Antidepressants W13 PDF

REMINDER: NEUROTRANSMISSION AND DRUGS Drugs can be: • Agonists (indirect & direct) • Antagonists (indirect & direct) • Mixed agonist-antagonist • Receptor binding • Noncompetitive binding 1 ANTIDEPRESSANTS PSY3142 AGENDA • Depression • Theories of depression • Pharmacology • Effects • Alterna...

REMINDER: NEUROTRANSMISSION AND DRUGS Drugs can be: • Agonists (indirect & direct) • Antagonists (indirect & direct) • Mixed agonist-antagonist • Receptor binding • Noncompetitive binding 1 ANTIDEPRESSANTS PSY3142 AGENDA • Depression • Theories of depression • Pharmacology • Effects • Alternative treatments 3 DEPRESSION 4 MAJOR DEPRESSIVE DISORDER 5 PREVALENCE 6 Data form Stats Canada, released Sept 2023 THEORIES OF DEPRESSION REMINDER: MONOAMINE PATHWAYS Dopamine neurons are involved in 4 major systems: 1. Tuberinfundibular pathway 2. Nigrostriatal pathway 3. Mesocortical pathway 4. Mesolimbic pathway Reward, motivation, voluntary behaviour Norepinephrine is involved in the noradrenergic system Serotonin is involved in the serotonergic system Attention, sleep/wake, feeding, emotions, fight/flight response Mood, arousal, sleep/wake cycle THEORIES: MONOAMINE THEORY • Three Brain Systems • NE fibers from locus coeruleus • Serotonergic fibers from raphé system – MFB forebrain * • Dopaminergic fibers from VTA • Decreased activity in the serotonin system is involved in depression Depression = • low levels of 5-HT, tryptophan, and 5-H1AA • Decreased numbers 5-HT transporter proteins = fewer serotonin neurons • Decreased binding protein and quantity of 5-HT1A receptors Main challenge: It can take 4-12 weeks for antidepressant medication to achieve it’s full effectiveness and relieve symptoms (and not necessarily in all) THEORIES: GLUCOCORTICOID THEORY • During chronic stress, the HPA axis may become overactive • Timing of stress is important GLUCOCORTICOID THEORY 11 MERGING THEORIES • Stress hormones interact in complex ways with monoamine systems • Chronic stress can have long-lasting consequences on the structure and function of monoamine systems • e.g. changes in the mesolimbic DA system, amydgala • Normalizing the stress response system may be important for effectiveness of antidepressant medications 12 QUICK HISTORY • Classes of antidepressants developed over time • First-generation antidepressants • Monoamine oxidase inhibitors (MAOIs) • Tricyclic antidepressants • Second-generation antidepressants • SSRIs • Third-generation antidepressants • SNRIs 13 FIRST & SECOND GENERATION ANTIDEPRESSANTS Generic Drug Class Name Tricyclic imipramine antidepressant amitriptyline s (TCAs) Drug Class Generic Name Trade Name Monoamine iproniazid oxidase phenelzine inhibitors (MAOIs) tranylcypromine Euphozid Nardil Parnate isocarboxazid Marplan selegiline Eldepryl moclobemide Aurorix Drug Class Trade Name Tofranil Elavil desipramine Norpramin doxepin Sinequan nortriptyline Pamelor clomipramine Anafranil Selective serotonin reuptake inhibitors (SSRIs) Generic Name Trade Name fluoxetine Prozac Citalopram Celexa Escitalopram Lexapro Paroxetine Paxil sertraline Zoloft THIRD-GENERATION ANTIDEPRESSANTS/ATYPICALS Generic Name Trade Name Mechanism of Action venlafaxine Effexor 5-HT and NE reuptake blockade; DA reuptake blockade only at high doses desvenlafaxine Pristiq 5-HT and NE reuptake blockade duloxetine Cymbalta 5-HT, NE, and DA reuptake blockade mirtazapine Remeron NE α2 autoreceptor and 5-HT1A autoreceptor blockade; 5-HT2-3 receptor antagonist; histamine H1 receptor antagonist bupropion Wellbutrin; Zyban DA receptor blockade; partial NE reuptake blockade; Ach nicotninic receptor antagonist PHARMACOLOGY 16 NEUROPHYSIOLOGY First-generation MAOIs • Inhibit MAO = increased Levels of Monoamine (MA) Neurotransmitters TCAs • Block reuptake transporter proteins = prevent Reabsorption of MA = increased levels MA Symptom relief comes weeks after treatment begins and is related to neuroadaptations triggered by antidepressant agents Second- and third-generation SSRIs • Blocks 5-HT reuptake transporter proteins = prevent reabsorption of 5-HT = increased 5-HT SNRIs • Blocks 5-HT, NE, and/or DA reuptake transporter proteins = prevent reabsorption of monoamines = increased 5-HT PRESENTATION TITLE MAOIs Blocks MAO-A, MAOB, or both = increased levels of Monoamine (MA) 18 Neurotransmitters PRESENTATION TITLE TCAs Block reuptake transporter proteins = prevent reabsorption 19 of MA = increased levels MAs SSRIs Blocks 5-HT reuptake transporter proteins = prevent reabsorption of 20 5-HT = increased 5-HT Source: Selective Serotonin Re-Uptake Inhibitors (SSRIs) - Neurot SNRIs Blocks MAO-A, MAO-B, or both = prevent reabsorption of 5-HT = 21 increased 5-HT Source: Serotonin and Noradrenaline Re-Uptake Inhibitors (SNRIs) - Neurotorium ABSORPTION • MAOIs, TCAs, and SSRIs have similar absorption pharmacokinetics • Absorption of SSRIs slower than TCAs (4-8 hrs vs 1-3 hrs) • Generally, have high levels of protein binding • Strong 1st pass metabolism • inhibited by alcohol • =alcohol greatly increases the amount absorbed from a specific dose • TCAs have severe reaction with alcohol • SSRIs have little interaction with alcohol DISTRIBUTION • Cross the blood-brain and placental barriers • Tend to be concentrated in the lungs, kidneys, liver, and brain • Many antidepressants can be found in significant quantities in breast milk EXCRETION Half-Life vary • MAOIs: 2 to 4 hrs • TCAs: 24 hrs • SSRIs: 15-20 • Considerable individual variability in pharmacokinetics of antidepressant EFFECTS AND EFFECTIVENESS OF ANTIDEPRESSANTS 25 TREATING DEPRESSION WITH ANTIDEPRESSANTS • Pharmacotherapy begins with treating with 1 drug • Often SSRIS or newer drugs • Evaluated after a few weeks and dosing adjusted if necessary • Evaluated again after a few weeks and if ineffective, drug may be switched • Evaluated again after a few weeks + dosing adjustments and if ineffective may consider combination of drugs 26 ANTIDEPRESSANT EFFECTIVENESS IN TREATING DEPRESSION APA practice guidelines for treatment of patients with major depressive disorder, 2010 suggest that any one antidepressant or category is fairly comparable in terms of efficacy. • Individual differences in determining the best fit likely related to different representations of symptoms • Comorbid disorders (most commonly anxiety) is a consideration as newer SSRIs and SNRIs are also useful to treat such conditions • Symptom severity is a major predictor of antidepressant effectiveness • 60 – 70% experience some relief; 28 – 50% show full remission • Placebo response rates are as high as 30% = expectation plays a major role in the effectiveness of treatment • For mild – moderate depression, placebos is as effective as antidepressants!!! 28 EFFECTS OF ANTIDEPRESSANTS: BODY • MAOIs: weight gain, dizziness, adverse interactions with other drugs and food • Tyramine: found in aged cheese, pickled herring, beer, wine, and chocolate • Serotonergic Syndrome • Disorientation, agitation, confusion, fever, shivering, and diarrhea • Coma and possible death • TCAs: Anticholinergic Effects • Dry mouth, constipation, dizziness, irregular heartbeat, blurred vision, ringing in ears, and retention of urine • Mild effects of SSRIs: nausea, headache, nervousness, and insomnia EFFECTS OF ANTIDEPRESSANTS: SLEEP ALL ANTIDEPRESSANTS AFFECT SLEEP DRUG DEPENDENT EFFECTS VARY FROM INDUCED SLEEP, DISTURBED REM, OR INSOMNIA HIGH DOSES CAN CAUSE NIGHTMARES EFFECTS ON BEHAVIOUR AND PERFORMANCE Subjective Effects • Feelings of tiredness, apathy, and weakness • High doses: impaired comprehension and confusion • Nausea Effects on Performance • TCAs can have detrimental effects on vigilance tasks and can cause cognitive, memory, and psychomotor impairment Effects on Personality • SSRIs useful in treating personality disorders TOLERANCE NOT SURE IF DEVELOP TOLERANCE TO TREATMENT EFFECTS TOLERANCE TO MANY OF THE SIDE EFFECTS DEVELOPS WITHIN SEVERAL WEEKS • Tolerance to tiredness of SSRIs does not develop 32 WITHDRAWAL • TCAs: Restlessness, anxiety, chills, muscle aches, and akathesia may occur upon sudden discontinuation. • SSRIs: dizziness, light-headedness, insomnia, fatigue, anxiety, nausea, headache, and sensory disturbances • May last up to 3 weeks • SNRIs: heart palpitations, nausea, delusions; can be serious SELF ADMINISTRATION • Neither TCAs nor MAOIs appear to be reinforcing • Some 2nd & 3rd generation antidepressants are used to treat addiction to other drugs • i.e. alcohol and smoking • Compliance • SSRIs best for compliance • Due to low rate of side effects HARMFUL EFFECTS Reproduction • TCAs: sexual functioning in males; difficulty achieving orgasm M & F • MAOIs, SSRIs, SNRIs: delayed ejaculation/loss of interest in sex • Miscarriages Violence and Suicide • Warning label on SSRIs • Children and adolescents are possible at higher risk Overdose • Serotonin syndrome • Tricyclics: drug-related deaths = effects on heart ALTERNATIVE TREATMENTS 36 MANY POSSIBLE ROUTES TO TREATMENT • • • • • • Natural remedies Electroconvulsive therapy (ECT) Deep Brain Stimulation Transcranial Magnetic Stimulation Exercise Therapy AGENDA • Depression • Theories of depression • Pharmacology • Effects • Alternative treatments 38