Neuroscience An extra bit Dr Sasha Gartside Institute of Neuroscience Newcastle University
Drugs, receptors, and transporters Most psychoactive drugs interfere with neurotransmission The main targets are enzymes, transporters and receptors
How does understanding neuroscience and psychopharmacology help? An example: The pharmacotherapy of depression
The pharmacotherapy of depression Reserpine causes depressive symptoms reserpine inhibits monoamine storage Iproniazid (MAOI) and imipramine (5-HT/NA uptake inhibitor) effective antidepressants both increase monoamine neurotransmitters The Monoamine theory (1950s) Shildkraut
The pharmacotherapy of depression Many tricyclic analogues synthesised and used to treat depression One TCA (clomipramine) found to be selective 5-HT uptake inhibitor Clinically, clomipramine as effective as imipramine. The 5-HT theory of depression (1960s) Rational design of SSRIs- fluoxetine, paroxetine, fluvoxamine, sertraline.
The 5-HT theory of depression Deficit in 5-HT neurotransmission Increase 5-HT, relieve depression! Drugs which block 5-HT reuptake or metabolism are antidepressant But Delay in onset of therapeutic effect
Theories of antidepressant action Explaining the delay Postsynaptic receptor adaptation Autoreceptor desensitization
Adaptation of postsynaptic receptors? 5-HT Antidepressants raise 5-HT and NA Postsynaptic 5-HT 2 and receptors down regulated by antidepressants (slowly) But.. 5-HT 2 and antagonists are not antidepressant ECT upregulates 5-HT 2 receptors
Desensitization of 5-HT autoreceptors? 5-HT 1A autoreceptor 5-HT 1B autoreceptor 5-HT release 5-HT uptake 5-HT 5-HT is released in both terminal and cell body regions...and is cleared by reuptake in both regions
5-HT autoreceptors restrain ability of ADs to increase terminal 5-HT 5-HT 1A autoreceptor 5-HT 1B autoreceptor 5-HT release 5-HT uptake X 5-HT X X X SSRIs block uptake in both regions 5-HT levels in raphe nuclei rise and activate autoreceptors Autoreceptors inhibit firing and terminal release
Desensitization of 5-HT autoreceptors 5-HT 1A autoreceptor 5-HT 1B autoreceptor 5-HT release 5-HT uptake X 5-HT X After several weeks autoreceptors desensitize Although 5-HT levels at the cell body remain high, firing is restored Release is restored and, because terminal reuptake is blocked, terminal 5-HT rises
The tap and plughole Normal situation- plug hole open tap on After acute SSRI plug in but tap off After chronic SSRI- plug in tap on again
Raising 5-HT is crucial for antidepressant effect Acute pharmacology and autoreceptor desensitization theory suggest increased 5-HT is crucial for AD efficacy How can we hasten the rise in 5-HT?
Hastening effect of AD on terminal 5-HT 5-HT 1A receptor antagonists to block autoreceptor activation Pindolol tested Mixed reuptake blocker 5-HT autoreceptor molecules in development
Hastening the onset of SSRI action: the problem with 5-HT 1A receptor antagonists. 5-HT 5-HT 1A autoreceptor antagonists will disinhibit firing Note: these will also block postsynaptic 5-HT 1A receptors
Increasing therapeutic efficacy ~ 70 % patients fail to respond fully to conventional AD treatment Can efficacy be improved by further increasing 5-HT? Can efficacy be improved by also increasing NA?
Adjuncts to antidepressants: increasing 5-HT α 2 antagonists to increase drive α 1 agonists to increase firing α 2 adrenoceptor antagonist to disinhibit release (mirtazepine) 5-HT 5-HT 1A autoreceptor antagonists to disinhibit firing 5-HT 1B autoreceptor antagonists to disinhibit release
Do we need to raise 5-HT and NA? 5-HT NA TCAs, MAOIs, SNRIs, mirtazepine all increase both
Understanding something of the neurophysiology and psychopharmacology could lead to development of improved treatments