PSY 320 - Ch 8 - Psychotherapeutics
PSY 320 - Ch 8 - Psychotherapeutics PSY 320
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PSY 320 Drugs & Behavior Chapter 8 Psychotherapeutics Mental Disorders: Medical Model • Model: ◦ Symptoms -> diagnosis -> determina▯on of cause -> treatment -> cure • Limita▯ons of model: ◦ Usually the only symptoms of mental disorders are behavioral ◦ Behaviors are varied & have many causes • Model guides much of current thinking: ◦ Psychoac▯ve drugs are used to control symptoms of mental illness ◦ Researchers seek to iden▯fy chemical imbalances associated w/ speciﬁc mental disorders Classiﬁca▯on of Mental Disorders • DSM-5 ◦ Developed by American Psychiatric Associa▯on ◦ Provides diagnos▯c criteria & deﬁni▯ons for disorders des u y l ed◦ iW Research Domain Criteria Project (RDoC) • Classiﬁes disorders based on behavioral dimensions & neurobiological measures • Uses modern research approaches in gene▯cs, neuroscience, & behavioral science • Framework for developing hypotheses & evalua▯ng results when inves▯ga▯ng mechanisms of psychopathology • Matrix of func▯onal dimensions grouped into domains Treatment of Mental Disorders • Mental Disorder - Impairment in normal behavioral, cogni▯ve, or emo▯onal func▯on ◦ Highly prevalent ◦ WHO es▯mates 450 million ppl qualify for a mental disorder diagnosis History & Consequences of Drug Treatments for Mental Illness • Historically, pa▯ents were hidden in dungeons or ins▯tu▯ons • 1917 "Malaria Therapy" ◦ Many ppl suﬀered from general paresis (syphili▯c infec▯on of the nervous system) ◦ Fever associated w/ malaria produced improvement ◦ Later discovery of an▯bio▯cs curing syphilis eliminated need for Malaria Therapy • Replaced w/ shock therapies, insulin therapies, etc. ◦ 1920s "Narcosis therapy:" • Depressants & barbiturates used to induce sleep for a week or more ◦ 1930s Intravenous thiopental sodium (truth serum): • Used in psychotherapy to help pa▯ents express repressed thoughts ◦ Insulin-shock therapy: • Used to treat schizophrenia • Ineﬀec▯ve, caused agita▯on ◦ Electroconvulsive therapy: • Ineﬀec▯ve to treat schizophrenia PSY 320 Drugs & Behavior • S▯ll used to treat severe depression that doesn't respond to medica▯on • First an▯depressant drugs emerged in 1950s ◦ Paraldehyde most commonly used, had a horrible odor • Mental hospitals' popula▯on decreased since 1950s • 1963 Community Mental Health Act ◦ Provided federal support to states to develop community-based mental health centers ◦ Intended to treat pa▯ents closer to home in a more natural/accessible se▯ng • Medicare & Medicaid in 1965 moved elderly pa▯ents w/ demen▯a into nursing homes • "Libera▯on" of mental pa▯ents to mainstream society ◦ Prescrip▯ons o▯en replaced psychotherapy ◦ 1/3rd of homeless ppl in the US have some form of mental illness that they cannot aﬀord to treat or do not have access to medica▯ons for DSM-5 Anxiety Disorders Characterized by excessive worry, fears, or avoidance • Speciﬁc phobia - Excessive or unreasonable fear of a speciﬁc object or situa▯on • Social anxiety disorder - A marked fear or anxiety about one or more social situa▯ons • Panic disorder - Recurrent & unexpected panic a▯acks, which consist of abrupt surges of intense fear or discomfort • Agoraphobia - Fear or anxiety about 2 or more of these situa▯ons: using public transporta▯on, being in open spaces, being in shops or theaters, standing in line, or being outside of the home alone • Generalized anxiety disorder - Excessive anxiety & worry about a number of events or ac▯vi▯es, las▯ng for a period of 6 months or longer Mental Disorders • Psychosis - Mental disorder involving loss of contact with reality ◦ Organic psychoses - Known physical cause ◦ Func▯onal psychoses - No known cause or obvious physical cause ◦ Schizophrenia - Severe, life-long mental illness consis▯ng of disturbed thought processes & poor emo▯onal responsiveness • Posi▯ve symptoms - Hallucina▯ons, delusions, thoughts of persecu▯on • Nega▯ve symptoms - Reduced emo▯onal responsiveness, social withdrawal, reduced movement, lack of mo▯va▯on • Types of schizophrenia: ▪ Paranoid type - posi▯ve symptoms ▪ Catatonic type - nega▯ve symptoms ▪ Disorganized type - disorganized/immature behaviors ▪ Undiﬀeren▯ated type - doesn't ﬁt into other categories ▪ Residual type - pa▯ents who currently exhibit few symptoms ▪ Prodromal phase - Years before a diagnosis, early/subtle signs & schizophrenic-like symptoms occurring less frequently & w/ less severity • Schizophrenia aﬀects 1% of world popula▯on • Around 1/3rd of pa▯ents w/ schizophrenia qualify as treatment-resistant pa▯ents: Minimal or no improvements a▯er 2 trials of either typical or atypical an▯psycho▯c drugs • Schizophrenic individuals typically have deﬁcits in cogni▯ve func▯oning including: Working memory, reference memory, a▯en▯on, & execu▯ve func▯oning PSY 320 Drugs & Behavior • Many pa▯ents demonstrate sensory-ga▯ng deﬁcit: Diminished capacity to ﬁlter out unimportant s▯muli in one's environment • Features of schizophrenia: ▪ Delusional thinking - Firmly held beliefs of: persecu▯on, jealousy, sin/ guilt, grandiosity, religious ▪ Hallucina▯ons - percep▯ons experienced w/o external s▯muli, auditory hallucina▯ons including commands & commentary ▪ Disorganized speech (thought disorder) ▪ Disorganized or bizarre behavior: catatonic stupor, inappropriate mannerisms, deteriora▯on of grooming, dress, home, social behavior, etc. ▪ Incongruity of aﬀect - I.E. inappropriate smiling ◦ Chronic psychosis characterized by 2 of the following: • Delusions, hallucina▯ons, disorganized speech, disorganized behavior, lack of emo▯onal response • Causes signiﬁcant interference w/ social/occupa▯onal func▯oning • Mood disorders - Characterized by depressed or manic symptoms ◦ Depression 4th leading cause of disability worldwide ◦ Due to prevalence & drama▯c eﬀects on life ◦ Major depressive disorder • Characterized by at least 5 of the depressive symptoms, las▯ng at least 2 weeks • Depressed mood, lack of interest/pleasure, change in body weight & sleeping pa▯erns, fa▯gue, feelings of worthlessness, diﬃculty thinking/concentra▯ng, recurrent thoughts of death • Prevalence during life▯me is 16% ◦ Dysthymic disorder • Depressed mood occurring nearly every day for at least 2 years ◦ Major depression w/ psycho▯c features • Presence of depression, hallucina▯ons, & delusions related to depressed mood ◦ Bipolar disorder - Characterized by abnormal changes btwn depressive & manic mood states • Depressive symptoms same as with depressed individuals • Mania consists of abnormal elevated or irritated mood, arousal, or energy levels ▪ Manic behavior: fast speaking, rapidly changing ideas, impulsive decision making • Bipolar 1 disorder - At least 1 manic episode & possible alterna▯ng depression • Type 1 bipolar disorder - Exhibits depression & episodes of severe mania • Type II - Exhibits depression along w/ episodes of less-severe mania • The most common incorrect diagnosis for bipolar disorder is depression • Bipolar depression far less prevalent than unipolar depression Categories of currently used an▯depressants: • Monoamine oxidase (MAO) inhibitors ◦ Monoamine hypothesis of depression: ◦ Monoamine neurotransmi▯er deﬁciency cause depressive mood ◦ An▯depressant drugs designed based on this hypothesis PSY 320 Drugs & Behavior ◦ Originally discovered in 1950s when trea▯ng pa▯ents for tuberculosis ◦ Alter metabolism of amino acid tyramine • "Cheese reac▯on" - Severe headache, palpita▯ons, nausea, & vomi▯ng may occur when ea▯ng cheese & could possibly result in deadly stroke • Tricyclic an▯depressants ◦ Block presynap▯c receptors/transporters for serotonin, dopamine, & norepinephrine ◦ Block diﬀerent numbers of postsynap▯c receptors for acetylcholine & histamine ◦ Main histamine eﬀect is drowsiness ◦ Mul▯ple ac▯on of TCAs some▯mes advantageous, promotes sleep ◦ All TCAs are toxic to the heart @ high doses ◦ Make eﬀec▯ve agents of suicide, fueled search for other an▯depressants ◦ Adverse eﬀects: • Dry mouth, dry eyes, cons▯pa▯on, urinary reten▯on - caused by muscarinic receptors • Dangerous cardiovascular eﬀects - caused by inhibi▯on of a1 adrenoceptors • Seda▯ve eﬀects - caused by inhibi▯on of histamine H1 receptors • Weight gain, type II diabetes ◦ Imipramine (Tofranil) discovered as modiﬁca▯on of phenothiazine (an▯psycho▯c) ◦ Amitriptyline (Elavil) higher seda▯ve & an▯cholinergic eﬀects, aﬀects serotonin more than imipramine does ◦ Clomipramine (Anafranil) has highest serotonin eﬀect of TCAs w/ li▯le an▯cholinergic or seda▯ve ac▯on • Selec▯ve serotonin reuptake inhibitors (SSRIs) ◦ By late 1970s researchers began to dis▯nguish btwn behavior-s▯mula▯ng & mood- enhancing eﬀects of an▯-depressants ac▯ng on NE & 5-HT systems • Believed that behavior-s▯mula▯ng eﬀects for mediated by blocking NE reuptake, while mood-enhancing eﬀects were mediated by 5-HT • Research focused on developing drugs to speciﬁcally enhance 5-HT transmission while simultaneously minimizing eﬀects on histamine & Ach receptors: the cause of most side eﬀects ◦ 1988 ﬂuoxe▯ne (Prozac) was approved • Increase extracellular levels of 5-HT by inhibi▯ng reuptake into presynap▯c cell, increasing level of 5-HT available to bind to receptors • Primarily used to treat clinical depression • Also used to treat anxiety disorders, social phobia, OCD, ea▯ng disorders, chronic pain, PTSD ◦ Fluoxe▯ne (Prozac) ﬁrst SSRI, one of the most prescribed drugs in history ◦ Sertaline (Zolo▯) quick ac▯on, less side eﬀects ◦ Paroxe▯ne (Paxil) for OCD & panic ◦ Fluvoxamine (Luvox, 1995) for OCD/panic/PTSD ◦ Serotonin Syndrome - Life-threatening condi▯on characterized by agita▯on, restlessness, cogni▯ve impairments, & hallucina▯ons ◦ Serotonin discon▯nua▯on syndrome - Caused by abrupt withdrawal of an▯depressant drug, resul▯ng in sensory/sleeping impairments, disequilibrium, ﬂulike symptoms, gastrointes▯nal eﬀects • Serotonin-norepinephrine reuptake inhibitors PSY 320 Drugs & Behavior ◦ Enhance levels of serotonin & norepinephrine by blocking serotonin & norepinephrine transporters ◦ Dual-ac▯on an▯depressants ◦ Need for new class of an▯depressant drugs resulted from: • Adverse eﬀects of SSRIs, par▯cularly sexual side eﬀects • Failure of signiﬁcant # of pa▯ents to respond to SSRIs/other drugs ) 4991 , roxeﬀE ( en i xa f a l n ◦e V • First & most commonly used SRNI • Reuptake eﬀects are dose dependent ▪ Low doses act just on 5-HT ▪ Moderate doses on 5-HT & NE ▪ High doses also aﬀect DA transmission ◦ Duloxe▯ne (Cymbalta) approved 2004 ◦ Eﬀexor similar mechanism, shorter half-life • Atypical an▯depressant drugs ◦ Reduce depression thru mechanisms that diﬀer from those of other an▯depressant drug classiﬁca▯ons ◦ One of the most prescribed is bupropion (Wellbutrin) • Reuptake inhibitor for norepinephrine & dopamine • Binds selec▯vely to dopamine transporter, tho behavioral eﬀects are a▯ributed to its inhibi▯on of NE reuptake • Also acts as nico▯nic Ach receptor antagonist • Eﬀect an▯depressant on its own • Par▯cularly popular as an add-on medica▯on in the cases of incomplete response to SSRIs • Doesn't cause weight gain, even shoes mild-moderate weight loss or appe▯te suppression • Bupropion currently 4th-most prescribed an▯depressant in the US a▯er sertraline (Zolo▯), escitalopram (Lexapro), & ﬂuoxe▯ne (Prozac) ◦ Bupropion (Zyban) • Ini▯ally researched/marketed as an▯depressant • Subsequently found to be eﬀec▯ve as smoking cessa▯on aid Limita▯ons in An▯depressant Drug Eﬀec▯veness & Development • All an▯depressant drugs have a lengthy response ▯me ◦ Clinically signiﬁcant eﬀects occur a▯er 2 weeks of treatment ◦ Full eﬀects a▯er 4 weeks • Treatment-resistant depression ◦ Successive failed a▯empts at signiﬁcantly reducing depressive symptoms ◦ Btwn 29-46% of pa▯ents are treatment-resistant • To gain FDA approval, new an▯depressants must be tested in clinical trials compared to placebos ◦ Clinically signiﬁcant improvements o▯en occur in placebo-treated pa▯ents ◦ Strong placebo eﬀects + cau▯ous nature of clinical drug tes▯ng = failure to ﬁnd clinically signiﬁcant an▯depressant eﬀects • Most an▯depressant drugs elevate brain serotonin levels • An▯depressant drugs increase dopamine concentra▯ons in prefrontal cortex PSY 320 Drugs & Behavior • Neuronal growth occurs during an▯depressant treatment • Risks: ◦ Individuals ﬁrst star▯ng an▯depressants may be anxious, irritable, hos▯le, impulsive, or restless ◦ Combina▯on of severe depression & restlessness especially dangerous ◦ An▯depressants may elevate energy enough for individuals to carry out suicide plans ◦ Advisory drugs: Prozac, Zolo▯, Wellbutrin, Zyban, Paxil, Celexa, Eﬀexor, Serzone, Luvox, Remeron Typical An▯psycho▯cs PSY 320 Drugs & Behavior Atypical An▯psycho▯cs Mood Stabilizers & Other Drugs • For bipolar disorder • Few drugs are considered pure mood stabilizers: drugs that reduce both depressive & manic symptoms • Beyond mood stabilizers, other treatments include an▯convulsant drugs & an▯psycho▯c drugs • Lithium ◦ One of the oldest & most eﬀec▯ve treatments for bipolar disorder ◦ Eﬀec▯veness ﬁrst realized by John Cade in 1949 ◦ Provides greater eﬃcacy for mania than for depression ◦ Requires 10-15 days before symptoms decrease ◦ Acts as mood-normalizing agent for manic depression ◦ Has serious side eﬀects: • Nausea, vomi▯ng, diarrhea • Narrow therapeu▯c index • Lithium's mechanisms of ac▯on ◦ Lithium aﬀects: • Second-messenger ac▯ons • Gene expression • Neuroprotec▯ve eﬀects • Inhibi▯on of glycogen synthase kinase 3 (GSK-3): Protein kinase that promotes apoptosis & regulates inﬂamma▯on • An▯convulsants: ◦ O▯en also used as mood stabilizers ◦ Valproic acid (Depakote), carbamazepine (Tegretol), lamotrigine (Lamictal) PSY 320 Drugs & Behavior ◦ Don't require blood levels to be monitored History of Schizophrenia Treatment • 1952 Henri Laborit administered preanesthe▯c agent chlorpromazine to manic pa▯ents ◦ Had calming eﬀect on pa▯ents w/ psychosis • Eﬃcacy of chlorpromazine for schizophrenia formally studied by Jean Delay & Pierre Deniker ◦ Revolu▯onized treatment of schizophrenia • Butyrophenones: ◦ Haloperidol (Haldol, 1967) & doperidol (Inapsine, mainly an▯nausea/an▯eme▯c) • Aripiprazole (Ambilify) ◦ Atypical an▯-psycho▯c & an▯-depressant ◦ Approved in 2002 to treat schizophrenia ◦ Approved in 2004 for manic episodes of bipolar disorder ◦ Approved in 2007 as adjunct for major depressive disorder, but not as a monotherapy for MDD ◦ Approved in 2009 to treat irritability in kids w/ au▯sm An▯psycho▯c Drugs • Dopamine hypothesis - Posi▯ve symptoms of schizophrenia arise from excessive dopamine release ◦ An▯psycho▯c drugs act as antagonists for D2 receptors ◦ Amphetamine causes psycho▯c symptoms via increases in dopamine release • Classes of an▯psycho▯cs 1. Typical or conven▯onal an▯psycho▯cs • All same eﬃcacy • Block pathway from ventral tegmental area (VTA) to basal ganglia, limbic structure, & frontal cortex • Many generic equivalents now available • Prototype - Phenothiazines ◦ Pharmacokine▯cs: • 24-48 hr half-life • Unpredictable absorp▯on & metabolism ◦ Pharmacodynamics: • Blocks D2 receptors • Also blocks ACh, 5-HT, NE, & histamine: seda▯ng, sympathomime▯c, an▯eme▯c ◦ Decrease sensi▯vity to emo▯onal expression ◦ Decrease RAS sensi▯vity to external s▯muli ◦ Acute extrapyrimidal eﬀects • Akathesia: anxious pacing, rocking, ﬁddling • Dystonia: spasms & posturing • Parkinsonsim ◦ Tardive dyskinesia • Butyrophenones ◦ Longer half-life: drug holidays of 3 days ◦ More speciﬁc D2 blocker ◦ Fewer side eﬀects, li▯le seda▯on PSY 320 Drugs & Behavior ◦ Parkinsonian eﬀects like those of high-potency phenothiazines 2. Atypical an▯psycho▯cs • Block typical pathways & 5-HT pathway from raphe nucleus to basal ganglia, limbic structures, & en▯re cortex • Diﬀerent side eﬀect proﬁles • Much more expensive • Clozapine (Clozaril, 1990) ▪ Some▯mes drama▯c improvement ▪ Relieves posi▯ve & nega▯ve symptoms of schizophrenia ▪ Agranulocytosis, NMS ▪ Acts on DA, 5-HT, ACh, & histamine • Risperidone (Risperdal, 1994) ▪ Inhibits D2 & serotonin-2 receptors ▪ Low side eﬀects: ﬁrst-line treatment • Pimazode (Orap, 1996) ▪ Used in US for Toure▯e's disorder, in Europe & South America for schizophrenia ▪ May also help delusional disorder • Olanzapine (Zyprexa, 1996) ▪ Like clozapine, but no agranulocytosis • Ser▯ndole (Serlect, 1997) ▪ Serotonin, adrenalin, & cor▯cal DA2; dual ac▯on • Quetapine (Seroquel, 1997) ▪ Treats posi▯ve & nega▯ve symptoms ▪ Selec▯ve 5-HT & D2 antagonist • An▯cholinergic side eﬀects: dry mouth, blurred vision, rapid heart rate (tachycardia), urine reten▯on, cons▯pa▯on, confusion & memory impairment • Main side eﬀects: ▪ EPS - Cogwheel rigidity, coarse tremor, hypokinesia, shuﬄing gait ▪ Tardive Dyskinesia - Involuntary/o▯en irreversible movements in the face, tongue, jaw, hands, & feet ▪ NMS - Life-threatening syndrome w/ "lead pipe" muscular rigidity, hyperthermia, unstable vitals, agita▯on ▪ Dystonia - Painful muscle contrac▯on in the jaw, neck, tongue ▪ Orthosta▯c hypotension, prolac▯nemia, akathisia/restlessness, lower seizure threshold, drug interac▯ons Mechanism of Ac▯on • Phenothiazines & other conven▯onal an▯psycho▯cs produce pseudoparkinsonsim ◦ Ini▯al eﬀect blocks D2 dopamine receptors ◦ Tho lag eﬀect requires 10-14 days to see an▯psycho▯c eﬀects ◦ Ul▯mate mechanism remains unknown ◦ Involves some response of the nervous system to repeated administra▯on of dopamine antagonists • Clozapine ◦ Risk of deadly suppression of white blood cell produc▯on PSY 320 Drugs & Behavior ◦ Use requires periodic blood samples to monitor white cells ◦ Aﬀects mul▯ple receptor types ◦ Blocks D2 dopamine & 5HT2A serotonin receptors • Serotonin-dopamine antagonists: ◦ Atypical an▯psycho▯cs ◦ Risperidone, olanzepine, etc. ◦ Don't aﬀect white blood cells ◦ Reduce pseudoparkinsonsim Ac▯ons to Eﬀects Ac▯ons: • Microdialysis studies ﬁnd atypical an▯psycho▯c drugs increase dopamine concentra▯ons in the prefrontal cortex • Ac▯ons of atypical an▯psycho▯cs on 5-HT & D2 receptors may account for eﬀects on cor▯cal dopamine neurotransmission ◦ As well as ability to improve cogni▯ve impairment & nega▯ve symptoms in schizophrenia Side Eﬀects: • Don't produce drug dependence • Extremely diﬃcult to use to commit suicide • Jaundice, skin rashes • Photosensi▯vity in skin to light (sunburns easily) • Agranuloctosis - low white blood cell count ◦ May result in high mortality rate • Facial ▯cs • Symptoms similar to Parkinson's disease • Weight gain, metabolic changes in children & increased risk for obesity or diabetes • Cardiovascular risk for the elderly Typical vs. Atypical: • Atypical ◦ 2nd genera▯on an▯psycho▯cs ◦ Marketed as oﬀering greater eﬃcacy in reducing psycho▯c symptoms w/ less side eﬀects ◦ Eﬀects o▯en lacked robustness ◦ Assump▯on increasingly challenged w/ increase in atypical prescrip▯ons ◦ One review found no diﬀerences, another found atypicals to be just moderately more eﬃcacious ◦ Olanzapine appears superior in terms of reducing psychopathology, tho associated w/ huge gains in weight & increase in fat/cholesterol ◦ 3rd genera▯on an▯psycho▯cs slightly less eﬀec▯ve than Olanzapine but safer for type II diabetes risk Long-Term Management of Chronic Mental Illness • Several studies suggest medica▯ons may be less eﬀec▯ve for outcomes that ma▯er most to ppl w/ serious mental illness: a full return to well-being & a produc▯ve place in society • Long-term follow-up studies: ◦ In the ﬁrst 6-10 months a▯er discon▯nua▯on: 25-55% of pa▯ents relapse PSY 320 Drugs & Behavior ◦ For those who don't relapse during this period, subsequent relapses are much less frequent even a▯er prolonged periods oﬀ medica▯on • For some, remaining on medica▯on long-term may impede a full return to wellness • For others discon▯nuing medica▯on could be disastrous • Reducing posi▯ve symptoms may be necessary but is rarely suﬃcient for a full return to normal func▯oning • Neither 1st or 2nd genera▯on an▯psycho▯cs help much with nega▯ve symptoms or problems w/ a▯en▯on & judgment • Family educa▯on, supported employment, & cogni▯ve behavioral therapy have all shown eﬃcacy in reducing likelihood of relapse