Antidepressants.docx

Learning Objectives By the end of this lecture, learners should be able to: Describe a hypothesized pathophysiology of depression Understand the rationale for progression of drug development for depression Recognize class versus specific medication side effects Select a medication based on patient c...

Learning Objectives By the end of this lecture, learners should be able to: Describe a hypothesized pathophysiology of depression Understand the rationale for progression of drug development for depression Recognize class versus specific medication side effects Select a medication based on patient comorbidities Patient Interview Overview: Medication Selection Past medication history  What did they do well on in the past?  What didn’t they do well on in the past? Family history  Family member treated successfully with psychiatric medications? Risk Factors/Comorbidities  Diabetes  Hyperlipidemia Social history  Is the patient compliant with taking medication and follow up visits?  What can the patient afford? Patient specific factors  Patient-susceptible side effects Sedation Insomnia Nutritional status Sexual activity  Other psychiatric illnesses Etiology of Depression Monoamine hypothesis: decrease in brain monoamine neurotransmitters Norepinephrine (NE) Serotonin (5HT) Dopamine (DA) Pharmacotherapy Antidepressants increase neurotransmitters in the synapse  NE  5HT  DA Classes of antidepressants  Monoamine Oxidase Inhibitors (MAOIs)  Tricyclic Antidepressants (TCAs)  Selective Serotonin Reuptake Inhibitors (SSRIs)  Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)  Miscellaneous   Nefazodone Trazodone Ketamine Goals of Treatment Reduce the symptoms Trial 4 – 8 weeks Response defined as 50% symptom reduction Up to 30% of patients do not respond Minimize side effects Facilitate return to baseline level of functioning MAOIs First effective medications Tranylcypromine (Parnate) Phenelzine (Nardil) Isocarboxazid (Marplan) Enzyme monoamine oxidase catalyzes deamination of monoamines MAO-A: 5HT, NE, DA, epinephrine, tyramine MAO-B: DA, tyramine Monoamine oxidase inhibitors prevent degradation of monoamines Irreversible and non-specific inhibition Increases NE, 5HT, and DA Not commonly used due to hypertensive crisis Increased blood pressure; SBP >30mmHg Nausea, vomiting Diaphoresis 43 Headaches “Cheese Crisis” Fish Sauerkraut Meat extract Yeast Beer Wine Drug Interactions: Monoamines Stimulants Decongestants (pseudoephedrine) Sympathomimetic agents Antidepressants Buspirone Cocaine 2 – 5 week washout period Tricyclic Antidepressants (TCA) Block 5HT and NE transporters to increase synaptic concentrations Used commonly in past before SSRIs Imipramine, nortriptyline, amitriptyline, desipramine, No difference in efficacy between TCAs and SSRIs TCAs more side effects Overdoses are potentially lethal Na channel and L-type calcium channel inhibition 12,000 cases of overdose in the US in 2004 Ten times total daily dose can be fatal SSRIs Advanced safety of treatment of depression 234 fluoxetine overdoses (up to 1500mg) = no fatalities 50% patients that overdose are completely asymptomatic Used to treat Depression Anxiety disorders Obsessive-compulsive disorder Eating disorders More expensive than TCAs; limited use previously All SSRIs are equally effective Mechanism of Action Block the reuptake of 5HT at the 5-HT reuptake transporter Highly lipophilic Increase 5HT in the brain Low affinity for other receptors Better tolerated than previous classes Delayed onset: 4 – 6 week trial SSRIs Comparison Table Name Initial Dose (mg) Usual Dosage (mg/d) Advantages Disadvantages Fluoxetine (Prozac) 10-20 mg 40-80 Half life 2 - 5 days ER once weekly formulation Activating Clinically significant drug interactions: potent CYP2D6 & 1A2 inhibitors Sertraline (Zoloft) 25-50 100-200 - Minimal drug interactions - Takes longer to titrate to an effective dose Citalopram (Celexa) 10-20 20-40 - Minimal drug interactions QT prolongation >40mg 20mg max if >60 years Escitalopram (Lexapro) 5-10 10-20 S-isomer of citalopram Starting dose is target dose Minimal drug interactions Fluvoxamine (Luvox) 25-50 200-300 - Most CYP drug interactions (6 CYP enzymes) Paroxetine (Paxil, Paxil CR) 10-20 mg 40-60 mg - CR form increases tolerability Sedating Half life 15 – 22 hours Potent CYP2D6 inhibitor Vilazodone SSRI + 5HT partial agonism Strong 3A4 drug interactions Must take with fatty food; fasted state ↓50% No clinical advantage over other SSRIs May decrease sexual side effects and weight gain Increased N/V/D  May improve with time?  Slow titration Vortioxetine Mechanism of action  5-HT3, 5-HT1D, and 5-HT7 antagonist (GI?)  5-HT1A agonist (CNS)  5-HT1B partial agonist (CNS) Goal: less sexual dysfunction Dose-related N/V/D Half life ~ 66 hours Discontinuation Syndrome Not life threatening Flu like symptoms Malaise Nausea Headache Occur 2 – 7 days after stopping medication Half life of most SSRIs 24 – 36 hours Exceptions: fluoxetine, paroxetine Rule of thumb: decrease by ~25% per week Serotonin Syndrome Due to 5HT overstimulation IS life threatening Symptoms Elevated body temperature Agitation Increased reflexes Tremor Sweating Dilated pupils Seizure Muscle breakdown Serotonin Syndrome: Causative Medications SSRI SNRI Bupropion TCA MAOI LSD, Ecstasy, cocaine Herbal supplements Metoclopramide Ondansetron Linezolid Serotonin Syndrome: Treatment Supportive care: Oxygen and fluids Control agitation with benzodiazepines Q 8 – 10 min PRN Treat hypotension with epinephrine or norepinephrine No utility in Tylenol Antidote: cyproheptadine  Histamine 1 receptor antagonist with 5HT antagonism  12mg loading dose; 2mg Q2hr until clinical response  Oral only; may be crushed SNRIs MOA is similar to SSRIs  Block reuptake of both 5HT and NE  ↑ 1 – 4 bpm with NE reuptake blockade Available SNRIs  Venlafaxine (Effexor, Effexor XR)  Desvenlafaxine (Pristiq)  Duloxetine (Cymbalta) No head to head trials, equally efficacious Must taper off, similar to SSRIs Also used for treatment of neuropathic pain Duloxetine Strong CYP2D6 inhibitor Neuropathic pain > Depression Most norepinephrine reuptake inhibition Hepatotoxicity Half life ~ 12 hours Venlafaxine & Desvenlafaxine Venlafaxine Weak 2D6 inhibitor; 2D6 substrate SSRI at lower doses SNRI at high doses 150 – 225mg Diastolic BP 5 – 7mmHg; some patients >20mmHg Desvenlafaxine $$ 50mg desvenlafaxine = 100mg venlafaxine(?) Miscellaneous – Just know that these exist Trazodone (Desyrel)  Mixed 5HT receptor activity  Used more commonly for insomnia  Adverse effects Sedation Orthostatic hypotension Priapism Nefazodone (Serzone)  Mixed 5HT receptor activity  Rarely used  Hepatotoxicity Mirtazapine (Remeron)  Mechanism of action  α2 antagonist  Histamine antagonist  Increases NE & 5HT neurotransmission Very sedating; ≥30mg may overcome this effect  Low doses = histamine > norepinephrine  High doses = norepinephrine > histamine Stimulates appetite; used for weight gain Can be used to augment SSRI/SNRI Limited sexual side effects https://proceedings.med.ucla.edu/wp-content/uploads/2016/11/Dose- Bupropion (Wellbutrin) NE and DA reuptake inhibitor (NDRI) 2D6 inhibitor No sexual side effects Very activating; insomnia Lowers seizure threshold  Do not use with seizure disorder  Do not use with bulimia or anorexia Also used for smoking cessation (Zyban®) Antidepressants and suicidality Black box warning for increased risk of suicidality Worsening depression Activation (anxiety, agitation, suicide ideation) Is this new? Or is this a progression of the disease? What does the data show? Fails to show clear relationship between use and risk of suicide in adults Children and adolescents may have increased risk of ideation and attempts No increase in completed attempts Patients should be followed for worsening depression or suicidality May induce manic episodes in bipolar disorder Nischal A, Tripathi A, Nischal A, Trivedi JK. Suicide and antidepressants: what current evidence indicates. Mens What’s the best antidepressant? Meta-analysis of 117 randomized trials (mean duration 8 weeks)  Compared 12 second-generation antidepressants in nearly 26,000 patients with unipolar major depression.  Concluded that escitalopram and sertraline showed the best efficacy and tolerability based on: Response (reduction of baseline symptoms ≥50 percent) Discontinuation of treatment for any reason was less probable Meta-analysis of 93 randomized trials evaluated 13 antidepressants:  Concluded that there were no substantial differences in efficacy and discontinuation rates  Most of differences in the first study were not replicated in the second study  No clinically relevant differences Prescribing strategy based on patient factors 64 Anxiety Types:  Generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, and acute stress Focus for today: general anxiety disorder (GAD) Pathophysiology Deficiency in neurotransmitters: DA, GABA, 5HT, NE Disruption of amygdala processing of fear and anxiety Overreaction to anxiety-inducing stimuli Amygdala projects to prompt NE release First Line: SSRI, SNRI Anxiolytic effect onset 2-4 weeks, may take up to 6-8 weeks for full effects Generally dosing is the same as in depression See previous slides TCA can also be used; avoid due to side effects Other Agents: Benzodiazepines Mechanism of action: Agonist of GABA-A Inhibitory neurotransmitter in central nervous system  Sedative  Hypnotic  Anxiolytic  Multiple uses Not preferred as monotherapy  Bridge therapy with SSRI/SNRI  Use as needed FYI: other uses  Usually first line for active seizures, not maintenance.  Alcohol withdrawal https://en.wikipedia.org/wiki/GABAA_r 68 eceptor#Target_for_benzodiazepines Oral Benzodiazepines for Anxiety y 69 * Adverse effects of benzodiazepines CNS effects:  Sedation  Psychomotor impairment  Cognitive dysfunction Respiratory depression Concerns:  Dependence: potential for abuse.  Withdrawal: need to taper slowly when used for a prolonged period of time. S/Sx: anxiety, dysphoria, tremor, psychosis, and seizures Benzodiazepine Withdrawal Life-threatening withdrawal seizures Increased withdrawal with short half life drugs Consider switch to long half life benzodiazepine Taper will be patient dependent Reduce by 5 – 10% each 1 – 2 weeks May slow once 50% original dose reached Other Agents: Buspirone (Buspar) Mechanism of action:  Unknown Agonist for presynaptic serotonin receptors Partial agonist of postsynaptic serotonin receptors Mild D2 antagonism Slow onset and modest efficacy  Effect seen in about 4 weeks; higher doses ~30mg/day  Multiple times a day dosing  Better S/E profile than benzodiazepines Cognitive/motor impairment, restlessness Lacks tolerance, dependence, and withdrawal Monotherapy or augmentation