Antipsychotics, antidepressant agents and lithium

Question 1

First generation of antipsychotics

Answer 1

typical, classical or conventional.
E.g. chlorpromazine, haloperidol, fluphenazine, flupentixol, clopentixol

Affinity: high affinity for D2 receptors.
Mechanisms: Blockade of dopamine D2 receptors in the mesolimbic pathway is believed to be the primary mechanism underlying their antipsychotic efficacy.
Side-effects: Blocking dopamine D2 receptors in the nigrostriatal pathway can lead to extrapyramidal symptoms (EPS).

Question 2

Second generation of antipsychotics

Answer 2

Atypical, newer.
E.g. clozapine, risperidone, sertindole, quetiapine, amisulpride, aripiprazole, zotepine, ziprasidone.

Affinity: Varies among different atypical antipsychotics, but generally lower affinity for dopamine D2 receptors compared to typical antipsychotics.
Mechanism: often exhibit serotonin-dopamine antagonism, meaning they block both dopamine D2 receptors and serotonin 5-HT2A receptors. This dual mechanism is believed to contribute to their efficacy against both positive and negative symptoms of schizophrenia with potentially fewer extrapyramidal symptoms.
Side-effects: Despite their lower affinity for dopamine D2 receptors, some atypical antipsychotics can still cause extrapyramidal at higher doses, but the risk may be lower compared to typical antipsychotics.

Question 3

Why less extrapyramidal side effects with second generation antiphycotics?

Answer 3

1. Better receptor selectivity: Serotonin 5-HT2A receptor antagonism (e.g. olanzapine) leads to more release of DA from nigrostriatal neurons. Muscarinic receptor antagonism (e.g. olanzapine) counteracts increased cholinergic tone.
2. Lower D2 receptor affinity with faster dissociation (rapid off- rate)? (e.g. olanzapine)

Question 4

Monoamine uptake inhibitors (antidepressant drugs)

Answer 4

Act by inhibiting uptake of noradrenaline and/or 5-HT by monoaminergic nerve terminals.

Question 5

Selective 5-HT uptake inhibitors (SSRI’s)
(Monoamine uptake inhibitors)

Answer 5

E.g. Fluoxetine, mirtazapine, sertraline, escitalopram.

MOA: inhibits the 5-HT transporter, so there is a higher concentration of 5-HT in the synaptic cleft.

Unwanted effects: Nausea, anorexia, insomnia, loss of libido and failure of orgasm. Some of these unwanted effects result from the enhanced stimulation of postsynaptic 5-HT receptors. This can be either stimulation of the wrong type of 5-HT receptor (e.g. 5-HT2, 5-HT3 and 5-HT4 receptors) or stimulation of the same receptor that gives therapeutic benefit= postsynaptic 5-HT1A receptors, but in the wrong brain region.

Question 6

Tricyclic antidepressant (TCA)
(Monoamine uptake inhibitors)

Answer 6

E.g. amytriptiline, imipramine, nortriptyline, chlomipramine.

MOA: The main immediate effect of TCAs is to block the uptake of amines by nerve terminals, by competition for the binding site of the amine transporter. Most TCAs inhibit noradrenaline and 5-HT uptake but have much less effect on dopamine uptake.

Side-effects: TCAs are also antagonists with varying affinity for several G protein coupled receptors (does not only bind the transporters):
* Muscarinic acetylcholine receptors: Dry mouth, urine retention, constipation, tachycardia, confusion etc.
* Histamine H1 receptor: Sedation and weight gain.
* alpha-adrenergic receptor: Orthostatic hypotension, sedation.

Question 7

Serotonin noradrenaline reuptake inhibitors (SNRI)
(antidepressant drugs)

Answer 7

E.g. venlafaxine, devenlafaxine, duloxetine.

MOA: Bind with high affinity to both the serotonin transporter and noradrenaline transporter.

Question 8

Selective noradrenaline reuptake inhibitors (SNI) (antidepressant drugs)

Answer 8

Bind with high affinity to the noradrenaline transporter. Less efficacy.

Side effects: Light side effects in relation to inhibition of NA uptake (light increase in blood pressure and increased heartbeat).

Question 9

Noradrenergic and specific serotonergic antidepressant (NaSSA)

Answer 9

Monoamine receptor antagonist. Antagonist at the histamine H1, 5-HT2A, 5-HT2C, 5-HT3, and α2- adrenergic receptors.

By blocking the pre-synaptic α2-adrenergic receptors which function as inhibitory auto receptors, mirtazapine disinhibits the release of norepinephrine and serotonin in certain areas so leads to increased release of serotonin and noradrenaline.

Side effects: drowsiness, increased appetite, and weight gain (all due to antagonism at H1 receptor).

Question 10

Monoamine oxidase inhibitors (antidepressant drugs)

Answer 10

E.g. phenelzine, tranylcypromine, iproniazid.

Monoamine oxidase inhibitors cause a rapid and sustained increase in the 5-HT, noradrenaline and dopamine content of the brain by preventing their degradation, 5-HT being affected most and dopamine least.

Side-effects: postural hypotension (sympathetic block); atropine-like effects (as with TCAs); weight gain; CNS stimulation, causing restlessness, insomnia; hepatotoxicity and neurotoxicity (rare).

Question 11

Lithium (used for e.g. bipolar disorder)

Answer 11

MOA: Lithium is a monovalent cation that can mimic the role of Na+ in excitable tissues, being able to permeate the voltage-gated Na+ channels that are responsible for action potential generation. It is, however, not pumped out by the Na+-K+-ATPase, and therefore tends to accumulate inside excitable cells, leading to a partial loss of monovalent cation mimicking Na+.

Side-effects:
* Narrow therapeutic interval (0.5 – 1.5 mM), death at 3-5 mM).
* Slow elimination by kidney (because taken up by the cells) (accumulates over two weeks before steady state is reached).
* Nausea, vomiting, diarrhoea.
* Tremor.
* Renal effects (polyuria due to decreased effect of ADH).
* Renal damage.
* Thyroid enlargement.
* Weight gain.