Week 6 Antidepressants PDF

ANTIDEPRESSANTS AND BENZODIAZEPINES Dr. Adam NMT150 Gratton MSc ND February 13 and 16, 2023 LECTURE COMPETENCIES Describe the mechanism of action of SSRIs, SNRIs, and benzodiazepines within the context of anxiety and depression Describe the adverse effects associated with SSRIs, SNRIs...

ANTIDEPRESSANTS AND BENZODIAZEPINES Dr. Adam NMT150 Gratton MSc ND February 13 and 16, 2023 LECTURE COMPETENCIES Describe the mechanism of action of SSRIs, SNRIs, and benzodiazepines within the context of anxiety and depression Describe the adverse effects associated with SSRIs, SNRIs, and benzodiazepines Describe antidepressant discontinuation syndrome and how to avoid it Describe serotonin syndrome INTRODUCTION Anxiety disorders are among the most common psychiatric illnesses with a lifetime prevalence of around 31% Anxiety disorders are frequently underdiagnosed and remain untreated in about 40% of diagnosed patients Major depressive disorder has a lifetime prevalent of 10% and accounts for over 5% of population illness-related productivity loss THE MONOAMINE HYPOTHESIS An incomplete theory attempting to describe the mechanisms of anxiety and depression and the mechanism by which antidepressants work Reverse engineering of the effects seen with treating patients with psychosis in the 1940s and 50s States that mood disorders result from abnormalities in serotonin, norepinephrine, and/or dopamine neurotransmission THE MONOAMINE HYPOTHESIS Several limitations Antidepressants only work in about 50 – 70% of people It takes several weeks before antidepressant effects are realized Changes to neurotransmitter levels occur with the first dose REUPTAKE INHIBITORS Tricyclic antidepressants (TCA) Selective serotonin reuptake inhibitors (SSRI) Serotonin and Norepinephrine reuptake inhibitors (SNRI) TRICYCLIC ANTIDEPRESSANTS Older class of reuptake inhibitors All TCAs block neuronal reuptake of norepinephrine and serotonin Increases the time neurotransmitters are present in the synapse and enhances neurotransmission TRICYCLIC ANTIDEPRESSANTS Rather non-specific for the serotonergic and noradrenergic neurons they target Affects more neuronal targets than necessary Cross reacts with cardiac adrenoreceptors Causes anticholinergic effects IMIPRAMINE Indicated for agoraphobia, generalized anxiety disorder, and panic disorder IMIPRAMINE CNS Adverse Effects Drowsiness, psychomotor impairment, agitation (especially when first started), headache, myoclonus, seizure IMIPRAMINE Anticholinergic adverse effects Dry mouth, constipation, blurred vision, urinary retention, cognitive impairment IMIPRAMINE Cardiovascular adverse effects Orthostatic hypotension, palpitations, dizziness, tachycardia, arrhythmias, QTc interval prolongation Also can cause increased appetite, weight gain, and sexual dysfunction IMIPRAMINE All TCAs are metabolized by the liver so caution must be used with drugs that can alter their metabolism Inhibitor of CYP2D6 and CYP2C19 Increased risk of additive adverse effects with concurrent use of other anticholinergic drugs or CNS depressants (like alcohol) IMIPRAMINE Contraindicated in patients with suicidal ideation Use with caution in patients with existing cardiovascular disease, cognitive impairment, or history of seizure Considered a second-line agent for anxiety and depression  IMIPRAMINE For anxiety disorders For major depressive disorder Initial dose: 25 mg/day PO Initial dose: 25 – 50 mg/day PO Target: 50 – 150 mg/day PO Usual: 75 – 200 mg/day PO High: 250 – 300 mg/day PO SSRI AND SNRI Considered first-line agents for anxiety and depression Significant research to determine which ones are best for each condition We’re going to focus on one from each class ESCITALOPRAM SSRI Considered one of the top antidepressants for both generalized anxiety disorder and major depressive disorder Also indicated for agoraphobia, panic disorder and social anxiety disorder ESCITALOPRAM CNS adverse effects Anxiety, agitation, insomnia, headache, extrapyramidal effects GI adverse effects Nausea, vomiting, diarrhea, constipation, increased risk of upper GI bleeding ESCITALOPRAM Other adverse effects Dry mouth, increased sweating, sexual dysfunction, and may prolong QTc interval Less potential to interact with other drugs compared to other SSRIs due to low CYP enzyme inhibition  ESCITALOPRAM For anxiety disorders For major depressive disorder Initial dose: 5 mg/day PO Initial dose: 10 mg/day PO Target: 10 – 20 mg/day PO Usual: 10 – 20 mg/day PO Max: 20 mg/day PO High: 20 mg/day PO Max 10 mg/day for those 65 years of age and older VENLAFAXINE SNRI Considered one of the top antidepressants for both generalized anxiety disorder and major depressive disorder Also indicated for social anxiety disorder VENLAFAXINE Adverse effect profile is very similar to that of escitalopram Metabolized by CYP3A4 and 2D6 It is recommended to monitor blood pressure and heart rate weekly during the first month of therapy and when increasing doses  VENLAFAXINE For anxiety disorders For major depressive disorder Initial dose: 37.5 mg/day PO Initial dose: 37.5 – 75 mg/day PO Target: 75 - 300 mg/day PO Usual: 112.5 – 225 mg/day PO High: 300 - 375 mg/day PO SEROTONIN SYNDROME Range from mild symptoms to life-threatening Symptoms usually begin within 24 hours of an increased dose of a serotonergic agent, the addition of another serotonergic agent, or overdosing. Usually a combination of altered mental status, neuromuscular abnormalities, and autonomic hyperactivity SEROTONIN SYNDROME Mild cases Mild hypertension and tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, and hyperreflexia SEROTONIN SYNDROME Moderate symptoms (in addition to mild symptoms) Hyperthermia (40°C), hyperactive bowel sounds, horizontal ocular clonus, mild agitation, hypervigilance, and pressured speech SEROTONIN SYNDROME Severe cases (in addition to all previous symptoms) More severe hyperthermia, dramatic swings in pulse rate and blood pressure, delirium, and muscle rigidity. May also result in seizures, renal failure, acute respiratory distress syndrome, respiratory failure, coma, and death. Hyperreflexia, rigidity and clonus tends to be more prominent in the lower extremities ANTIDEPRESSANT DISCONTINUATION SYNDROME Occurs with rapid discontinuation or dose reduction Any antidepressant taken for 6 weeks or more may be associated with discontinuation-related symptoms Greatest risk is with shorter half-life drugs (venlafaxine is one of them) ANTIDEPRESSANT DISCONTINUATION SYNDROME Symptoms include: Anxiety, crying, headache, increased dreaming, insomnia, irritability, myoclonus, nausea, electric shocks, tremor, flulike symptoms, imbalance, and sensory disturbances Not considered serious or life-threatening but can be significantly troublesome to the patient ANTIDEPRESSANT DISCONTINUATION SYNDROME Occurs within 1 – 7 days of stopping the drug If untreated, symptoms typically last between 3 days and 3 weeks, but may occasionally persist for several months Gradual tapering by approximately 25% per week may prevent or reduce the severity Slower tapering may be needed in some individuals ANTIDEPRESSANT DISCONTINUATION SYNDROME The syndrome can be reversed by restarting the antidepressant and tapering more slowly BENZODIAZEPINES Act as positive allosteric modulators of GABA-A receptors GABA-A receptors are found in high concentrations in the cortex and limbic system GABA is inhibitory and reduces the excitability of neurons BENZODIAZEPINES When bound to GABA-A receptors the flow of chloride ions through the channel is enhanced in the presence of GABA Enhanced inhibitory neurotransmission BENZODIAZEPINE RECEPTOR The allosteric binding site has been classified into several types Of note are BZ1 and BZ2 BZ1 BZ1 is highly concentrated in the cortex, thalamus, and cerebellum and is responsible for the sedative effects and anterograde amnesia adverse effects Amnesia is a common adverse effect and the risk is higher in those benzodiazepines with higher lipid solubility Higher lipid solubility allows or faster absorption and faster onset of action BZ2 BZ2 are highly concentrated in the limbic system, motor neurons, and dorsal horn of the spinal cord The anxiolytic effects and muscle relaxant properties are thought to stem from BZ2 interaction The different affinities for these two receptors account for the different effects of the various benzodiazepines BENZODIAZEPINES Classified by their elimination half-life Short acting – 1 – 12 hours Intermediate acting – 12 – 40 hours Long acting – 40 – 250 hours Generally, five half-lives are necessary for a drug to be eliminated from the body BENZODIAZEPINES Can also be classified by potency Lower potency options usually have fewer adverse effects Higher potency options usually have a faster onset of action but increase the risk of adverse effects BENZODIAZEPINES Some are considered second-line agents for generalized anxiety disorder None are indicated for major depressive disorder CLONAZEPAM Also indicated for agoraphobia, panic disorder, and social anxiety disorder A high-potency long-acting benzodiazepine Half-life: 18 – 50 hours Onset of action: 20 – 60 minutes Peak concentration: 1 – 4 hours Duration: 6 – 8 hours CLONAZEPAM Lower lipid solubility than others so less likely to cause anterograde amnesia Long half-life reduces the risk of rebound anxiety CLONAZEPAM CNS adverse effects: Drowsiness, psychomotor impairment, fatigue, muscle weakness, reduced concentration, confusion, dysarthria, and ataxia. In rare instances, can cause paradoxical agitation and retrograde amnesia CLONAZEPAM Tolerance to drowsiness develops with chronic use Risk of addiction Increased risk of additive adverse effects and respiratory depression with concurrent use of other CNS depressants (like alcohol) Elderly are more likely to experience psychomotor and cognitive impairments which increases the risk for falling CLONAZEPAM Initial dose: 0.25 – 0.5 mg BID PO Target: 1 – 2 mg daily PO SAMPLE QUESTION Which of the following drugs enhances inhibitory GABAergic neurotransmission? A. Escitalopram B. Clonazepam C. Venlafaxine D. Imipramine SAMPLE QUESTION A patient complaining of increased dreaming, electric shocks, and flulike symptoms after cutting their pills in half to make them last longer may be experiencing which of the following? A. Antidepressant discontinuation syndrome B. Benzodiazepine withdrawal C. Serotonin syndrome D. Typical adverse effects of antidepressant therapy