Neuropsychopharmacology Introduction PDF - Fall 2023

An#depressants-1; Intro PCOL825A/Fall 2023 Adam’s Song 4:13 blink-182 MV 1 1 Neuropsychopharmacology-Introduction ! The next five lectures will be concerned with the drugs used to treat neuropsychiatric disorders; which will include: • the antipsychotics; e.g. drugs used to treat psychoses, whi...

An#depressants-1; Intro PCOL825A/Fall 2023 Adam’s Song 4:13 blink-182 MV 1 1 Neuropsychopharmacology-Introduction ! The next five lectures will be concerned with the drugs used to treat neuropsychiatric disorders; which will include: • the antipsychotics; e.g. drugs used to treat psychoses, which includes schizophrenia, but also includes dementias • the antidepresssants; e.g. drugs used to treat depressed mood or “affect” which primarily includes major depressive disorder • drugs used to treat bipolar disorders (manic-depressive) ! The impact of these disorders is huge both in terms of their shear numbers and the emotional and financial impact: I • The life time incidence of schizophrenia is ~1%; another 2-3% have “schizotypal” symptoms Effect you • The life time incidence of depressive disorders is 10-20% • The life time incidence of bipolar disorders is ~1% 2 2 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 Antidepressants-1; Intro PCOL825A/Fall 2023 Neuropsychopharmacology-Introduction ! It is important to understand that neuropsychiatric disorders are NO DIFFERENT from other medical disorders; like heart or kidney disease, diabetes, or infections, etc. ! Although many individuals and some cultural groups think otherwise. ! Common public perceptions related to depression: • the patient is to blame: “character flaw,” mental or emotional “weakness,” or by their actions and behavior, etc. • others are to blame: bad parenting, bad partner in a relationship, bad job, etc. • depression can be “willed” away ! Less common perceptions as to the causes of depression: • there is a biological basis to depression • it can be effectively treated 3 3 Neuropsychopharmacology-Introduction ! You might think that these drugs would be prescribed exclusively by psychiatrists: but you would be wrong ! ~⅔ are prescribed by non-psychiatrists for a variety of conditions: • aggression/behavioral issues associated with dementias; Alzheimer’s, Huntingtons’s, Parkinson’s, etc. • aggression/behavioral issues associated with brain injury; strokes, tumors, etc. • aggression/behavioral issues associated with autism • mania associated with bipolar disorder • sleep disorders • pain disorders; fibromyalgia, chronic pain • “random” uses: emesis, intractable hickups, premature ejaculation 4 4 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Antidepressants-1; Intro PCOL825A/Fall 2023 Mood Disorders-Introduction ! Antidepressants are primarily used for the treatment of “affective” disorders involving depressed mood ! “Affect” derives from “affectus” meaning state of mind/body/emotion • euthymia: good-stable mood (eu = well; thymo = soul or emotion) • depression: blunted or decreased mood; unhappy, sad, loss of interest.. • hypomania: highly elevated mood, but less than mania • mania: extremely elevated; often irritable, possibly psychotic 5 5 Major Depressive Disorder ! A pathological depression of mood involving the presence of five or more of the following criteria for more than two weeks • decreased appetite or weight loss • decreased concentration • decreased interest in pleasurable activities • dysphoria: sad, unhappy, anxious/uneasy/irritable, pessimistic, hopeless • excessive self-blame, guilt, low self-worth • excessive fatigue, decreased energy • sleep disturbances • thoughts of death, suicidal ideation or attempts ! Life time risk, 10-20%, with ~5% of the population affected at any give time ! Significant morbidity and mortality; risk of suicide ~3% (300 x general population) ! 2nd leading cause of death in ages 15-24; 11th cause of death overall 6 6 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Antidepressants-1; Intro PCOL825A/Fall 2023 Bipolar Disorder (Manic-Depressive) ! A combination of a pathological elevation of mood followed by depression (or vice versa) occurring in a cyclical manner with the following characteristics • hypomania: highly elevated mood or energy • mania: extremely elevated mood, occasionally transitioning to psychosis • increased talkativeness, “pressure of speech”, flight of ideas • irritable mood, easily annoyed, anger, aggressive behavior • exaggerated confidence; increased risk taking (gambling, sexual, business schemes) • decreased fatigue, decreased sleep • SYMPTOMS OF MAJOR DEPRESSIVE DISORDER ! Life time risk, ~1% with risk of suicide ~5% ! Incidence similar in males and females ! Evidence of genetic component 7 7 “Primary” vs “Secondary” Depression Vince Foster Bri Matthews ! A “primary” depression occurs independently of any other medical diagnosis or life circumstances, which is usually the case with MDD • in this regard it is “insidious” in that it is difficult for the patient or others around them to “attribute” their depression to an obvious “cause” • but the same is also true of other diseases, like cancer: “why me?” ! A “secondary” depression occurs in the context of another medical diagnosis, but does not compel a “cause and effect” relationship • psychiatric; eg schizophrenia, obsessive-compulsive disorder, anxiety disorder • organic; eg metabolic (hypoglycemia), endocrine (hypothyroid), trauma, cancer • substance use disorder; eg alcohol, stimulants (cocaine, amphetamine), reserpine 8 8 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 Antidepressants-1; Intro PCOL825A/Fall 2023 Underlying Pathology of Depression ! A disorder of “monoamine neurotransmission” • norepinephrine (NE) • dopamine (DA) • serotonin (5HT) 9 9 Underlying Pathology of Depression ! A disorder of “monoamine neurotransmission” • norepinephrine (NE) • dopamine (DA) • serotonin (5HT) ! Virtually all presently available drugs for the treatment of depression facilitate some aspect of monoamine metabolism • inhibitors of monoamine oxidase (MAOIs) • tricyclic antidepressants (TCAs) • selective serotonin reuptake inhibitors (SSRIs) ! Furthermore, other classes of drugs that affect monoamine metabolism have been shown to influence mood • cocaine blocks dopamine reuptake and enhances mood • reserpine depletes monoamines and causes depression 10 10 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Antidepressants-1; Intro PCOL825A/Fall 2023 Guide to Figures postsynaptic neuron presynaptic neuron Primary Synapse 11 11 presynaptic neuron Guide to Figures Secondary Synapse postsynaptic neuron 12 12 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Antidepressants-1; Intro PCOL825A/Fall 2023 Guide to Figures NOTE: the pre-synaptic neuron is either serotonergic, noradrenergic, or dopaminergic: it does not release multiple neurotransmitters monoamine neurotransmitters: vesicles 5-HT (serotonin) NE (norepinephrine) DA (dopamine) MAO post-synaptic receptors serotonergic noradrenergic dopaminergic reuptake transporters SET (serotonin) NET (norepinephrine) DAT (dopamine) 13 13 Guide inhibitory presynaptic HETERO-receptors to Figures monoamine neurotransmitters Activation will depend upon the activity of the secondary presynaptic neuron post-synaptic receptors reuptake transporters inhibitory presynaptic AUTO-receptors Activation will depend upon the activity of the primary presynaptic neuron 14 14 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 Antidepressants-1; Intro PCOL825A/Fall 2023 Monoamine Oxidase Inhibitors (MAOIs) inactive metabolites liver MAO tyramine intestine ! The original antidepressants ! First discovered in 1952 when antidepressant effects were noted in depressed patients being treated for tuberculosis with iproniazid ! Subsequently it was discovered that iproniazid inhibited the enzyme, monoamine oxidase, thereby increasing monoamines (5-HT, NE, DA) ! In 1968 two forms were discovered: MAO-A and MAO-B • • MAO-A is particularly important in the liver where it metabolizes dietary sympathomimetic amines (esp tyramine) both are widely distributed and have overlapping substrate specificities 15 15 Monoamine Oxidase Inhibitors (MAOIs) ! 1st generation agents were irreversible and nonselective • phenelzine (Nardil®) • • tranylcypromine (Parnate®) isocarboxazid (Marplan®) ! Although efficacious and very successful in the 1950’s to 60’s, they were supplanted by TCAs and then the SSRIs (largely because of their risk of causing hypertensive crisis) ! 2nd generation agents that are more selective have been re-introduced • • • moclobemide; reversible (MAO-A > MAO-B); approved for Parkinson’s Disease selegiline (Emsam®); irreversible (MAO-B > MAO-A); transdermal patch for approved for MDD (also, Deprenyl® for Parkinson’s Disease) rasagiline; irreversible (MAO-B > MAO-A); approved for Parkinson’s Disease 16 16 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 An#depressants-1; Intro PCOL825A/Fall 2023 Monoamine Oxidase Inhibitors (MAOI) increased synaptic release of 5-HT, NE, DA MAO X 5-HT receptor activation dopamine receptor activation inhibition of MAO (in all neurons) adrenergic receptor activation 17 17 Tricyclic Antidepressants (TCAs) ! The TCAs came into prominence in the 1960s, largely replacing the MAOIs until the introduction of fluoxetine and the SSRIs ! Chemically related to the phenothiazine antipsychotics, they share many of the same interactions with various neurotransmitter receptors (alpha-1, histamine, muscarinic, serotonin, K+ channels, etc.) imipramine tricyclic an-depressant chlorpromazine phenothiazine antipsychotic 18 18 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 Antidepressants-1; Intro PCOL825A/Fall 2023 Tricyclic Antidepressants (TCAs) ! The TCAs came into prominence in the 1960s, largely replacing the MAOIs until the introduction of fluoxetine and the SSRIs ! Chemically related to the phenothiazine antipsychotics, they share many of the same interactions with various neurotransmitter receptors (alpha-1, histamine, muscarinic, serotonin, K+ channels, etc.) ! Their clinical efficacy arises from the inhibition of SERT and NET ! 8 TCAs are presently available in the U.S., which include: • imipramine (Tofranil® 1957) • amitriptyline (Elavil® 1961) • desipramine (Norpramin® 1963) • nortriptyline (Pamelor® 1963) • trimipramine (Surmontil® 1966) • doxepine (Sinequan® 1969) • clomipramine (Anafranil® 1989) • amoxapine (Asendin® 1992) 19 19 Tricyclic Antidepressants (TCAs) secondary amines: NE > 5-HT >> DA tertiary amines: NE ≥ 5-HT >> DA 5-HT reuptake inhibition (on serotonin neurons) X 5-HT receptor activation no significant DA receptor activation adrenergic receptor activation X NE reuptake inhibition (on NE neurons) 20 20 JW Regan/Department Pharmacology & Toxicology/The University of Arizona College of Pharmacy 10 Antidepressants-2 PCOL825A/Fall 2023 Paint it Black 4:01 live Rolling Stones Ready Steady Go! M ay 27 1966 1 1 Tricyclic Antidepressants (TCAs) ! The TCAs came into prominence in the 1960s, largely replacing the MAOIs until the introduction of fluoxetine and the SSRIs ! Chemically related to the phenothiazine antipsychotics, they share many of the same interactions with various neurotransmitter receptors (alpha-1, histamine, muscarinic, serotonin, K+ channels, etc.) firstantipsychotic imipramine tricyclic antidepressant chlorpromazine phenothiazine antipsychotic 2 2 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 1 Antidepressants-2 PCOL825A/Fall 2023 Tricyclic Antidepressants (TCAs) ! The TCAs came into prominence in the 1960s, largely replacing the MAOIs until the introduction of fluoxetine and the SSRIs ! Chemically related to the phenothiazine antipsychotics, they share many of the same interactions with various neurotransmitter receptors (alpha-1, histamine, muscarinic, serotonin, K+ channels, etc.) ! Their clinical efficacy arises from the inhibition of SERT and NET ! 9 TCAs are presently available in the U.S., which include: • imipramine (Tofranil® 1957) • amitriptyline (Elavil® 1961) • desipramine (Norpramin® 1963) • nortriptyline (Pamelor® 1963) • trimipramine (Surmontil® 1966) • protriptyline (Vivactil® 1966) • doxepine (Sinequan ® 1969) • clomipramine (Anafranil® 1989) • amoxapine (Asendin® 1992) 3 3 Tricyclic Antidepressants (TCAs) secondary amines: NE > 5-HT >> DA tertiary amines: NE ≥ 5-HT >> DA 5-HT reuptake inhibition (on serotonin neurons) X 5-HT receptor activation no significant DA receptor activation adrenergic receptor activation X NE reuptake inhibition (on NE neurons) 4 4 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Antidepressants-2 PCOL825A/Fall 2023 Tricyclic Antidepressants-Adverse side effects Na+ channel blockade (cardiac arrhythmias) X X X a1 adrenergic receptor antagonist (hypotension) muscarinic receptor antagonist (anti-cholinergic) narrowangle X glaucoma histamine-H1 receptor antagonist (sedation, weight gain) X K+ channel blockade-QT prolongation (cardiac arrhythmias) 5 5 Fluoxetine (Prozac®): the First of the “Selective Serotonin Reuptake Inhibitors (SSRI) and a “Game Changer” ! Developed by Eli Lilly & Company in the early 1970’s. ! By this time it was understood that the TCAs produced their antidepressant effects through the inhibition of serotonin (5-HT) and norepinephrine reuptake. ! David Wong hypothesized that selective inhibition of 5-HT reuptake might yield a better antidepressant with fewer “off target” effects. ! Starting with a compound closely related to diphenhydramine, ! They discovered fluoxetine. diphenhydramine anti-histamine (H1) fluoxetine SSRI anti-depressant devolped 6 from antihis 6 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Antidepressants-2 PCOL825A/Fall 2023 Fluoxetine (Prozac®): the First of the “Selective Serotonin Reuptake Inhibitors (SSRI) and a “Game Changer” ! FDA approved for MDD in 1987 • • a “block-buster” drug projected to make ~$175M by 1990 (3 years after approval) • it actually reached ~$350M by 1989 (2 years after approval) • by 1991 (4 years after approval) it reached ~$1,000M (a billion $$/year!!!) • essentially by creating its own market ! Has since been FDA approved for Know these in just case • obsessive compulsive disorder (OCD) • bulimia nervosa • panic disorder • • premenstrual dysphoric disorder (Sarafem®) childhood depression and OCD • separation anxiety in dogs and cats (Reconcile®) • aggression in cats, “bully cats” (Reconcile®) 7 7 Fluoxetine (Prozac®): the First of the “Selective Serotonin Reuptake Inhibitors (SSRI) and a “Game Changer” ! The success of fluoxetine was followed by the development of: • • sertraline (Zoloft®, 1991) paroxetine (Paxil®, 1992) • fluvoxamine (Luvox®, 1994) • citalopram (Celexa®, 1998) • escitalopram (Lexapro®, 2002) (the (s)-stereoisomer of citalopram) ! Side Effects of fluoxetine and SSRIs generally include: • nausea, vomiting (5HT3 activation) • insomnia (5HT2A activation) • sexual dysfunction (5HT2A activation) • • anxiety (5HT2A activation) appetite suppression (5HT2C activation) • suicidal ideation, increased risk of suicide Black Box Warning • serotonin syndrome 8 8 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 Antidepressants-2 PCOL825A/Fall 2023 Some Concerns About the Black Box Warning ! Since the FDA issued its Black Box Warning in 2004 on the use of antidepressants in adolescents... • There has been a decrease diagnosis and treatment of childhood depression • There has been an overall decrease in the use of antidepressants by all age groups (with no corresponding increase in other treatments) • And there has been a decrease in the diagnoses of MDD • And most concerning, there is some evidence of an increase in teen suicide, which had been down trending prior to 2004 9 9 Selective Serotonin Reuptake Inhibitors (SSRI) 5-HT reuptake inhibition 5-HT2A activation-sexual dysfunction 5-HT2C activation-anorexia serotonergic neuron Whathappens if you 5-HT3 activation-nausea, vomiting, GI X 5-HT1A activation-improved mood activate 5H Taareceptor activationleadstosexual 5-HT2A dysfunction 5-HT2C 5-HT3 5-HT receptor activation 5-HT1A 10 10 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Antidepressants-2 PCOL825A/Fall 2023 Serotonin Syndrome ! Drugs that either increase serotonin (e.g. SSRIs), or that have serotonergic activity (e.g., trazodone), can induce the “serotonin syndrome” especially if they are combined. ! Such drugs include most antidepressants, especially monoamine oxidase inhibitors and SSRIs, as well as drugs such as sibutramine, tramadol, meperidine, dextromethorphan, amphetamines and ecstasy. ! Symptoms include a variety of cognitive, autonomic and somatic effects; such as headache, mental confusion, mania, hypertension, fever, tachycardia, GI symptoms, muscle twitching, tremor and hyperreflexia. lifethreathing ! Treatment is mostly supportive; discontinuation of implicated drugs; use of the antagonist cyproheptadine; use of dantrolene to control rigidity and fever if present. block ca release 11 in muscle 11 Trazodone and Nefazodone (SARIs) ! Trazodone (Desyrel®) was actually the first of the “2nd generation antidepressants” (before SSRIs, but after MAOIs and TCAs) ! FDA approved for the treatment of MDD in 1981; trazodone also has extensive off-label use as a sedative ! Nefazodone (Serzone®) which is chemically and pharmacologically related, was approved in 1994 ! Both produce m-CPP (m-chlorophenylpiperazine), an active metabolite and serotonergic agonist ! Adverse effects include: • • • postural hypotension (alpha-1 antagonism) weight gain/sedation (histamine H1 antagonism) anorexia (5-HT2C activation via 5-HT and m-CPP) • • • nausea/vomiting (5-HT3 activation via 5-HT and m-CPP) minimal sexual dysfunction (5-HT2A antagonism) minimal anticholinergic (lack of muscarinic receptor antagonism) 12 12 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 6 Antidepressants-2 PCOL825A/Fall 2023 s ADRsexualside TraziatiS Trazodone and Nafazodone (SARI) weak 5-HT reuptake inhibitor 5-HT2A receptor antagonist serotonergic neuron X (less sexual adverse effects) X 5-HT2A 5-HT2C 5-HT3 5-HT receptor activation 5-HT1A m-CPP, active metabolite and serotonergic agonist 13 13 Bupropion (NDRI) ! Bupropion produces its antidepressant actions through inhibition of the dopamine and norepinephrine transporters. (Wellbutrin®) ! It was first approved for the treatment of MDD in 1986 and has since been approved for smoking cessation (as Zyban®) and is present in Contrave®, a weight loss drug containing bupropion and naltrexone, and it is in Auvelity®, along with dextromethorphan, as an antidepressant. ! Other properties: • increased risk of seizures, which lead to its withdrawal from 1986-1989; risk of seizures is dose-dependent, ranging from ~ 0.5-5% • • may cause anorexia can worsen psychotic symptoms (increased dopamine) • • less anticholinergic, hypotensive and cardiotoxic effects than TCAs minimal adverse effects on sexual function (no activation of 5-HT2A) • less nausea/vomiting than SSRIs (no activation of 5-HT3) 14 14 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 Antidepressants-2 PCOL825A/Fall 2023 Bupropion (NDRI) DA reuptake inhibition (on DA neurons) X dopamine receptor activation 5-HT receptors, no effect adrenergic receptor activation X NE reuptake inhibition (on NE neurons) 15 15 Serotonin and Norepinephrine Reuptake Inhibitors (SNRI) ! Venlafaxine (Effexor®), approved for the treatment of MDD in 1994, was the first in this class of antidepressants, which also includes: • desvenlafaxine (Pristiq®) metabolite of venlafaxine; approved 2008 • duloxetine (Cymbalta®) ~100x more potent than venlafaxine; approved 2004 • milnacipran (Savella®) approved in 2009 for fibromyalgia (but not MDD) • levomilnacipran (Fetzima®) l-isomer of milnacipran; approved 2013 ! This group produces their antidepressant actions through inhibition of SERT and NET; similar to the TCAs, but with fewer adverse effects related to blocking other receptors (alpha-1, histamine, muscarinic, serotonin, K+ channels, etc); therefore safer than TCAs ! The effects of venlafaxine are dose-dependent • low dose (<150 mg/day), selective inhibition of SERT • high dose (>150 mg/day), inhibition of SERT and NET 16 16 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 Antidepressants-2 PCOL825A/Fall 2023 Serotonin and Norepinephrine Reuptake Inhibition (SNRI) 5-HT reuptake inhibition (on serotonin neurons) X 5-HT receptor activation DA receptors, no effect adrenergic receptor activation venlafaxine: 5-HT >> NE duloxetine: 5-HT > NE milnacipran: 5-HT ≥ NE X NE reuptake inhibition (on NE neurons) levomilnacipran: NE ≥ 5-HT 17 17 Vilazodone and Vortioxetine (SRIARM) ! Vilazodone (Viibryd®) and vortioxetine (Trintellix®) are two relatively new antidepressants, approved for MDD in 2011 and 2013, respectively, with similar mechanisms of action ! They both produce their antidepressant actions primarily through inhibition of SERT, but they differ from SSRIs by having their own intrinsic activity to activate 5-HT1A receptors (like buspirone) ! Some adverse effects: • • they both produce considerable nausea, vomiting, and diarrhea (>10%) there is concern about an increased risk of pancreatitis with vilazodone 18 18 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 Antidepressants-3 PCOL825A/Fall 2023 Vilazodone and Vortioxetine (SRIARM) 5-HT reuptake inhibition vortioxetine 5-HT3 antagonist serotonergic neuron X vomiting X 5-HT3 nausea 5-HT2A 5-HT2C 5-HT receptor activation 5-HT1A vortioxetine 5-HT1A agonist vilazodone 5-HT1A partial agonist 3 3 Mirtazapine (NASSA) ! Mirtazapine (Remeron®) is uniquely different because its antidepressant activity is generated through blockade of a2-adrenergic receptors rather than through inhibition of monoamine reuptake ! Approved for MDD in 1996 (but often used off-label for insomnia and sometimes for weight-gain and nausea/vomiting) ! Antagonism of inhibitory presynaptic a2-adrenergic receptors • increases the release of NE on adrenergic neurons (auto-receptor effect) • increases the release of 5-HT on serotoninergic neurons (hetero-receptor effect) ! Actions at other receptors include: • strong antagonism of histamine H1 receptors (sedation; weight gain; antihistamine) • • • antagonism of 5-HT3 receptors (antiemetic; less nausea/vomiting) antagonism of 5-HT2A receptors (sedation; less anxiety; less sexual dysfunction) antagonism of 5-HT2C receptors (decreased satiety; increased hunger, weight gain) • minimal antagonism of muscarinic receptors (little anticholinergic effects) 4 4 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 2 Antidepressants-3 PCOL825A/Fall 2023 Mirtazapine (NASSA) a2-adrenergic receptor antagonist (increases release of 5-HT by serotonergic neurons) (increases release NE by adrenergic neurons) X 5-HT2A, 5-HT2C, 5-HT3 receptor antagonist X X X 5-HT2A 5-HT2C 5-HT3 5-HT1A receptor activation adrenergic receptor activation 5 5 Some Other FDA-Approved Drugs with Antidepressant Activity Gepirone (Exxua®), 5HT1A Receptor Agonist Ketamine and Esketamine, NMDA Receptor Antagonists Dextromethorphan + Buproprion (Auvelity®) Brexanolone and Zuranolone, Neuroactive Steroids PAMs of GABAA Receptors 6 6 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 3 Antidepressants-3 PCOL825A/Fall 2023 Gepirone (Exxua®) ! Gepirone is unique as an antidepressant in that it is a selective partial agonist (PA) for the serotonin 5HT1A receptor and its metabolite, 1-pyrimidinylpiperazine (1-PP) is an a2-adrenergic (a2-AR) receptor antagonist. ! Chemically, it is closely related to buspirone, which is also a partial agonist of the 5HT1A receptor that is approved for the treatment of anxiety. ! Approved this year (2023) for MDD. ! In principle • has the advantages of SSRI’s without the adverse effects • plus, antidepressant effect is augmented by pre-synaptic a2-AR antagonism ! But…. 1-pyrimidinyl piperazine buspirone gepirone 7 7 Gepirone (Exxua®) But…. ! There are serious questions about its efficacy in the treatment of MDD • It failed to get FDA approval in 2004, 2007, and 2015 because lack of evidence for effectiveness. ! There are serious questions about QT prolongation • Package insert notes that any electrolyte abnormalities need to be corrected and that an electrocardiogram (ECG) should be taken before starting treatment. ! High incidence of adverse effects include • dizziness, 49% • nausea, 35% • headache, 31% 8 8 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 4 Antidepressants-3 PCOL825A/Fall 2023 Gepirone, 5-HT1A Partial Agonist gepirone metabolite 1-PP, a2-AR receptor antagonist (increases release of 5-HT by serotonergic neurons) (increases release NE by adrenergic neurons) X 5-HT2A less sexual dysfunction 5-HT2C less anorexia 5-HT3 less nausea, vomiting, GI serotonergic neuron 5-HT3 5-HT2A 5-HT2C NO activation of 5-HT2A 5-HT2C 5-HT3 5-HT1A activation-antidepressant effect 5-HT1A partial agonist 9 Ketamine and Esketamine Appear to have Some Antidepressant Activity ! Esketamine (the S(+) enantiomer of ketamine) was first approved in 2013 for the management of treatment-resistant depression (TRD) by iv administration • TRD is defined by the failure of patients to respond adequately to two separate treatments with different antidepressants • Ketamine itself does not have approval for TRD or MDD, although it is used “off-label” ! A nasal spray version of esketamine (Spravato®) was approved in 2019 ! The use of esketamine and ketamine has surged with the approval of Spravato® and the growth of “Ketamine Wellness” clinics 10 10 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 5 Antidepressants-3 PCOL825A/Fall 2023 Ketamine and Esketamine Treatments are Expensive and are Extensively Promoted by the “Ketamine Wellness” Industry ® ! Spravato must be administered “under medical supervision” • cost is in the range of $4,700-$6,800 for the 1st month of treatment • treatment should be in conjunction with another antidepressant ! Ketamine is typically given at “Wellness Centers” by “infusion” (iv) • cost is high (~$500/infusion) and involve multiple infusions • claims of effectiveness are often exaggerated and have extended beyond the treatment of MDD into chronic pain, PTSD, OCD and “hidden affections” Note: Ketamine itself does not have FDA approval for the management of TRD or MDD and its use for these conditions is “off-label” Feb 16, 2022 13 13 The Clinical Trials for the FDA Approval of Esketamine were Very Marginal ! Esketamine failed to show clinically significant effectiveness (compared to placebo) in two of the three trials conducted for efficacy. ! Normally for approval of a potential antidepressant the applicant must provide evidence of efficacy from at least two clinical trials. ! However, since the FDA designated esketamine as a “breakthrough therapy*” they could change the normal requirements for approval. • Thus they allowed a “randomized drug withdrawal” trial that was significant to be used as evidence of efficacy, even though it was not designed an efficacy trial. ! The interpretation of the trials was confounded by two significant factors. • Ketamine produces marked sedation and dissociation, so even through the trials were “double-blinded” most patients knew if they were getting the “active” drug. • Both placebo and esketamine-treated groups were given an additional oral antidepressant as part of the study design, making it essentially impossible to attribute a positive response solely to the esketamine treatment. *A drug that holds promise for substantial improvement of existing therapies, hopefully to provide relief for an unmet medical need. 14 14 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 7 Antidepressants-3 PCOL825A/Fall 2023 Causes for Concern Regarding the Use of Ketamine and Esketamine Effectiveness, Safety and Abuse Potential ! The improvement in depression symptoms with esketamine was only a 6% better than placebo in the one clinical trial that was significant. ! Six patients died, including three by suicide, in the esketamine-treatment group. ! No patients died in the placebo group. ! Marked increases in blood pressure were observed in the esketamine treatment group that were not observed in the placebo group. • There have since been enough post-marketing reports of hypertensive crisis in patients receiving Spravato® that the FDA is “considering the need” for regulatory action ! Ketamine is a well known drug of abuse, taken for its dissociative (out-of-body) and hallucinogenic effects. The Problem with Approving Drugs Like Esketamine • vulnerable population • desperate.. there is an unmet need • but approving ineffective drugs is harmful • does not remedy the unmet need • creates a false hope • wastes time and money that could have been spent on more effective treatments 15 15 Mechanism of Action: Ketamine and Esketamine Act on a Glutamate Pathway and not the Monoamine Pathway ! Ketamine and esketamine “deviate” from the “monoamine hypothesis of depression” in that their primary pharmacological effects are on the excitatory neurotransmitter, glutamate, and its receptors • this does not preclude effects on monoaminergic pathways, however, such effects would be indirect ! Ketamine and esketamine are antagonists of the NMDA receptor, one of the three subtypes of glutamate receptors • the other two subtypes are the AMPA and kainate receptors 16 16 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 8 Antidepressants-3 PCOL825A/Fall 2023 Mechanism of Action: Ketamine and Esketamine Act on a Glutamate Pathway and not the Monoamine Pathway has good anesthetic effect ! At sub-anesthetic doses*, ketamine and esketamine antagonize a presynaptic NMDA receptor on GABAergic inhibitory interneurons • this decreases the release of GABA and increases glutamate release by the post-synaptic neuron • increased glutamate release increases activation of downstream AMPA receptors and increases BDNF release, which has an antidepressant effect • BDNF, or Brain-Derived Neurotrophic Factor, has many actions including promoting neuronal survival and the growth and differentiation of neurons and is believed to contribute to an antidepressant effect !At anesthetic doses, the predominant effects of ketamine and esketamine are antagonism of postsynaptic NMDA receptors to decrease neuronal excitation, causing anesthesia without depression of respiration and blood pressure (can increase BP) *Occasionally referred to as “micro-dosing.” 17 17 GABAergic Inhibitory Interneuron Ketamine/Esketamine GABA NMDA receptor X NMDA receptor antagonist !NMDA receptor activation increases the release of GABA !blocking the NMDA receptor decreases the release of GABA GABA GABAA receptor Glutamatergic Neuron less GABA = less activation of GABAA receptors = less presynaptic inhibition = more release of glutamate = more AMPA receptor activation AMPA receptor (a glutamate receptor subtype) FYI Only you will NOT be responsible for knowing this BDNF* = more BDNF release = anti-depressant effect *Brain-Derived Neurotrophic Factor 18 18 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 9 Antidepressants-3 PCOL825A/Fall 2023 Dextromethorphan + Bupropion (Auvelity®) ! Auvelity® is a new drug combination product that was FDA-approved for the treatment of MDD in 2022. ! It claims to be “first in class” with dextromethorphan (DXM) acting as an NMDA antagonist to produce its antidepressant effects. ! It also states that bupropion is present for the purpose of inhibiting CYP 2D6 to prolong the actions of DXM, which is also a substrate for 2D6. ! It claims to have a rapid onset of action. ! All these claims are essentially for marketing purposes and there is very little evidence to support any of them. bupropion dextromethorphan 19 19 from Auvelity website 20 20 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 10 Antidepressants-3 PCOL825A/Fall 2023 from Auvelity website NMDA receptor Na+/Ca++ K+ dextromethorphan ! In fact, there is NO EVIDENCE from the clinical trials that Auvelity® acts on the NMDA receptor to produce its antidepressant effects, it is pure speculation. ! This speculation is based on literature that shows DXM can interact with the NMDA receptor, but this same literature also shows that the amount of DXM in Auvelity® is unlikely to yield the blood concentrations needed for an interaction. • Reported IC50 values of DXM for NMDA receptors are in the range of 1,000-9,000 nM • Blood concentrations of DXM are much lower, in the range of 50-200 nM • At the very best, only a partial interaction with the DMDA receptor would result 21 21 from Auvelity website ! DXM is a “dirty” drug because it interacts with a number potential targets, most notably the serotonin and norepinephrine transporters (SERT and NET) and the “sigma-1” receptor (s1). DXM blood conc ~100 nM • Reported IC50 values of DXM for SERT are ~30 nM, where it is an antagonist • Reported IC50 values of DXM for NET are ~250 nM, where it is an antagonist ! It is highly likely that DXM inhibits SERT in much the same way as SSRIs. • It is well documented that DXM increases levels of serotonin and is a significant risk factor for serotonin syndrome when co-administered with SSRIs • The adverse sexual dysfunction (6%)** reported in the package insert for Auvelity® is also consistent with the inhibition of SERT. Dextromethorphan Inhibition of SERT and NET **Sexual dysfunction was not reported as an adverse effect in either the Phase-2 or 3 trials conducted by Axsome,22 both of which stated that sexual dysfunction was not observed ! 22 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 11 Antidepressants-3 PCOL825A/Fall 2023 from Auvelity website ! Axsome states in its literature that bupropion is in Auvelity® for the purpose of inhibiting CYP2D6, but it fails to mention that bupropion is an antidepressant in its own right and is present in an amount that exceeds a typical starting starting dose for the treatment of MDD (Auvelity® 210 mg/day; Wellbutrin ® 150 mg/day). ! It is distressing that many of the reviews of Auvelity® repeat this intentionally misleading statement and fail to mention the likelihood that much, if not all, of the antidepressant effect of Auvelity® comes from bupropion and not DXM. • A combination of DXM and quinidine for the treatment of MDD was dropped by Otsuka Pharma for lack of efficacy • Quinidine an inhibitor of CYP2D6, lacking antidepressant activity, was used in Otsuka’s product for the same reason that bupropion is supposedly being used in Auvelity® • Obviously, the combination of DXM and quinidine should have had yielded similar efficacy as Auvelity® given that both quinidine and bupropion strongly inhibit CYP2D6 23 23 from Auvelity website ! A big marketing claim for Auvelity® is that it is the “first and only rapid-acting oral medicine approved for the treatment of MDD.” ! This is simply not true and Axsome’s own studies show it. • The earliest time points in Axsome’s clinical trials is 1-week after initiation of therapy • These results from their Phase-2 trial show a “rapid” antidepressant effect at 1-week for BOTH Auvelity® and bupropion, with no statistical difference between them Bupropion Auvelity Phase-2 Trial 42% of final response Auvelity ® 41% of final response WEEK 24 24 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 12 Antidepressants-3 PCOL825A/Fall 2023 Antidepressants -- Time Before Onset of Action -- The Myth ! It is commonly accepted that the onset of the antidepressant effects of “traditional” antidepressants (MAOIs, TCAs, SSRIs, SNRIs, etc) is on the order of 2-3 weeks and that a full therapeutic response takes as long as 12 weeks. ! This is a myth and there is abundant evidence showing that antidepressants produce significant antidepressant effects in their first week of use. Fig 12.4 Lippincott’s Illustrated Review of Pharmacology, 3rd ed. 25 25 Auvelity’s Onset of Antidepressant Activity is Similar to Other Antidepressants ! The marketing for Auvelity® claims that it is “rapidly acting” in the same way that ketamine is “rapidly acting” (within hours) because DXM, like ketamine, is an NMDA receptor antagonist. ! However, the clinical trials for Auvelity® did not actually examine if its antidepressant effect was a consequence of antagonism of the NMDA receptor. ! Furthermore, the earliest time point in both the Phase-2 and Phase-3 trials for Auvelity® is one week, there are no earlier time points. ! It this regard Auvelity® does not differ from fluoxetine, which shows significant antidepressant effects in the first week of treatment. Auvelity Phase-3 Trial Auvelity ® 45% of final response WEEK Antidepressant Score Week P Fluoxetine n = 930 Placebo n = 468 0 25.5 25.5 0.740 1 -5.7 -4.6 0.016 2 -8.1 -6.5 0.003 3 -9.7 -7.4 <0.001 4 -10.5 -8.0 <0.001 5 -11.3 -8.3 <0.001 6 -11.7 -8.3 <0.001 [Ann Gen Hosp Psychiatry 3:2, 2004] 26 26 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 13 Antidepressants-3 PCOL825A/Fall 2023 It is Important to be Critical—Patients Depend Upon YOU to give Them Accurate Information ! You must be exceptionally critical of drug marketing information. • Check their references and especially any footnotes. • LOOK at their data… what does it say?? Don’t let them tell you what it says. • READ the package insert carefully. from Auvelity website footnote †In this study of 609 adults with MDD, both the researchers and patients knew they were taking Vuvelity. (e.g., it was not blinded and is of low quality) This study was not designed to evaluate the long-term effectiveness of Auvelity. (in other words, the above statement is meaningless) Patients were removed from the study after 6 weeks if they did not experience at least a 25% improvement in their depression score. (in other words, this study is rigged) 341 patients were evaluated at Month 9 and 29 were evaluated at month 12. (WTF!! does this really mean that 95% of the patients did NOT complete the study??) 27 27 It is Important to be Critical—Patients Depend Upon YOU to give Them Accurate Information ! Read published reviews carefully. • Is it repeating the same words and conclusions as the marketing information? • Who was it written by? Do the authors work for the company producing the product? Are the authors associated in some way with product, for example through their research or publications? Do the authors have a vested financial interest in the product? “fast-acting” is repeated 5 times in reference to describing Auvelity. “Of note, the use of dextromethorphan-bupropion was not associated with weight gain or increased sexual dysfunction as commonly seen with other agents used in the treatment of MDD.9” (pg 27, column-2, lines 2-6) The reference for this statement is the GEMINI Phase-3 clinical trial, which indeed stated that “Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or increased sexual dysfunction (Table 3). 28 28 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 14 Antidepressants-3 PCOL825A/Fall 2023 It is Important to be Critical—Patients Depend Upon YOU to give Them Accurate Information BUT THIS IS WHAT THE AUVELITY PACKAGE INSERT SAYS Auvelity ® Placebo 29 29 Factors Contributing to the Development of (Auvelity®) ! Novel fixed dose drug combinations of previously FDA approved drugs is driven in part by significant economic incentives to drug manufacturers. • Pre-clinical research and development costs are essentially eliminated • Accelerated regulatory pathway, fewer phase-1, -2, or -3 clinical studies • The potential to obtain new patents on generic drugs, providing market exclusivity ! Having and patent and market exclusivity allows for control of prices. • 1-month supply (30, 150 mg tablets) of generic bupropion is $10-50 • 1-month supply (180, 15 mg tablets) of dextromethorphan is $15-30 • 1-month supply (60 tablets, 45 dex/110 bupr) of Auvelity® is $1,300 ! Factors important for the success of Auvelity®. • • • • Different mechanism of action Rapid onset of antidepressant effect No weight gain No sexual dysfunction 30 30 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 15 Antidepressants-3 PCOL825A/Fall 2023 Dextromethorphan + Bupropion (SNDRIwG) NMDA receptor inhibition??? Dextromethorphan 5-HT reuptake inhibition X X NE reuptake inhibition 5-HT receptor activation adrenergic receptor activation DA receptor activation X Bupropion X NE reuptake inhibition DA reuptake inhibition 31 31 Brexanolone (Zulresso®) and Zuranolone (Zurzuvae®) (neuroactive steroids, GABAA receptor positive allosteric modulator) ! Brexanolone, approved (2019) for the treatment of postpartum depression (PPD). ! Zuranolone just approved (2023) for PPD, but not MDD. ! Incidence of PPD is ~11% in U.S; often undiagnosed and untreated. ! Brexanolone falls under Risk Evaluation & Mitigation Strategy (REMS) and must be administered iv at a certified facility. Zuranolone is oral. ! Although its molecular interactions with GABAA receptors is well documented, it is not clear how this translates to a therapeutic effect. Brexanolone treatment consists of a single continuous IV infusion over SIXTY HOURS!! Zuranolone cost: $15,900 for 14-day treatment!! 32 32 JW Regan/Department of Pharmacology & Toxicology/The University of Arizona College of Pharmacy 16