Antidepressants PDF 2024

Antidepressants Simón Quetzalcoatl Rodríguez Lara MD, PhD. Patricia Anaid Romero MD. Sonia Guadalupe Barreno Rocha MD. Sandra Guzmán Silahua MD, PhD. Objectives Differentiate the pharmacokinetics and pharmacodynamics of the main Anti- depressants. Understand the pharmacokinetics, pharmaco...

Antidepressants Simón Quetzalcoatl Rodríguez Lara MD, PhD. Patricia Anaid Romero MD. Sonia Guadalupe Barreno Rocha MD. Sandra Guzmán Silahua MD, PhD. Objectives Differentiate the pharmacokinetics and pharmacodynamics of the main Anti- depressants. Understand the pharmacokinetics, pharmacodynamics, adverse effects, and drug interactions of Anti- depressants. Definition It is important to recognize the potential for confusion engendered by multiple uses of the term "depression". Depression may refer to: 1. Mood state, which may be normal or part of a psychopathological syndrome. 2. Syndrome, which is a constellation of symptoms and signs (major depression or minor depression) 3. Mental disorder that identifies a distinct clinical condition (unipolar major depression) Universidad Autonoma de Guadalajara A.C., 2024. 3 Definition “Major depression” is a syndrome that occurs as a consequence of several disorders, including unipolar major depression (also called "major depressive disorder"), bipolar disorder, schizophrenia, substance/medication-induced depressive disorder, and depressive disorder due to another (general) medical condition. Definition Major depressive disorder represents the classic condition in this group of disorders. It is characterized by discrete episodes of at least 2 weeks duration (although more episodes last considerably longer) involving clear-cut changes in effect, cognition, and neurovegetative functions and inter-episode remissions. A diagnosis base on single episode is possible, although the disorder is recurrent one in the majority of cases. Universidad Autonoma de Guadalajara A.C. 5 , 2019. Definition Major depressive episode it is persistent depressed mood and the inability to anticipate happiness or pleasure. The depressed mood of MDE is persistent and not tie to specific thoughts or preoccupations, accompanied with pervasive unhappiness and misery, self-critical, pessimistic ruminations, feelings of worthlessness and self-loathing. Individual thinks about death and dying are focused on ending ones own life because of feeling worthless, undeserving of life, unable to cope with the pain of depression. Universidad Autonoma de Guadalajara A.C. , 2019. 6  1) Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad, empty, hopeless) or observations made by others (eg, appears tearful). (NOTE: In children and adolescents, can be irritable mood.) 2) Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3) Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (NOTE: In children, consider failure to make expected weight gain.) 4) Insomnia or hypersomnia nearly every day. A. Five (or more) of the following symptoms have been present during the same two-week period and represent a change from previous functioning; at least one of the 5) Psychomotor agitation or retardation nearly every day (observable by symptoms is either (1) depressed mood or (2) loss of others, not merely subjective feelings of restlessness or being slowed down). DSM-5-TR diagnostic interest or pleasure. depressive episode criteria for a major B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important 6) Fatigue or loss of energy nearly every day. areas of functioning. C. The episode is not attributable to the direct 7) Feelings of worthlessness or excessive or inappropriate guilt (which may be physiological effects of a substance or to another delusional) nearly every day (not merely self-reproach or guilt about being medical condition. sick). D. The occurrence of the major depressive episode is not better explained by schizoaffective disorder, 8) Diminished ability to think or concentrate, or indecisiveness, nearly every schizophrenia, schizophreniform disorder, delusional day (either by their subjective account or as observed by others). disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. 9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal E. There has never been a manic or hypomanic episode. ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide.  Physiopathology Universidad Autonoma de Guadalajara A.C., 2019. 9  Adrenaline Noradrenalin Antidepressants e Monoamine Dopamine misbalance Serotonin Nonspecifical ly treatment. Changes in Over activity the behave of glutamate patrons Depression Apoptosi Chronic s Exitotoxicity lesion Autophag y Necrosis Corticotrophin release Neuroendocri Inflammatory IL-1β, IL-2, IL- hormone ne changes response 6, TNF-α, ACTH, cortisol, Oxytocin, brain derived neurotrophic NFκ-B. Universidad Autonoma de Guadalajara A.C. 10 factor (BDNF) , 2019. Universidad Autonoma de Guadalajara A.C. 11 , 2019. Serotonin receptors As compared to other endogenous monoamines, serotonin (5- hydroxytryptamine, 5-HT) is undoubtedly unique for its complex effects that are mediated by a wide variety of receptors (i.e., 5- HT15-HT7). In mammals, 5-HT is predominantly found in platelets, enterochromaffin cells, and in the central nervous system (CNS), where it plays a role as a neurotransmitter. There are at least seven 5-HT receptor types that can be grouped into (1) six metabotropic (G-protein-coupled) receptors, namely the 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptor types and (2) one ligand-gated ion channel(s) represented by the ionotropic 5-HT3 receptor type. Universidad Autonoma de Guadalajara A.C. 12 , 2019. Serotonin receptors All known 5-HT receptors have been cloned, and at least for some of them, there is structural knowledge as determined from X-ray crystallography. Receptor subtype-selective ligands have become available for most receptors, although the notion of selectivity is blurred by the existence of multiple receptor splice- and even editing variants and other complicating factors, such as biased signaling, which affects both apparent affinity and efficacy, since a single compound may act as partial or full agonist or inverse agonist or behave as neutral antagonist, depending on receptor effector coupling and expression. Universidad Autonoma de Guadalajara A.C., 2019. 13 Universidad Autonoma de Guadalajara A.C., 2019. 14 Serotonin transporter Receptor structure The serotonin transporter (5-HTT or SERT) is a solute carrier family 6 member 4 protein that is encoded by the SLC6A4 gene. The 5-HTT receptor is composed of 630 aa, and 12 inverted topological repeats of transmembrane (TM)-spanning helices with NH2- and COOH-termini located in the cytoplasm. TM domains are connected by two intracellular (IL1 and IL5) and three extracellular (EL2, EL3 and EL4) hydrophilic loops. The primary binding site for antidepressants is located between TM 1, 3, 6, 8 and 10, which directly blocks 5-HT binding and subsequent translocation. UNIVERSIDAD AUTONOMA DE GUADALAJARA A.C., 2019. 15 Serotonin transporter The primary physiological function of the 5-HTT (SERT) is to terminate 5-HT signaling and limit its action on its receptors by the uptake of the 5-HT into the presynaptic neurons. The transport of the 5-HT is actively generated by ATP-hydrolysis through the Na+/K+ ATPase pump. The transport of the 5-HT is electroneutral, with one Na+ and Cl- ions cotransported with 5-HT(+) by the 5-HTT and one K+ ion extruded. The reuptake of 5-HT from the extracellular to intracellular space relies on conformational changes of SERT to allow 5-HT, Na+ and Cl- to be transported across to the intracellular space. UNIVERSIDAD AUTONOMA DE GUADALAJARA A.C., 2019. 16 Neuroendocrine changes modulates the gen expression: Receptors (serotonin & noradrenaline) Antidepressants Transporters (serotonin modulate the & noradrenaline) kinetics and Reuptakers (serotonin & noradrenaline) effects of Enzymes for amines. metabolism or synthesis (serotonin & noradrenaline) Universidad Autonoma de Guadalajara A.C. 17 , 2019. Treatment Universidad Autonoma de Guadalajara A.C., 2019. 18 Psychological and behavioral treatments For major depression of mild to moderate severity: Cognitive behavior therapy (CBT) (A), behavioral activation (BA) and interpersonal psychotherapy (IPT) (A) are alternatives to antidepressants in acute treatment. CBT is recommended if psychological treatment is used as monotherapy for recurrent depression. Universidad Autonoma de Guadalajara A.C., 2019. 19 Psychological and behavioral treatments For severe major depression: Psychological or behavioral treatment is not recommended as sole therapy (B) but routinely consider adding CBT or BA to antidepressant treatment. Therapists using psychological and behavioral techniques should be experienced in treating depression. Universidad Autonoma de Guadalajara A.C. 20 , 2019. Indications for antidepressants Antidepressants are a first-line treatment for: Moderate and severe major depression in adults irrespective of environmental factors and depression symptom profile. Depression of any severity that has persisted for 2 years or more. Antidepressants are a treatment option in short-duration mild major depression in adults and should be considered if there is a prior history of moderate to severe recurrent depression or the depression persists for more than 2–3 months. Universidad Autonoma de Guadalajara A.C. 21 , 2019.  Citalopram, Escitalopram, Selective serotonin Fluoxetine, Fluvoxamine, reuptake Paroxetine and Sertraline inhibitors (SSRIs) Desvenlafaxin Monoamine Serotonin- e, Duloxetine, Isocarboxazid, oxidase norepinephri inhibitors ne reuptake Levomilnacipr moclobemide, an, (MAOIs) inhibitors phenelzine, selegiline, Milnacipran and tranylcypromine. and Pharmacologi Venlafaxine cal treatment Tricyclic Atypical antidepressa antidepressa Bupropion and Mirtazapine nt nts Imipramine, amitriptyline, Serotonin modulators Nefazodone, Trazodone, Vilazodone and amoxapine, clomipramine, Vortioxetine desipramine, doxepin, nortriptyline, protriptyline and  Complexity of the mechanism of action  KVDC KVDC Drug therapy NaVDC NaVDC mAChR Fluoxetine target 5-HTR mAChR Sodium-dependent serotonin transporter nAChR inhibitor 5-HTR Potassium voltage-gated SDST SDST channel inhibitor nAChR 5-hydroxytryptamine receptor 2C antagonist 5-HTR 5-HTR Neuronal acetylcholine mAChR receptor subunit alpha-2, alpha-3, beta-4 antagonist Universidad Autonoma de Guadalajara A.C. 24 , 2019.  KVDC KVDC Drug therapy NaVDC NaVDC mAChR 5-HTR mAChR Paroxetin target Sodium-dependent serotonin transporter nAChR inhibitor 5-HTR Sodium-dependent SDST SDNT noradrenaline transporter nAChR 5-hydroxytryptamine receptor 2A antagonist 5-HTR 5-HTR Muscarinic acetylcholine mAChR receptor subunit M-1, M-2, M-3, M-4, M-5 antagonist Universidad Autonoma de Guadalajara A.C. 25 , 2019.  KVDC KVDC Drug therapy NaVDC NaVDC mAChR 5-HTR mAChR Sertraline target Sodium-dependent serotonin transporter 5-HTR nAChR inhibitor SDDT SDST Sodium-dependent nAChR dopamine transporter Sigma receptor 5-HTR 5-HTR Increase in uterine mAChR adenocarcinomas in animals models Universidad Autonoma de Guadalajara A.C. 26 , 2019.  KVDC KVDC Drug therapy NaVDC NaVDC Citalopram target Sodium-dependent serotonin mAChR 5-HTR mAChR transporter inhibitor Histamine receptor antagonist Antagonism of nAChR 5-HTR muscarinic, histaminergic, SDST SDST and adrenergic receptors is thought to be associated with nAChR several anticholinergic, sedative, and cardiovascular effects of other psychotropic 5-HTR 5-HTR drugs mAChR Pregnancy category C, excreted in human milk. Universidad Autonoma de Guadalajara A.C. 27 , 2019. Adverse effects  “Serotonin syndrome (ie, serotonin toxicity) is a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system. Serotonin syndrome may involve a spectrum of clinical findings, which often include mental status changes, autonomic hyperactivity, and neuromuscular abnormalities.”  Hyperthermia Increased Flushed skin bowel sounds and diaphoresis Muscle Dilated pupils rigidity (mydriasis) Seroton in syndro me Inducible or (seroto spontaneous nin muscle toxicity Agitation clonus ) (common) Slow, continuous, horizontal Deep tendon eye hyperreflexia movements (common) (referred to as ocular clonus) Akathisia Tremor  Selective Serotonin Reuptake Inhibitors SSRI Family Selective Serotonin Reuptake Inhibitors Fluoxetine, fluvoxamine, paroxetine, sertraline, escitalopram, citalopram. MOA Clinical Adverse Use effects Inhibit 5-HT Depression Fewer than TCAs. reuptake Generalized anxiety disorder Serotonin syndrome, Panic disorder GI distress, SIADH, OCD sexual dysfunction Bulimia (anorgasmia, erectile Binge-eating disorder dysfunction, ↓ libido), Social anxiety disorder mania precipitation if PTSD underlying bipolar Premature ejaculation disorder Premenstrual dysphoric disorder  Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) Family Venlafaxine, desvenlafaxine, duloxetine, levomilnacipran, milnacipran. MOA Clinical Adverse Use effects Depression ↑BP Inhibit 5-HT Generalized Anxiety Disorder Stimulant effects and NE Diabetic neuropathy Sedation reuptake Sexual dysfunction Venlafaxine: is also indicated for Nausea. social anxiety disorder, panic disorder, PTSD, OCD. Duloxetine and milnacipran: are also indicated for fibromyalgia.  Atypical anti-depressants Family (Unicyclic) Bupropion. MOA Clinical Adverse Use effects Stimulant effects Norepinephrin Depression Tachycardia, insomnia e/dopamine- Smoking cessation Headache, and reuptake seizures in patients inhibitor with bulimia and anorexia nervosa. Less risk to develop sexual adverse effects and weight gain compared to another antidepressants  Atypical anti-depressants Family (Tetracyclic) Noradrenaline and Specific Serotonin Antidepressant (NaSSA) Mirtazapine. MOA Clinical Adverse Use effects α2-adrenergic receptors Depression Sedation Anorexia nervosa, weight gain, Increase appetite, antagonist (which increase sleep disturbances, pain-relieving weight gain, dry the effect of NE and effect. mouth, suicidal serotonin). 5-HT2 and 5-HT3 receptors ideation and antagonist. behavior. Peripheral α1-adrenergic antagonist. Histamine H1 receptor antagonist Kappa-type opioid receptor  Atypical anti-depressants Family (Serotonin modulator) Trazodone. MOA Clinical Adverse Use effects Sedation, nausea, Strong 5-HT2 antagonist Primarily in insomnia priapism, postural Low antagonist effect in Depression hypotension and QT- 5-HT3. interval prolongation. α1-adrenergic and α2- adrenergic receptor antagonist. Histamine H1 receptor antagonist.  Atypical anti-depressants Family (Serotonin partial agonist reuptake inhibitor) Vilazodone. MOA Clinical Adverse Use effects Headache, diarrhea, 5-HT3 Depression nausea, antagonist [Major depressive disorder (MDD)] anticholinergic effect. 5-HT1A Increase the risk of agonist serotonin syndrome if is taken with other serotonergic agents.  Atypical anti-depressants Family (Serotonin modulator and stimulator) Vortioxetine. MOA Clinical Adverse Use effects Nausea, sexual 5-HT3, 5-HT1D and 5- Depression dysfunction, sleep HT7 receptors [Major depressive disorder (MDD)] disturbances, antagonist. anticholinergic effects, 5-HT1A agonist. and may cause 5-HT1B partial agonist. serotonin syndrome if taken with other serotonergic agents. Tricyclic MOA: Tricyclic targets: Inhibition of the Several Inhibition re-uptakers Ion channels inhibition7TMCGP inhibition neuronal Sodium-dependent noradrenaline transporter Potassium voltage-gatedMuscarinic acetylcholine receptors M1-M5 reuptake of the Sodium-dependent serotonin transporter channel subfamily D α-1 adrenergic receptors neurotransmitter Sodium-dependent dopamine transporter member 2 &3 5-HTR 1A, 2C, 6 & 7 s Potassium voltage-gatedHistamine receptor 1 Sometimes Psychiatric treatment is more art than science. A lot of Psychiatrists don’t get that. Universidad Autonoma de Guadalajara A.C. 39 , 2019.