PHA 6575 Lecture 10

Bipolar Disorder (BD) and Major Depressive Disorder (MDD)

two major mood disorders

Serotonin (5-HT) and Norepinephrine NE)

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

Major Depression

by 2030, _________ will be the leading cause of disease burden

Spinal Cord

serotonergic projections to the ______ modulates pain perception, visceral regulation, and motor control

Forebrain

serotonergic projections to the ________ modulate mood, cognition, and neuroendocrine function

Noradrenergic System

modulates vigilance, stress responses, neuroendocrine function, pain control, and sympathetic nervous system activity

Tyrosine Hydroxylase

rate-limiting step for dopamine synthesis

Tryptophan Hydroxylase

rate-limiting step for 5-HT

True

T/F: both tyrosine and tryptophan hydroxylase enzymes are regulated via inhibitory feedback from autoreceptor-mediated signaling

Auto-Regulatory Loop

explains the time delay for clinical actions of antidepressants

Serotonin Transporter (SERT)

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

Selective Monoamine Reuptake Transporters

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

Selectivity, High Affinity, and Low Capacity

monoamine reuptake transporters are __________, ___________, and _______

False

T/F: SERT, NET, and DAT are only capable of transporting their respective monoamines

Transported into Vesicles or Degraded

once 5-HT is returned to neuronal cytoplasm, it is __________ or ___________

Vesicular Monoamine Transporter (VMAT)

responsible for transporting 5-HT into vesicles after it is returned to neuronal cytoplasm

Monoamine Oxidase

responsible for degradation of 5-HT after it is returned to neuronal cytoplasm

5-HT, NE, and DA

MOA-A oxidizes _______

DA

MOA-B preferentially oxidizes __________

Flavin Adenine Dinucleotide (FAD)

cofactor of MOA used as an electron acceptor

Catechol-O-Methyltransferase (COMT)

enzyme that breaks down catecholamines and important for degradation of monoamines

5-HT3

5-HT receptor subtype that is ligand-gated ion channel receptor

GPCRs

all 5-HT receptors except one are ________

5-HT1B Serotonergic and a2-Adrenergic Receptors

two presynaptic autoreceptors important for feedback inhibition

Major Depressive Disorder (MDD)

characterized by single or recurrent depressive episodes)

Bipolar Disorder (BD)

characterized by presence of mania or hypomania as well as periods of depression

Dysthymia

referred to as persistent depressive disorder

Cyclothymia

less extreme manifestations of depression and mania

Monoamine Hypothesis

a hypothesis that states that depression is caused by a low level of activity of one or more monoaminergic synapses

Psychotic Depression

most severe and disabling forms of depression

Manic Episode

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

Grandiosity and Distractibility

associated symptoms of manic episodes

Hypomanic Episodes

short duration (last for four days) of manic episode

False

T/F: based on the monoamine theory of depression, MDD cannot be treated by medications

Delay of Onset

__________ in antidepressants remains a strong challenge to the monoamine theory

True

T/F: each person responds differently to drugs that selectively increase 5-HT or NE

Desensitization of Presynaptic Autoreceptors

chronic use of antidepressants results in __________, which reduces the inhibition of neurotransmitter synthesis and exocytosis leading to a therapeutic response

Storage

amphetamine, methamphetamine, methylphenidate, and lisdexamfetamine inhibit serotonin ________

Lisdexamfetamine

prodrug that is converted into dextroamphetamine

ADHD

lisdexamfetamine is widely used for ___________ and has less abuse potential than other amphetamine derivatives

MOA

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

Substance Abuse

inhibitors of serotonin storage have high potential for ________

Atypical Depression, Narcolepsy, and Sleep Apnea

disadvantages of using serotonin storage inhibitors

Heart Rate, Blood Pressure, and Tremors

adverse effects of serotonin storage inhibitors on peripheral nervous system

Monoamine Oxidase Inhibitors (MAOIs)

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

Iproniazid, Phenelzine, and Isocarboxazid

irreversible MAOIs

Moclobemide, Befloxatone, and Brofaromine

reversible MAO-A selective inhibitors

Selegiline

MAO-B selective inhibitor at low levels with MAO-A inhibition at high levels

Serotonergic Tone

the balance between transmitter release and reuptake maintains _________

Reuptake Inhibitors

drugs that alleviate the symptoms of a variety of common psychiatric conditions including depression, anxiety, and OCD

Tricyclic Antidepressants (TCAs)

drugs that inhibit the reuptake of 5-HT and NE from the synaptic cleft by blocking reuptake transporters

Secondary Amines

TCAs with _________ preferentially affect the NE system

Tertiary Amines

TCAs with _________ primarily affect the 5-HT system

NE

tetracyclic (maprotiline) antidepressants tend to be more selective for the _______ system

Imipramine, Amitriptyline, Climpramine, Desipramine, and Nortriptyline

examples of TCAs

Muscarinic Cholinergic, a1, and H1

heterocyclic antidepressants are potent _________, weak ________, and weak ________ antagonists

Cardiovascular System and Mania

major adverse effects of TCAs involve the __________ and may precipitate ________ in patients with BD

Selective Serotonin Reuptake Inhibitors (SSRIs)

selectively inhibits serotonin reuptake and results in potentiation of serotonergic neurotransmissions (Luvox, Paxilo, Prozac, Zoloft)

Fluoxetin (Prozac), Fluvoamine, Paroxetine, Sertraline, Citalopram, and Escitalopram

examples of SSRIs

Depression, Anxiety, OCD, PTSD, and Pain Syndromes

SSRIs are used to treat

Serotonin Syndrome

characterized by hyperthermia, muscle rigidity, myoclonus, rapid fluctuation in mental status, and vital signs

Sexual Dysfunction

all SSRIs can cause some degree of _________

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

blocks 5-HT reuptake transporter and NE reuptake transporter in a concentration dependent manner

Duloxetine, Venlaxafine, Desvenlaxafine, and Milnacipran

examples of SNRIs

Neuroleptic Malignant Syndrome, Hepatitis, Blurred Vision, Nervousness, Sexual Dysfunction, Tachycardia, Serotonin Syndrome, and Suicidal Thoughts

adverse effects of SNRIs

Norepinephrine Reuptake Inhibitors (NRIs)

selectively block NE uptake transporters leading to increased NE levels and used to treat ADHD

Reboxetine, Atomoxetine, and Maprotiline

examples of NRIs

TCAs and SNRIs

inhibit both the norepinephrine transporter (NET) and serotonin transporter (SERT)

SSRIs

specifically inhibit the SERT-mediated reuptake of 5-HT

True

T/F: all antidepressant drugs, including MAOIs, are hydrophobic and cross the BBB

Reserpine

can induce depression in humans and animal models, and blocks the VMAT-mediated uptake of monoamines into synaptic vesicles which ultimately destroys the vesicles

Buspirone

5-HT1A selective agonist used for treating anxiety

Sumatriptan

serotonin receptor agonist example

Ketanserin

5-HT2 serotonin receptor antagonist

Ondansetron

5-HT3 serotonin receptor antagonist

Adrenergic, Histamine, and Muscarine

drugs show varying degree of receptor subtype selectivity and often cross-react with __________ receptors

IBS

adverse effect of serotonin receptor antagonists

Carbamazepine

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

Valproic Acid

MOA that inhibits the low-threshold T-type calcium channels

Lithium

MOA that blocks phsophatidylinositol signaling cascade in the brain

Therapeutic Index (TI)

lithium, the standard drug for bipolar disorder, has a low _________ and severity of adverse effects are directly related to the serum levels

Bupropion

aminoketone that weakly inhibits neuroal uptake of 5-HT, DA, and NE and used for treatment of smoking cessation

Mirtazapine

blocks 5-HT2A, 5-HT2C, and a-2 adrenergic autoreceptors and decreases neurotransmission at 5-HT synapses while increasing NE

Nefazodone and Trazodone

block 5-HT2 receptors and are atypical antidepressants