluN2B (antagonism) containing receptors proposed. Other possible RAADs include scopolamine (centrally acting muscarinic receptor antagonist) and the psychedelic psilocybin (5-HT2A agonist)