Psychiatric Medications Antipsychotics & Antidepressants

1. Psychiatric MedicationsAntipsychotics & Antidepressants

2. Psychiatric Disorders Medical Model of Mental Illness • Pros and Cons • Assumes biological etiology • Potentially treatable with psychotropic drugs • There are no simple diagnostic tests for mental disorders. • Diagnosis is based on assessment of behavioral symptoms.

3. Classification of Mental Disorders • Anxiety Disorders • Generalized Anxiety Disorder, Phobic Disorder, Panic Disorder, Obsessive Compulsive Disorder, Post-traumatic Stress Disorder • Psychotic Disorders • Schizophrenia, Schizoaffective Disorder • Affective (Mood) Disorders • Dysthymia, Major (Unipolar) Depression, Bipolar Disorder

4. Historical Developments in the Treatment of Mental Disorders • Before 1950, “Malaria therapy” • Thiopental sodium – truth serum • Insulin shock therapy • Electroconvulsive therapy • Development of Phenothiazines in 1950s

5. ANTIPSYCHOTIC DRUGS • Historical Background • “Accidental” discovery of promethazine and then chlorpromazine by Henri Laborit, 1951 • Largactil marketed in Europe, 1953 • Thorazine marketed in U.S., 1955 • Other Names for Antipsychotic Drugs • Neuroleptic • Literally means “clasping the neuron” • Refers to parkinsonian-like side effects of these drugs • “Major” Tranquilizers • Refers to sedating effects • Misleading terminology , chemically and pharmacologically distinct from “Minor” tranquilizers (the benzodiazepines and barbiturates)

6. Consequences of Psychiatric Medications for Society • Dramatic decline in numbers of people institutionalized • Increase in outpatient treatment programs • Psychiatrists roles have changed • From hospitals to jails or on the streets Number of patients in nonfederal hospitals, 1946-2002 (Figure from Ksir et al., 2007).

7. Classifying Antipsychotics • Typical (Classical or Traditional) • Phenothiazines or similar to phenothiazines • e.g., chlorpromazine, haloperidol • Atypical , 2nd generation • e.g., clozapine, risperidone, olanzapine, quetiapine, • Atypical, 3rd Generation • e.g., aripiprazole, amisulpride, ziprasidone

8. PHENOTHIAZINES: PHARMACOKINETICS • Routes of Administration/Absorption • Oral administration common, although absorption is erratic and unpredictable. • In some cases (e.g., poor compliance with oral meds), Depot injections (I.M.) may be given, once a month. • Distribution • Rapid distribution throughout the body • Easily cross blood brain barrier and placenta • Considerable protein binding in blood • Lower brain concentration compared to other body tissues • Absorbed in body fat and released slowly • Elimination • Half-life: 24-48 hours • Slow elimination due to protein binding and accumulation in body fat • Determining optimal dose, trial and error.

9. PHENOTHIAZINES: NEUROPHARMACOLOGY • Neuropharmacological Mechanisms • Block DA, NE, ACh, and histamine receptors • CNS actions • Limbic System: main therapeutic effects • Brain Stem: suppress behavioral arousal, antiemetic effects • Basal Ganglia: akathesia, dystonia, parkinsonism, and Tardive Dyskinesia • Hypothalamus-Pituitary: temperature regulation impaired, breast enlargement, lactation, impotence, infertility

10. PHENOTHIAZINES: SIDE EFFECTS • Side Effects/Toxicities • Sedation due to antihistamine and antiadrenergic effects • Postural hypotension due to antiadrenergic effects • dry mouth, blurred vision, constipation, urinary retention tachycardia due to anticholinergic effects • Extrapyramidal effects due to antidopaminergic effects in basal ganglia • Impaired cognition due to anticholinergiceffects • Despite many side effects, antipsychotics are not lethal; high therapeutic index (100 to 1000) Tolerance/Dependence • Tolerance develops to some of the side effects, but there is NO evidence of tolerance to the therapeutic effects. • These drugs do not produce physical dependence, perhaps due to extremely slow elimination from the body.

11. OLDER ALTERNATIVES TO PHENOTHIAZINES • haloperidol (Haldol) • Structurally distinct from phenothiazines • Similar pharmacological mechanisms and similar side effect profile • Effective for treating acute psychosis due to rapid onset, especially by injection • molindone (Moban) • Introduced in 1970s, structurally similar to 5-HT • Similar therapeutic and side effects to traditional antipsychotics • loxapine (Loxitane) • Despite structural similarity to clozapine, effects more similar to traditional antipsychotics • pimozide (Orap) • In U.S. primarily used in tx. of tics in Tourette’s Syndrome • Similar side effects to traditional neuroleptics, QT prolongation potentially severe

12. ATYPICAL ANTIPSYCHOTICS • clozapine (Clozaril) • Background • Synthesized in 1959 and introduced into clinical practice in Europe in early 1970s • Fatalities due to agranulocytosis delayed introduction in the U.S. • 1986, clinical trials in U.S. • Pharmacokinetics • p.o., absorbed well, peak plasma levels in 1-4 hours • variable half-life 9-30 hours • Blood monitoring especially important

13. ATYPICAL ANTIPSYCHOTICS • clozapine continued • Pharmacodynamics • High binding affinity for D4, 5-HT1C, 5-HT2, NEa1, muscarinic and histamine receptors • Low D2 affinity • Side Effects/Toxicity • Sedation in about 40% of patients • Weight gain for up to 80% of patients • Constipation in about 30% of patients • Agranulocytosis rare • Withdrawal symptoms may occur upon discontinuation, alleviated by olanzapine

14. ATYPICAL ANTIPSYCHOTICS • risperidone (Risperdal) • Introduced in 1993 • Pharmacokinetics • p.o., well absorbed • Highly bound to plasma proteins • Half-life about 3 hours, active metabolite with 22 hr. half-life • Pharmacodynamics • Less effective than clozapine in relieving positive symptoms, equally effective in relieving negative symptoms • Better safety profile than clozapine • Side Effects • Somnolence, agitation, anxiety, headache, nausea • EPS at high doses (> 8 mg/day) • Weight gain less than with clozapine or olanzapine

15. ATYPICAL ANTIPSYCHOTICS • olanzapine (Zyprexa) • Introduced in 1996 • structurally/pharmacologically similar to clozapine, no agranulocytosis • Pharmacokinetics • p.o., well absorbed, peak plasma levels 5-8 hours • Half-life 27-38 hours • Pharmacodynamics • Superior or comparable to haloperidol • Comparable efficacy to clozapine • Side Effects • Weight gain • no agranulocytosis • occasional EPS • Other Uses of Olanzapine • Bipolar disorder • Pervasive Developmental Disorder • Agitation and Aggression

16. ATYPICAL ANTIPSYCHOTICS • Other Atypicals • sertindole (Serlect) • 1997 • D2/5-HT2 antagonist, no antihistaminic effects • Prolonged QT interval, removed from market • quetiapine (Seroquel) • 1998 • D2/5-HT2 antagonist, similar to clozapine • Side effects: nausea, sedation, dizziness, weight gain no different from placebo • Other uses: bipolar, OCD • ziprasidone (Geodon) • D2/5-HT2 antagonist, 5-HT1A agonist • Relieves positive and negative symptoms, no weight gain • First atypical approved for IM use • Antidepressant activity, also effective in Bipolar disorder • Cardiac effects are a limiting factor, prolongs QT interval

17. “Third Generation” Antipsychotics • Aripiprazole • Pharmacodynamics • Considered a DA-5-HT system stabilizer • 5-HT2 antagonist, partial D2 and 5-HT1A agonist • No serious side effects • Other recent uses • Bipolar disorder, conduct disorder in children • Amisulpride • D2/D3 antagonist in limbic areas, not b.g. • Low doses inc. DA release, high doses block • First atypical that doesn’t block 5-HT receptors

18. ATYPICAL ANTIPSYCHOTICS • Potential Health Risks of Atypical Antipsychotics • Weight Gain • hinders patient compliance • Diabetes/Hyperglycemia • Electrocardiographic Abnormalities

19. Behavioral Effects of Antipsychotics • Subjective Effects • In healthy subjects, classical neuroleptics produce slow and confused thinking, difficulty concentrating, clumsiness, sedation, some anxiety and irritability. • These effects probably responsible for poor compliance among patients prescribed these drugs. • Atypical antipsychotics less of a problem. • Performance • Few studies and reports are variable (deficits, improvements, no effect) • Studies of acute effects on cognitive performance indicate impairments are due to sedation and tolerance to these effects occur within 14 days.

20. Laboratory Studies in Nonhumans • Unconditioned Behavior • Suppression of spontaneous movement with high doses causing immobility (which gave rise to the name neuroleptic) • Diminish frequency and intensity of aggressive behavior in most species, possibly due to decreased motor function. • Conditioned Behavior • Decrease responding on schedules maintained by positive reinforcement, although low doses may increase low response rates (rate dependency similar to amphetamine) • Decrease avoidance responding without affecting escape behavior, similar to CNS depressants.

21. Laboratory Studies in Nonhumans • Drug Discrimination • Some antipsychotics not easily discriminated, large doses and extended training required. • Generalization does not occur between Atypicals (e.g., clozapine) and Typicals (chlorpromazine) or between antipsychotics and other drug classes. • Self-administration • Antipsychotics are NOT self-administered by nonhumans. • They are never abused by humans. • In fact, compliance among patients is often a problem.

22. Antidepressants &mood stabilizers

23. DEPRESSION • Symptoms • extreme sadness/despair, diminished interest in pleasure, diminished energy, loss of appetite/weight loss, mental slowness, concentration difficulties, restless agitation, insomnia, recurrent suicidal thoughts • DSM-IV criteria list nine categories of symptoms with five or more symptoms present during same two week period • Prevalence in U.S. • Approx 14 million (6.6 % of adults) • 50% receive medical treatment, which is effective in only about 42% of those treated

24. Depression • Pathophysiology of Depression • A “reversible brain disease” • Structural, neurochemical changes in hippocampus, frontal cortex • Once thought to be a consequence of neurotransmitter deficiencies (e.g., NE, 5-HT) • More recent evidence suggests reductions in neurotrophic hormones and reduced neuronal plasticity are key factors in pathophysiology of depression.

25. Classifying Antidepressants • First Generation (introduced in 1950s-1960s) • MAO Inhibitors • Tricyclics • Second Generation, Atypical (1970s-1980s) • SSRIs (~ 1990s) • SNRIs • Dual-Action Antidepressants • Combined SSRI + 5-HT2 antagonist or combined SSRI/SNRI

26. MAO Inhibitors • Examples of MAOIs • Iproniazid: first one introduced in 1950s, no longer on the market • phenelzine (Nardil) • tranylcypromine (Parnate) • moclobemide (Ludiomil): not available in U.S. • Pharmacokinetics • Short half-life, 2-4 hours • Neuropharmacological Actions • Block degradation of monoamines by MAO • Indirect Agonist for all Monoamines

27. MAO Inhibitors • Side Effects • potentially fatal interactions with foods containing tyramine or with adrenergic drugs; hypertensive crisis. • MAO-A vs. MAO-B • Both in CNS: MAO-A mainly acts on NE and 5-HT; MAO-B mainly acts on DA. • MAO-A, in gastrointestinal tract; MAO-B, in liver and lungs • Older MAOIs acted on both types, side effects such as hypertensive crisis with tyramine rich foods. • Recent advances • Selective MAO-A inhibitor, moclobemide (not available in U.S.) • Transdermal delivery of selegiline (Eldapril)

28. Tricyclic Antidepressants • Examples • imipramine (Tofranil) • amitriptyline (Elavil) • desipramine (Norpramin) • Pharmacokinetics • well absorbed with oral administration • long half-lives, ~ 24 hours • metabolized in liver

29. Tricyclic Antidepressants • Neuropharmacological Effects • monoamine reuptake blockade • Indirect agonist for all monoamines • Side Effects • Antihistaminergic effects: sedation • Anticholinergic effects: dry mouth, blurred vision, urinary retention, increased heart rate, cognitive impairments • overdose can be fatal due to cardiac toxicity, concern with suicidal patients

30. SSRIs & SNRIs • SSRIs • fluoxetine (Prozac) • Sertraline (Zoloft) • paroxetine (Paxil) • Fluvoxamine (Luvox) • citalopram (Celexa) • SNRIs • atomoxetine (Straterra) • Commercially available in 2003 for ADHD treatment • reboxetine (Edronax, Vestra) • Not currently available in U.S.

31. Dual Action Antidepressants • nefazodone (Serzone) • 5-HT2 receptor antagonist and 5-HT/NE reuptake blocker; chronic use down regulates NE/5-HT receptors. • mirtazepine (Remeron) • Tetracyclic and NaSSA • 5-HT2/5-HT3 receptor antagonist; also antihistamine • duloxetine (Cymbalta) • 5-HT/NE reuptake blocker • also prescribed for chronic pain conditions, such as diabetic neuropathy and fibromyalgia • venlafaxine (Effexor) • 5-HT/NE reuptake blocker • also prescribed for general anxiety disorder

32. Behavioral Effects of Antidepressants • Subjective Effects • These drugs do not produce euphoric or pleasant effects and may produce fatigue, apathy, weakness. • High doses may impair comprehension, cause confusion and reduce concentration. • Performance • Acute doses have detrimental effects on vigilance tasks and can cause memory and psychomotor impairments related to sedation. • With repeated use, these effects show tolerance.

33. Laboratory Studies in Nonhumans • Unconditioned Behavior • Antidepressants tend to increase locomotor activity in rodents • Conditioned Behavior • Increase response rates in operant assays, both low and high rates • Decrease avoidance responding without affecting escape behavior, similar to anxiolytic and antipsychotic drugs. • Do not increase, but tend to decrease punished responding.

34. Laboratory Studies in Nonhumans • Drug Discrimination • MAOIs and tricyclics are not discriminated, except at extremely high doses • SSRIS and SNRIs are discriminated at therapeutic doses. • Self-Administration • None of the antidepressants are self-administered by nonhumans.

35. Health Risks of Antidepressants • Reproduction • Males, delayed or impaired ejaculation • Males and females, Reduced sex drive and difficulties achieving orgasm. • Teratogenic effects with some antidepressants • e.g., increased risk of miscarriage with fluoxetine and TCAs. • e.g., Lithium in early pregnancy can cause cardiac malformations in fetus. • Violence/Suicide • Evidence for this largely from case studies. • Large scale studies actually show reduced incidence of suicide and violence.

36. Health Risks of Antidepressants • Overdose • SSRIs at high doses or combined with other antidepressants or stimulants can cause Serotonin Syndrome (excess serotonin transmission) • Disorientation, agitation, fever, chills, diarrhea • If untreated, can lead to respiratory, circulatory, and kidney failure. • TCAS third most common cause of drug-related fatalities • Therapeutic index of TCAs only ~10-15. • SSRIs considerably safer in this regard.

37. Bipolar Disorder • Characteristic Symptoms • recurrent episodes of mania and depression • widespread cognitive deficits • subtypes of varying severity (I, II, cyclothymia) • Prevalence • up to 5% of population

38. Bipolar Disorder • Treatment Issues • long-term management is key • Ideal treatment is to: • stabilize acute symptoms • not induce alternate mood symptoms • prevent future relapses

39. Bipolar Disorder • Neuropathology of BD • Initially conceptualized as a neurochemical imbalance • Recent evidence of neuronal injury • Regional differences in neuronal density • Evidence of neuronal pathology in hippocampus • Cause or Effect? • Mechanisms of Drug Action • Recent evidence indicates antimanic drugs (e.g., lithium, valproic acid) increase levels of cellular-protective proteins and appear to reduce brain damage.

40. Lithium • History • 1940s, Lithium Chloride was used as salt substitute • severe toxicity, deaths • 1949, John Cade’s studies in Guinea Pigs • acceptance by medical community delayed • Lithium Carbonate • 1970s, clinical research demonstrated clear evidence for superior efficacy • Today’s “gold standard” in treating Bipolar Disorder. • Problems with compliance, largely due to side effects

41. Lithium • Pharmacokinetics • Absorption • Rapid by p.o. route • Peak blood levels within 3 hours, complete absorption within 8 hours • Therapeutic efficacy directly correlated to blood levels • Crosses BBB slowly and incompletely • Elimination • excreted unchanged by kidneys • 18-24 hr. half-life • When initiating once daily dosing, blood levels accumulate slowly over 2 weeks until steady levels reached. • Determining Therapeutic Dose • Close blood level monitoring required • Recommended levels ~ 0.5-0.7 mEq/l • Salt intake/excretion should be constant to avoid adverse effects of Lithium

42. Lithium • Pharmacodynamics • Lithium produces specific actions on mania, with no psychotropic effects in normal individuals. • Mechanism of action not well understood • second messenger signaling pathways • e.g., modulation of intracellular protein kinase enzymes • elevation of cellular protective protein, bcl-2

43. Lithium • Side Effects and Toxicities • Multiple Organ Systems • GI: nausea, vomiting, diarrhea, abdominal pain • Kidneys: increased urine output, increased thirst and water intake • Thyroid: depressed function, becomes enlarged, weight gain • Skin: rashes • CNS: tremor, lethargy, impaired concentration and memory, dizziness, slurred speech, ataxia, muscle weakness, nystagmus • Cardiovascular: cardiac arrhythmia

44. Lithium • Effects in Pregnancy • Teratogenic potential, particularly heart • Generally not advised during pregnancy, especially during first trimester. • If necessary tx. in a pregnant woman, discontinue use several days before delivery. • Problems with Compliance • Up to 50% of patients stop using AMA. • recurrent manic episodes and greatly increased suicide risk • Noncompliance largely due to intolerance of side effects, in particular weight gain and cognitive effects.

45. Neuromodulators/Anticonvulsants • Carbamazepine (Tegretol) • Studies in early 1990s indicated efficacy equivalent to lithium, although more recent studies show lithium to be superior. • Some patients resistant to both drugs respond to combination of the two. • Adverse effects include GI upset, sedation, ataxia, impaired vision, skin reactions, modest cognitive effects. • More serious risk: low white blood cell count, requires blood monitoring • Drug interactions due to stimulation of CYP3A4 liver enzymes • Teratogenic: neural tube defects in 1%

46. Neuromodulators/Anticonvulsants • Valproic Acid (Depakote) • Introduced in 1994 • GABA agonist • specific mechanisms of antimanic actions not yet determined • some evidence that gene expression modulated • Particularly effective in tx of acute mania, schizoaffective disorder, rapid cycling bd • Positive response in 71% of lithium-resistant pts. • Increased efficacy in combination with Lithium compared to either drug alone. • Side effects: • GI upset, sedation, lethargy, tremor, hair loss, cognitive impairments (in females, weight gain, polycystic ovaries, increased androgens) • Potential toxicities: • liver, pancreas, also teratogenic

47. Neuromodulators/Anticonvulsants • Gabapentin (Neurontin) • Introduced in U.S. as anticonvulsant in 1993 • Similar clinical efficacy to valproic acid, except gabapentin superior analgesic, valproate superior in tx of BD • GABA analogue, increases GABA levels in brain • Excellent pharmacokinetic profile: no binding to plasma proteins, not metabolized, excreted unchanged by kidneys, few pk drug interactions, half-life 5-7 hours • Results of clinical studies suggest this agent is most effective as adjunctive med. In pts. resistant to other more effective mood stabilizers. • Side effects: dizziness, dry mouth, somnolence, nausea, flatulence, reduced libido

48. Neuromodulators/Anticonvulsants • Other Neuromodulators • Pregabalin • under development for tx of GAD • Lamotrigine • effective tx of acute bipolar depression, poor tx of acute manic episodes • Inhibits glutamate release • Skin rashes possible serious side effect • Oxcarbazine • Improvement on carbamazepine • Topiramate • antiepileptic, alcohol relapse prevention; key advantage weight loss • Tiagabine • limited efficacy, no controlled studies in tx of BD • Zonisamide • Mid-2000 became available in U.S., prelim. studies show promise

49. Atypical Antipsychotics for Bipolar Disorder • Olanzapine (Zyprexa) • Recent studies have shown equivalent efficacy to lithium or valproic acid • mid-2000 FDA approved for short-term treatment of acute mania • Quetiapine (Seroquel) • Recent studies show efficacy in treatment of Bipolar Disorder • Others to be investigated • ziprasidone • aripiprazole