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Home , Levomilnacipran

10/4/2019

Case Studies in the Clinical Use of COLLEGE OF PHARMACY in Ambulatory Care Setting

Ali J. Olyaei, PharmD, BCPS Professor of Medicine & Pharmacotherapy Nephrology & Hypertension Oregon State University and Oregon Health & Science University

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Neurotransmitter Effects

Cerebral cortex

Sensory input Information integration Motor output cognition, thought, mood, emotion

acetylcholine histamine

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Do Not commit to memory Sedation Anti- Serotonin Norepinephrine Dopamine muscarinic Drug +++ +++ +++ ++ 0 ++ ++ + ++ + 0 0 +, 0 +, 0 ? 0 0 +++ 0 0 +++ ++ +++ +++ 0 + + 0 +++ 0 +++ +++ ++ + 0 - 0,+ +++ 0,+ 0,+ 0 0 +++ 0 0 ++ ++ +++ ++ 0 ++ ++ 0 +++ 0 +++ 0 0 +++ 0 ++ +++ +, 0 0 0 ++ ++ +++ ++ 0 + ++ +++ 0 0 0 ++ ? +++ ? + 0 +++ 0 0 +++ 0 ++ 0 0 0 0 +++ ++ 0, +

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Available Antidepressants

• Serotonin Selective Reuptake Inhibitors (SSRIs): – Fluoxetine, Fluvoxamine, Sertraline, Paroxetine, Citalopram

• Dual Serotonin and Norepinephrine (SNRI) Venlafaxine ,

• Serotonin‐2 Antogonist and Reuptake Inhibitors (SARIs) Nefazodone, Trazodone

• Norepinephrine and Dopamine Reuptake Inhibitor (NDRI) Bupropion

• and Tetracyclics (TCA) Imipramine, Doxepin, Desipramine, Amitriptyline , Nortriptyline

• Noradrenergic and Specific Serotonergic Mirtazapine

. Others; MOA‐I, stimulants, Atypical , others [next lectures]

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The purpose of antidepressants is the increase the [neurotransmitters] in the synapse

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Treatment options

• All antidepressants equally effective in a population – Response varies from person to person • What to consider when choosing an agent – Side effects – Drug interactions – Past history of pt response or family response • All antidepressants have black box warning – Increased risk of suicidal ideation in children, adolescents, and young adults <24yo • Failure to respond to 1 class or 1 drug in a class does not predict failed response to another drug class or another drug within the class

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N=nearly 100,000 patients, N=372 clinical studies and 11 different antidepressants

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Risk of Suicide

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Selective Serotonin Reuptake Inhibitors (SSRI)

– Fewer anticholinergic and cardiovascular adverse effects than TCAs – Not usually associated with significant weight gain – Common adverse effects generally mild, short lived • , , diarrhea • Sexual dysfunction • Headache •

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Selective Serotonin Reuptake Inhibitors (SSRI)

• Increase brain serotonin levels • First line agents – fluoxetine – citalopram – sertraline – paroxetine – – Fluvoxamine

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Withdrawal

• Serotonin discontinuation syndrome – F = flu‐like symptoms – I = insomnia – N = nausea – I = imbalance – S = sensory disturbances – H = hyperarousal • Typically start 24 to 72 hours after the last antidepressant dose (peaking at 1 week).

• Typically resolve within 1 to 3 weeks.

• Severe and disabling withdrawal syndrome seen 5% of patients.

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Fluoxetine (Prozac)

• Pros – Long half‐life so decreased incidence of discontinuation syndromes. Good for pts with medication noncompliance issues – Initially activating so may provide increased energy

• Cons – Long half life and active metabolite may build up (e.g. not a good choice in patients with hepatic illness) – Significant P450 interactions so this may not be a good choice in pts already on a number of meds – Initial activation may increase anxiety and insomnia – More likely to induce mania than some of the other SSRIs

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Paroxetine (Paxil)

• Pros – Short half life with no active metabolite means no build‐up (which is good if hypomania develops) – Sedating properties (dose at night) offers good initial relief from anxiety and insomnia • Cons – Significant CYP2D6 inhibition – Sedating, wt gain, more anticholinergic effects – Most likely to cause a discontinuation syndrome

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Sertraline (Zoloft)

• Pros – Very weak P450 interactions (only slight CYP2D6) – Short half life with lower build‐up of metabolites – Less sedating when compared to paroxetine – A great agent for older patients • Cons – Increased number of GI adverse drug reactions

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Citalopram (Celexa) and Escitalopram (Lexpro) • Pros – Low overall inhibition of P450 so fewest drug‐drug interactions of the SSRIs – Drug’s intermediate half life leads to low incidence of discontinuation syndrome – Escitalopram less ADRs • Cons: – Can be sedating (has mild antagonism at H1 histamine receptor) – GI side effects (less than sertraline??) – QT prolongation

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Norepinephrine/Serotonin reuptake inhibitors

• Venlafaxine/Duloxetine • Increase levels of norepinephrine/serotonin • Recent studies show no benefit vs SSRI • Same side effects as SSRI + hypertension risk • Inhibit both serotonin and noradrenergic reuptake like the TCAS but without the , antiadrenergic or anticholinergic side effects

• Used for depression, anxiety and possibly neuropathic pain

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Venlafaxine/

• Pros – Minimal drug interactions and almost no P450 activity – Short half life and fast renal clearance avoids build‐up (good for geriatric populations??) – Desvenlafxine a good choice in patients with disease • Cons – Can cause a 10‐15 mmHG dose dependent increase in diastolic BP. – May cause significant nausea, primarily with immediate‐release (IR) tabs – Can cause a bad discontinuation syndrome, and taper recommended after 2 weeks of administration – QT prolongation – Sexual side effects in >30%

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Duloxetine (Cymbalta)

• Pros – Some data to suggest efficacy for the physical symptoms of depression – Thus far less BP increase as compared to venlafaxine, • Cons – CYP2D6 and CYP1A2 inhibitor

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Buproprion (Wellbutrin)

• Pros – Good for use as an augmenting agent – Mechanism of action likely reuptake inhibition of dopamine and norepinephrine – No weight gain, sexual side effects, sedation or cardiac interactions – Low induction of mania – Is a second line ADHD agent so consider if patient has a co‐occurring diagnosis • Cons – May increase seizure risk at high doses (450mg+) and should avoid in patients with Traumatic Brain Injury, bulimia and anorexia. – Does not treat anxiety unlike many other antidepressants and can actually cause anxiety, agitation and insomnia – Has abuse potential because can induce psychotic sx at high doses [poor man’s ]

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SSRI—Key Differences

• Least likely to cause drug interacons → citalopram, escitalopram

• Least likely to cause withdrawal symptoms → fluoxetine

• Most likely to cause withdrawal symptoms → paroxetine and Venlafaxine

• Most likely to cause QTC prolongation → citalopram

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Mirtazapine (Remeron)

• Pros – Different mechanism of action may provide a good augmentation strategy to SSRIs. It is a 5HT2 and 5HT3 receptor antagonist – Can be utilized as a hypnotic at lower doses secondary to antihistaminic effects – CA patients: weight gain • Cons – Increases serum cholesterol by 20% in 15% of patients and triglycerides in 6% of patients – Very sedating at lower doses. At doses 30mg and above it can become activating and require change of administration time to the morning. – Associated with weight gain (particularly at doses below 45mg)

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Newer anti‐depressants

• Levomilnacipran: – Levomilnacipran is unique because it is more of an NSRI, than an SNRI: That is, the drug’s uptake inhibition of norepinephrine is more potent than its serotonin inhibition – Suitable for the treating functional impairment in depression • : – The drug increases serotonin in synapses through a strong dual action: • blocking serotonin reuptake through the • partial agonism of the 5‐HT1A presynaptic receptor [dopamine and NE] – Suitable for patients who have depression and a comorbid anxiety disorder • – Serotonin modulator and stimulator – vortioxetine is helpful for depressed patients who have cognitive deficits, especially geriatric patients. – Significant GI ADRs – Low incidence of sexual dysfunction

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Esketamine nasal spray. • is a Schedule III nasal spray which is a non‐competitive N‐methyl D‐aspartate (NMDA) receptor antagonist indicated for use in conjunction with oral antidepressants for the treatment of TRD in adults.

• Patient must be enrolled in the esketamine REMs to receive treatment. • Provider must supervise administration, post‐administration monitoring and provide patient education about potential serious outcomes associated with sedation and dissociation. • Patients must be observed as least 2 hours administration for resolution of dissociation effects and sedation. • should also be monitored for transient blood pressure increases lasting around 4 hours. • $$$$ $4,720 to $6,785

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Brexanolone

• Is a GABA A receptor positive modulator (similar to progesterone, which is reduced after pregnancy) indicated for the treatment of moderate to severe PPD • Administration: IV Administer as a continuous infusion over 60 hours

• Patients treated with brexanolone are at risk of excessive sedation or sudden loss of consciousness during administration. Because of the risk of serious harm, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring.

• CONs: • $$$$ [The long administration time, as well as the cost of US$34,000]

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A 34‐year‐old male patient who was prescribed citalopram for depression has decided he wants to stop taking the drug. When questioned, he said that it was affecting his sexual performance. You ascertain that he is also trying to overcome his dependency on tobacco products. If you decide to reinstitute drug therapy in this patient, the best choice would be (A) Amitriptyline (B) Bupropion (C) Fluoxetine (D) Imipramine (E) Venlafaxine

An appropriate length of time to assess the efficacy of sertraline 150 mg daily in the treatment of PTSD is which of the following? A. 1 week B. 3 weeks C. 6 weeks D. 24 weeks

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Herbal Treatment

• St. John’s Wort – Rated A – Same AE profile as SSRIs – High number of drug‐drug interactions • – Rated C – GI Upset – Interactions with many antidepressants/triptans – Renal – Caution in epilepsy

• S‐adenosyl‐L‐methionine (SAM‐e) – Rated C – GI Upset – Possibly Lowers Blood Glucose

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Alternative Treatments

• Electroconvulsive Therapy (ECT) – Recommended for: • No response to medications • Psychotic or catatonic features • Previous response to ECT • Light Therapy – UV light

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Antidepressants Costs

Drug Average Dose Average Cost* Comment Brintellix (vortioxetine) 20mg QD $253 Brand only Bupropion XL 150mg BID $28 Citalopram 20mg QD $5 LCA, $ Cymbalta (duloxetine) 30mg QD $39 Brand only Escitalopram 10mg QD $12 Fetzima (levomilnacipran) 40mg QD $201 Brand only Fluoxetine 20mg QD $5 LCA Fluvoxamine 100mg BID $14 Mirtazapine 30mg QD $13 Paroxetine 20mg QD $9 LCA, $ Pristiq (desvenlafaxine) 100mg QD $157 Brand only Sertraline 100mg QD $9 LCA Venlafaxine XR 150mg QD $17 Viibryd (vilazodone) 40mg QD $176 Brand only *GoodRx.com price comparison; LCA=low cost alternative; $=Walmart $4/$10 generic 31

Conclusions

• Depression is an underreported treatable disease state • Pharmacologic treatment should be chosen based on adverse effects and patient response

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Nightmare and Night Sweat suppression

– Alpha blockers (prazosin) • Doses from 1‐15mg at bedtime, start with 2‐5mg, then titrate upward based on response and tolerability • Recent research with prazosin doses up to 20mg total

– Atypicals (/seroquel, , zyprexa) • Used for sedation and nightmare suppression, do not help suppress nightsweats.

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SGA or “Atypical Antipsychotics”

Asenapine (Saphris) Clozapine (Clozaril) (Zyprexa) Quetiapine (Seroquel) Iloperidone (Fanapt) (Latuda) Paliperidone (Invega) Risperidone (Risperdal) (Geodon) (Abilify) (Rexulti) Cariprazine (Vraylar)

From: Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications, 4th Edn

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Do Not commit to memory Effects from Receptor Blockade Receptor Therpeutic Effect ADRs

EPS, Prolactinemia, D2 reduced positive Sx Cognative def.

D2 PA reduced positive Sx Low risk of EPS

D3 Reduced Positive/Negative/Antidepressants Unknown

5HT1A Antidepressant; Anxiolytic Unknown

5HT2A Reduced EPS; Reduced hyperprolactinemia cardiometabolic

5HT2C Antidepressant cardiometabolic

Reduced, circadian rhythm, dysfunction; Reduced 5HT7 Unknown negative symptoms; Pro cognitive

Sedation and alpha‐1 Reduced nightmares hypotension M1 Reduced EPS cardiometabolic

M3 Reduced EPS cardiometabolic cardiometabolic/sedatio H1 Hypnotic n 35

Conclusions

• Depression is an underreported treatable disease state • Pharmacologic treatment should be chosen based on adverse effects and patient response

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A 45‐year‐old woman comes to the physician because of shivering, sweating, and low‐grade fever. She was recently discharged from hospital. On exam, she is found to be tachycardic, exhibiting sudden contractions of various muscle groups, and has 4+ deep tendon reflexes. She has a history of depression and chronic pain for which she takes sertraline and . According to the discharge paperwork she was given for her pain. Which one of the following is the most appropriate pharmacotherapy? A. Bromocriptine B. Cyproheptadine C. Dantrolene D. Diazepam E. Metoprolol

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• A 21‐year‐old man with a history of hearing voices is brought to the emergency department by his family. Over the past 3 months, the voices have been telling him to kill himself because he has a demon in him. He does not have depression or manic episodes. A diagnosis of schizophrenia is made and he is started on . Two weeks after initiation of therapy, his temperature is 41°C (105.8°F), blood pressure is 150/85 mmHg, and pulse is 110/min. Physical examination shows muscular rigidity, agitation, delirium and normal reflexes. Which of the following is the most likely diagnosis? A. Acute dystonia B. Malignant hyperthermia C. Meningitis D. Neuroleptic malignant syndrome E. Serotonin syndrome

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FYI

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