Antidepressants and Bipolar Disorder PDF

Antidepressants “It was inevitable: the scent of bitter almonds always reminded him of the fate of unrequited love.” “Intoxicated with the madness Love in the time of Cholera I'm in love with my sadness” Gabriel Garcia Marques Smas...

Antidepressants “It was inevitable: the scent of bitter almonds always reminded him of the fate of unrequited love.” “Intoxicated with the madness Love in the time of Cholera I'm in love with my sadness” Gabriel Garcia Marques Smashing Pumpkins “I felt a Funeral, in my brain. And Mourners to and fro…” Emily Dickenson  Depression Major depression: point prevalence 5-6% 10% of population will experience depression in lifetime; 10-15% of drugs prescribed. Under diagnosed Vague complaints- sleep problems etc. or described as neurotic could be depressed  Depression Classification Reactive Secondary in response to stimuli, grief, illness, drugs/alcohol--60% of all depressions Endogenous Genetically determined inability to experience ordinary pleasure or cope with ordinary life events—25% of cases, physical changes: sleep, libido, appetite; recurs throughout life Bipolar disorder: Manic depression—10-15% of cases Might be a paradigm shift (up to 50% MDD might be bipolar)  Depression Suicide High percentage of patients display suicidal behavior Major depression: 10-15% Bipolar: 25% Genetic predisposition Major depression 1.5-3 xs Bipolar: much higher Both parents—child has 50-75% chance  Depression Herbal remedies St. John’s wort Fish oil, SAMe, l-tryptophan, saffron, Curcumin/turmeric, DHEA Effectiveness? 2002 St. John’s wort no more effective than placebo for moderate depress (flaw sertraline was also no better than placebo). Other studies—as effective as Paxil/TCAs No regulations so potential for bad side effects and variable potencies and drug interactions  Depression So the herbal remedies may not be efficacious. How about the approved medications? NJM article 1-17-08 “Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy” Erick H. Turner, M.D., Annette M. Matthews, M.D., Eftihia Linardatos, B.S., Robert A. Tell, L.C.S.W., and Robert Rosenthal, Ph.D. Depression Observed and Estimated Change in HDRS Scores Following Treatment With ADM and Placebo Fournier, J. C. et al. JAMA 2010;303:47-53. Copyright restrictions may apply.  Amine hypothesis Found that Reserpine (antihypertensive) can induce depression Inhibits storage of amines like 5-HT and NE So depression could be caused by a decreased amine mediated neurotransmission Causes: Genetic Childhood trauma, emotional stress, illness, even virus  Amine hypothesis So antidepressive agents alter the actions of monoamines (Primarily Serotonin and Norepinephrine) by: Altering the metabolism Decreasing the reuptake Receptor antagonism (Mirtazapine) Question: The actions of these drugs are immediate but clinical efficacy takes weeks. amine dysregulation underlies depression.  Antidepressant Classes Serotonin selective reuptake inhibitors Fluoxetine (Prozac) Heterocyclics, 2nd and 3rd generation antidepressants, Atypical Bupropion (Wellbutrin, Zyban) Selective Serotonin NE Reuptake inhibitor Venlafaxine (Effexor) Tri-cyclic antidepressants Amitriptyline (Elavil) Monoamine oxidase inhibitors Phenelzine (Nardil) Mechanism of reuptake inhibitors Note that in depression there is an upregulation of receptors since there is reduced monoamines Pre-synaptic neuron Post-synaptic neuron Transporter vesicles signal  Mechanism of reuptake inhibitors Pre-synaptic neuron Post-synaptic neuron Transporter vesicles signal Blockade of reuptake  Mechanism of reuptake inhibitors Pre-synaptic neuron Post-synaptic neuron Transporter vesicles signal Decreased release Presynaptic autoreceptor activation Decreased release  Mechanism of reuptake inhibitors Pre-synaptic neuron Post-synaptic neuron Transporter vesicles A Desensitization Presynaptic autoreceptor desensitization  There is also a delay in effectiveness presumably due to adaptive processes Pre-synaptic neuron Post-synaptic neuron Transporter Increasing cAMP-BDNF vesicles signal Desensitization of this MAO pathway allows for greater signal via other receptors Desensitization  Antidepressants increase BDNF expression BDNF infused Less BDNF in into rodent Post mortem ventricles had Depr Brains. antidepressant effects Not the same for treated Gluccocorticoids patients Berton et al. Nature Reviews Neuroscience 7, 137–151 (February 2006) | doi:10.1038/nrn1846 Hippocampal neurons: Stress/pain leads to reduced BDNF and arborization  General info about Antidepressants Pregnancy Some potential risk (SSRIs+ persistent pulmonary hypertension in the newborn (??) and Fetal heart defects (paxil) TCAs and limb formation defects; MAOIs not recommended in pregnancy All are secreted in breast milk (ECT may be alternative). Risk of sudden switch to hypomanic or manic excitement phase. Children are vulnerable to cardiotoxicity + seizures (TCAs) and benefit is not clear Fluoxetine and Sertraline trials prove benefit  General info Adolescents and teenagers suicidal ideation increases: FDA requires warning. More in depth look more ideation, more attempted suicides but overall # of deaths not greater. So increased risk. Acute poisoning with TCAs life threatening ~2gs. Use caution with certain patients. Weight gain is common Some physical dependence can occur so withdrawal should be gradual. Antidepressant discontinuation syndrome  Drug interactions MAO inhibitors can cause dangerous levels of catecholamines (hypertensive crisis) if given with indirect acting sympathomimetics like tyramine (Cheeses and wines), ephedrine “Serotonin syndrome” too much 5HT; MAOI + SSRIs/meperidine/triptans and others; can be fatal. The decrease in degradation and reuptake inhib combine to produce excessive amounts of synaptic serotonin which can cause a potentially fatal syndrome. hyperthermia, muscle rigidity, myoclonus, changes in vital and mental signs.  Therapeutic uses Major adult depressive disorder Enuresis children and Geriatric ADHD: Non responsive to stimulants Severe anxiety disorders (weeks to develop) Post-traumatic stress disorder (SSRIs) Psychosomatic disorders: chronic pain, fatigue, IBS Neuropathic pain/postherpetic neuralgia (Na channels/NE reuptake block in spinal cord?) COPD/apnea Premature ejaculation Migraine prophylaxis Table 5. Remission Rates for Select Antidepressants in Age & Gender Subgroups 1.Cell values show percent of patients experiencing remission. Number of treatment episodes receiving the antidepressant is given in parentheses. Best remission rates are in bold. Within the age and gender group, bold antidepressants are significantly (alpha NET – Anxiety, depression and pain with diabetic neuropathy, osteoarthritis  Trazodone (Oleptro) (SARI) #24 2020  Highly sedating (antihist) low doses are used as hypnotic  Higher doses necessary for antidepressant actions (5HT1A) causes daytime sedation  controlled release high dose form (Oleptro) at night good with little daytime sedation  Bupropion (Wellbutrin, Zyban) #34 #18 2020 a higher affinity for DAT and some action at NET. Active metabolites with >NET activity (amphetamine like) Little to no sedation, muscarinic effects,