Serotonin lecture

Major mood disorders

• bipolar disorder (BD)

• major depressive disorder (MDD)

Modulators of mood, the sleep-wake cycle, motivation and reward, cognitive processing, pain perception, and neuroendocrine function, migraine, and GI system

• serotonin

• norepinephrine

Rate-limiting step for monoamines

• tyrosine hydroxylase for dopamine

• tryptophan hydroxylase for serotonin

• FIRST synthetic step

What may explain the time delay for clinical actions of anti-depressants?

The auto-regulatory loop

What regulates tyrosine hydroxylase and tryptophan hydroxylase?

inhibitory feedback via autoreceptor-mediated signaling

SERT

• selective serotonin reuptake transporters

• recycle 5-HT from extracellular space back into presynaptic neuron

• 12-transmembrane-spanning proteins that couple neurotransmitter transport to the transmembrane sodium gradient

• individual SERT show selectivity, high affinity, and low capacity

Can SERT, NET, and DAT transport the other monoamines?

Yes, although less efficiently

Once 5-HT is returned to the neuronal cytoplasm, what happens to the neurotransmitter?

transported into vesicles via VMAT or degraded by monoamine oxidase (MAO)

MAO-A oxidizes

5-HT, NE, and DA

MAO-B preferentially oxidizes

DA

All 5-HT receptors but one are…

GPCR

What 5-HT receptor is the only ligand-gated ion channel receptor?

5-HT₃

Presynaptic autoreceptors important for feedback inhibition:

• 5-HT1B serotonin receptor

• Alpha2-adrenergic receptor

Major Depressive Disorder

single or recurrent depressive episodes

MDD

Bipolar disorder

mania or hypomania as well as periods of depression

BD

Dysthymia

persistent depressive disorder

Cyclothymia

less extreme manifestations of depression and mania

Monoamine Hypothesis

decreased 5-HT and/or NE levels cause mood disorders, based largely on the molecular mechanism of action of known antidepressants as well as animal models suggested to correspond to depression or mania

Types of major depressive disorder

• psychotic depression

• manic episode

• hypomanic episode

Psychotic depression

most severe and disabling form of depression

Manic episode

associated with irritable, elevated, or euphoric mood, as well as increased overall activity

associated symptoms often include an inflated sense of self-worth (grandiosity) and distractibility

Hypomanic episode

last for at least 4 days without such an adverse outcome

“little mania”

Monoamine theory of depression

depression results from pathologically decreased 5-HT and/or NE neurotransmission

Based on the monoamine theory of depression, how can depression be treated?

Increasing 5-HT and/or NE neurotransmission could ameliorate or reverse depression

should be treatable by medications

Antidepressants including what molecule shows unexplained delay in their onset of full effect?

reserpine

How long is the unexplained delay in the onset of effect of antidepressants including reserpine?

6 or more weeks

What remains a central conundrum and strong challenge to the monoamine theory?

the unexplained delay in the onset of full effect of antidepressant including reserpine

Each individual responds differently to drugs that selectively increase 5-HT or NE (T/F)

T

Postulated mechanism of the delay in onset of the therapeutic effect of antidepressant medications

• before treatment: neurotransmitters released at pathologically low levels and exert steady-state levels of autoinhibitory feedback

• acute treatment: blocks NE or 5-HT re-uptake transporter, results in increased release of neurotransmitter

• long-term treatment:

All antidepressant drugs increase the concentration of norepinephrine or serotonin in the synaptic cleft. (T/F)

T

Serotonin is involved in physiologic processes

• multiple (centrally and peripherally)

5 major classes of antidepressants

1. Serotonin reuptake inhibitor

2. ?

3. Tricyclic

4. Monoamine oxidase inhibitors

5. Seroton

Inhibitors of Serotonin Storage

• amphetamine, methamphetamine, methylphenidate, lisdexamfetamine

  • substantial abuse potential

• displace 5-HT, NE, and DA from storage vesicles

• treat atypical depression and elderly depression, narcolepsy, and obstructive sleep apnea

• adverse effects: increased peripheral NE increases HR and BP, induce tremors

Lisdexamfetamine

• inhibitor of serotonin storage

• prodrug

• converted to dextroamphetamine

• less abuse potential than other amphetamines

• widely used for ADHD

Inhibitors of Serotonin Degradation (MAOI)

• inhibit MAO

• block the deamination of monoamines by binding to and inhibiting the FAD cofactor of MAO

• increase 5-HT and NE available in cytoplasm of presynaptic neurons

• classified into MAO-A AND MAO-B, reversibility or irreversibility of binding

Irreversible MAOI

iproniazid, phenelzine, isocarboxazid

first-generation, not recommended bc of covalent binding

MAO-A selective MAOI, reversible

moclobemide, befloxatone, brofaromine

MAO-B selective MAOI

Selegiline

also inhibits MAO-A at higher doses

Classes of reuptake inhibitors

• nonselective tricyclic antidepressants (TCAs)

• Selective serotonin re-uptake inhibitors (SSRIs)

• serotonin-norepinephrine re-uptake inhibitors (SNRIs)

• newer norepinephrine-selective re-uptake inhibitors (NRIs)

Serotonergic tone is maintained at a steady state by

the balance between transmitter release and reuptake

Inhibitors of the serotonin reuptake transporter decreases the reuptake rate, resulting in

a net INCREASE in the concentration of 5-HT in the extracellular space

Tricyclic Antidepressants

• Imipramine, Amipriptyline, Clomiparmine, Desipramine, Nortriptyline

• inhibit reuptake of 5-HT and NE from synaptic cleft by blocking 5-HT and NE reuptake transporters, thereby enhancing postsynaptic responses

• potent muscarinic cholinergic antagonists, weak Alpha1 and H1 antagonists

  • account for side effects

• adverse effects: involve cardiovascular system, mania in patients with BD

TCAS with secondary amines preferentially affect..

NE

TCAs with tertiary amines primarily affect..

5-HT

Tetracyclic antidepressants tend to be selective for

NE

ex. maprotiline

Selective Serotonin Reuptake Inhibitors

• SSRI

• Fluoxetine (Prozac), Fluvaxamine, Paroxetine, Sertraline, Citalopram, Escitalopram

• selectively inhibit re-uptake of serotonin and thereby increase synaptic serotonin levels

• increase 5-HT receptor activation and enhance postsynaptic responses

• at high doses, binds to NE transporters

• treat: depression, anxiety, OCD, PTSD, pain syndromes

• adverse effects: serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, rapid fluctuation in mental status and vital signs), mania in Bipolar patients, sexual dysfunction (lower libido/delay orgasm), GI distress

Serotonin-Norepinephrine Reuptake Inhibitors

• SNRIs

• Duloxetine, Venlafaxine, Desvenlafaxine, Milnacipran

• blocks 5-HT re-uptake transporter and NE re-uptake transporter in a concentration dependent manner

• treats: depression, anxiety, pain disorder, agoraphobia, fibromyalgia

• adverse effects: neuroleptic malignant syndrome, hepatitis, mania/depression, blurred vision, nervousness, sexual dysfunction, tachycardia, serotonin syndrome, suicidal thoughts

Norepinephrine Reuptake Inhibitors

• NRIs

• Reboxetine, Atomexetine, Maprotiline

• selectively block NE uptake transporters leading to increased NE levels

• treats: ADHD

• adverse effects: Cardiovascular system, liver injury, seizure, psychotic disorder, suicidal thoughts, weight loss, GI discomfort, headache insomnia, xerostomia, urinary retention, dysmenorrhea

All antidepressant drugs, including MAOIs, are hydro. and do/do not cross the blood-brain barrier

1. Phobic

2. do

Reserpine…

• induce depression in humans and animal models

• blocks VMAT-mediated uptake of monoamines into synaptic vesicles, which ultimately destroys the vesicles

Serotonin Receptor Agonist

• Buspirone (5-HT1A selective agonist, treats anxiety), Sumatriptan, Rizaztriptan, Almotriptan, Frovatriptan, Eletriptan, Zolmitriptan, Ergotamine

• treats: migraine headaches

• adverse effects: myocardial ischemia or infarction, stroke, dizziness, confusion, headache, excitement, blurred vision, hostile feelings/behavior, nervousness, hypertensive crisis, chest pains, flushing, nausea

Serotonin Receptor Antagonist

• drugs have varying degrees of receptor subtype selectivity and often cross-react with adrenergic, histamine, and muscarinic receptors

• Ketanserin, Ondansetron

• treat EXCESS serotonin

  • glaucoma, hypertension, nausea, IBS

• adverse: IBS due to GI motility disorder

Mood stabilizers for bipolar disorder

• Carbamazepine

• Valproic acid

• Lithium

Carbamazepine

• inhibits electrical neurotransmission by use of dependent block of neuronal voltage gated sodium channels

• treat bipolar

Valproic acid

• inhibits low-threshold T-type calcium channels

• treats bipolar

Lithium

• standard BD treatment

• blocks phosphatidylinositol signaling cascade in brain

• low therapeutic index

  • must have low dose

• frequency and severity of adverse reactions directly related to serum levels

• no specific mechanism of action:

  • enters via NA channels, inhibits inositol phosphatase; increase 5-HT neurotransmission by increasing transmitter synthesis and release; decrease NE and DA neurotransmission; adenylyl cyclase decoupling G-proteins from receptor; altering electrochemical gradients across cell membranes by substituting for Na and/or blocking K channels

Atypical antidepressants

• Bupropion

• Mirtazapine

• Nefazodone

• Trazodone

• treat: depression, smoking cessation, insomnia

Bupropion

• atypical antidepressants

• aminoketone that weakly inhibits neuronal uptake of 5-HT, DA, and NE

• used for treatment of smoking cessation