1. IzBen C. Williams, MD, MPH Lecturer

2. Biological Therapies and ECT  OVERVIEW A. Neurotransmitter abnormalities are implicated in the etiology of most psychiatric illnesses B. Although normalization of neurotransmitter levels by pharmacologic agents can ameliorate many of the symptoms, these agents cannot cure psychiatric disorders C. Psychotropic agents may also be useful in the treatment of symptoms of certain medical conditions

3. Biological Therapies and ECT  OVERVIEW: Pharmacokinetic principles : “  Please review Lecture #3: “Genetics, Anatomy, and Biochemistry of Behavior”. Recall…………. A. Absorption: function of dosage given and route of administration B. Distribution: occurs as a result of passage across membranes, via diffusion, transport, or endocytosis. Extent of deposition throughout body fluids, and lipid solubility of a drug affect its ability to cross the bbb.

4. Biological Therapies and ECT  OVERVIEW: Pharmacokinetic principles C. Elimination of a drug is a function of metabolism within and excretion from the body. Metabolites of a drug may have pharmacologic activity. The half-life of a drug is the time required for its plasma concentration to decrease by 50%. D. The Therapeutic Index of a drug is the ratio between a lethal dose and a clinically effective dose. Thus, the higher the therapeutic index, the safer the drug in clinical use.

5. Biological Therapies and ECT  OVERVIEW:  Drugs may act on one or more of the steps related to neurotransmission  Drugs may act on one or more of the steps related to neurotransmission (i.e. synthesis, release degradation, reuptake, or postsynaptic receptor augmentation or blockade)  This activity accounts for most of the therapeutic effects of and side effects of a specific drug (next slide)

6. Biological Therapies and ECT  Pharmacologic properties and side effects of psychotropic medication Pharmacologic PropertySide Effects Dopamine D 2 receptor blockadeExtrapyramidal movement disorders Serotonin 5-HT 2 receptor blockadeOrganic and ejaculatory disturbances, hypotension Histamine H 1 receptor blockadeSedation, drowsiness, weight gain Muscarinic receptor blockadeDry mouth, blurred vision, constipation, urinary retention, sinus tachycardia, memory disturbances

7. Biological Therapies and ECT  Pharmacologic properties and side effects of psychotropic medication (cont’d) Pharmacologic PropertySide Effects Adrenergic α₁ receptor blockadePostural hypotension, dizziness, reflex tachycardia, ejaculatory disturbances Adrenergic α₂ receptor blockadepriapism Dopamine reuptake inhibitionPsychomotor activation, aggravation of psychosis Serotonin reuptake inhibitionGastrointestinal disturbances, insomnia, restlessness, orgasmic disturbances Norepinephrine reuptake inhibition Tremor, tachycardia

8. - ANTIPSYCHOTIC AGENTS

9. Antipsychotic Agents ANTIPSYCHOTICS General considerations A. Antipsychotic drugs are primarily used to treat the signs and symptoms of psychosis. B. Their beneficial effects on psychotic symptoms are observed in a range of conditions, from schizophrenia, affective psychoses (psychotic mania, psychotic depression), paranoia, various substance- induced psychotic disorders, psychoses 2° to various medical and neurologic disorders, and delirium.

10. Antipsychotic Agents ANTIPSYCHOTICS General considerations C. Antipsychotics are also used medically to treat nausea, hiccup, intense anxiety and agitation, and Tourette disorder D. Commonly taken orally, but long-acting, “depo” forms available for non compliant patients (Fluphenazine LA, Haloperidol LA, and Resperidone LA among others) E. Antipsychotics can be classified as traditional or atypical depending on their side effect profile

11. Antipsychotic Agents ANTIPSYCHOTICS Traditional antipsychotic agent  Traditional antipsychotic agents act primarily by blocking central dopamine-2 (D₂) receptors.  Traditional anti psychotics are most effective against positive symptoms, although the negative symptoms of schizophrenia, (such as social withdrawal, flattened affect, cognitive disturbances) may improve with their continued treatment,

12. Antipsychotic Agents ANTIPSYCHOTICS Traditional antipsychotic agent  Traditional antipsychotics are classified according to their potency  Low potency agents, (eg. chlorpromazine and thioridazine) are associated primarily with non- neurologic adverse effects  High potency agents (eg. haloperidol and trifluoperazine are associated primarily with neurologic side effects

13. Antipsychotic Agents ANTIPSYCHOTICS Atypical antipsychotic agent include  Clozapine - clozaril  Olanzapine - zyprexa  Quetiapine – Seroquel  Resperidone - Resperidol  Ziprasidone – Geodon  Aripiprazole - Abilify

14. Antipsychotic Agents ANTIPSYCHOTICS Atypical antipsychotic agent 1. Serotoninergic systems appear to mediate the major mechanism of action in the atypical antipsychotics, in contrast to the traditional group which uses dopamine-2 (D₂) systems 2. However, atypical antipsychotics also affect to some extent the dopaminergic and noradrenergic systems

15. Antipsychotic Agents ANTIPSYCHOTICS Atypical antipsychotic agent 3. Atypical agents are now first line agents for treating psychotic symptoms 4. Advantages of atypical over traditional agents are a. Atypical agents may be more effective when used to treat the treat the negative, chronic and refractory symptoms of schizophrenia b. They are less likely to cause extrapyramidal symptoms, TD, and NMS

16. Antipsychotic Agents ANTIPSYCHOTICS Atypical antipsychotic agent 5. Disadvantages of atypical agents: a. Increased likelihood of hematologic problems, such as agranulocytosis (granulocyte count <1,000 facilitating severe infections), clozapine being the most problematic agent b. Increased likelihood of seizures, anticholinergic side effects, pancreatitis, weight gain, and type 2 diabetes

17. . ANTIDEPRESSANT AGENTS

18. Antidepressant Agents Overview: They are used to treat depression (but also have other clinical uses) 1. Heterocyclic antidepressants (HCAs) 2. Selective serotonin reuptake inhibitors (SSRIs) 3. Selective serotonin and norepinephrine reuptake inhibitors (SSNRI) 4. Monoamine oxidase inhibitors (MAOIs) 5. Atypical antidepressants

19. Antidepressant Agents Overview:  All antidepressants are believed to increase the availability of serotonin and/or NE in the synapse by way of inhibition of reuptake mechanisms (HCAs, SSRIs SSNRIs) or blockade of MAO (MAOIs), which ultimately leads to down- regulation of post synaptic receptors and improvement of mood

20. Antidepressant Agents Overview:  Because of their more positive side effect profile, SSRIs (eg fluoxetine) are now used as first line agents  All antidepressants take about 3-6 weeks to work and all have equal efficacy  Antidepressants do not elevate mood in depressed persons and have no potential for abuse. They can, however, precipitate manic episodes in potentially bipolar patients

21. Antidepressant Agents Overview:  Stimulants such as methylphenidate or dextroamphetamine may also be useful in treating depression. They work quickly hence…  Useful in improving mood in the terminally ill or elderly  Also useful in patients with depression which is refractory to other treatments and in those at risk for development of adverse effects to other antidepressants  Disadvantages include their addiction potential

22. Antidepressant Agents Heterocyclic Agents  Heterocyclic antidepressants block reuptake of norepinephrine and serotonin at the synapse. Some also block reuptake of dopamine  Heterocyclics also block muscarinic Acetylcholine receptors, resulting in anticholinergic effects (dry mouth, blurred vision, urine retention, constipation). They are contraindicated in patients with glaucoma  Histamine receptors are also blocked by HCAs resulting in antihistaminic effects (eg weight gain and sedation)

23. Antidepressant Agents Heterocyclic Agents  Other adverse effects include cardiovascular effects such as orthostatic hypotension, and neurologic effects such as tremor, weight gain and sexual dysfunction  HCAs are dangerous (potentially lethal) in overdose

24. Antidepressant Agents SSRIs and SSNRIs  SSRIs: selective serotonin reuptake blockade;  SSNRIs: serotonin and norepinephrine reuptake blockade  SSRI and SSNRI have little effect on dopamine, acetylcholine, or histamine systems  Because of their selectivity SSRIs and SSNRIs cause fewer side effects and are safer in overdose, and also safer in the elderly, and in pregnancy, than the HCAs or MAOIs  SSNRI may work more quickly (2-3 weeks) and cause fewer sexual side effects then SSRIs

25. Antidepressant Agents MAOIs  MAOIs inhibit the breakdown of neurotransmitters by monoamine oxidase A (MAO A ) in the brain in a reversible reaction (review lecture 3)  MAOIs may be particularly useful in the treatment of atypical depression and treatment resistance to other agents

26. Antidepressant Agents MAOIs  A major drawback to the use of MAOIs is its potential for lethality when taken in conjunction with certain foods. This reaction occurs because a. MAO metabolizes tyramine, a pressor in the GI tract b. If MAO is inhibited, ingestion of tyramine-rich foods or sympatomimetic drugs can increase tyramine levels c. Increase in tyramine can cause a hypertensive crisis, which can lead to stroke and death  Also, when administered with SSRIs, MAOIs can cause serotonin syndrome and death

27. . MOOD STABILIZERS

28. Mood Stabilizers Mood Stabilizers: U Mood Stabilizers: Used to treat Bipolar Disorder  Lithium (carbonate or citrate)  Anticonvulsants  Carbamazepine (Tegretol)  Oxycarbamazepine(Trileptal)  Valproic Acid (Depakote)

29. Mood Stabilizers Mood Stabilizers: U Mood Stabilizers: Used to treat Bipolar Disorder  Lithium (carbonate or citrate)  Mood stabilizer used to prevent both the manic and depressive phases of bipolar disorder  May be used also to increase the effectiveness of antidepressant agents in depressive illness and to control aggressive behavior

30. Mood Stabilizers Mood Stabilizers: U Mood Stabilizers: Used to treat Bipolar Disorder  Lithium (carbonate or citrate)  Adverse effects from chronic use include: hypothyroidism, tremor, renal dysfunction, cardiac conduction problems, gastric distress, mild cognitive impairment,  Takes 1-3 weeks to work hence use antipsychotics for acute manic phase  Maintain blood levels between.6 – 1.2 mEqL

31. Mood Stabilizers Mood Stabilizers: U Mood Stabilizers: Used to treat Bipolar Disorder Anticonvulsants  Used to treat mania, particularly rapid cycling bipolar disorder (more than four episodes annually) and mixed episodes (mania and depression occurring concurrently)  Carbamazepine  associated with aplastic anemia and agranulocytosis  Valproic acid  Useful in treating bipolar symptoms resulting from cognitive disorders, and migraine prophylaxis  Adverse effects include GI & liver problems, congenital neural tube defects and alopecia

32. . ANTIANXIETY AGENTS

33. Antianxiety Agents A. Benzodiazepines  BZs activate binding sites on the GABA A receptor thereby decreasing neuronal and muscle cell firing  These agents have a short, intermediate, or long onset and duration of action and may be used to treat disorders other than anxiety disorders  Their characteristics of action are related to their clinical indications and their potential for abuse;  For example, short acting agents are good hypnotics but have a higher potential for abuse than longer acting agents

34. Antianxiety Agents A. Benzodiazepines  BZs commonly cause sedation but have few other adverse effects  Tolerance and dependence may occur with chronic use of these agents  In cases of overdose, or when used for sedation during surgical procedures, Flumazenil, a BZ receptor antagonist can reverse the effects of BZs

35. Antianxiety Agents B. Non-benzodiazepines I. Buspirone (BuSpar) is an azaspirodecanedione. It is not related to the benzodiazepines a. It is non sedating and not associated with dependence, abuse or withdrawal problems, in contrast to the BZs b. It is used primarily to treat conditions causing chronic anxiety, in which BZ dependence can become a problem (eg generalized anxiety disorder) c. Buspirone takes up to two weeks to work and may not be acceptable to patients who are accustomed to BZs

36. Antianxiety Agents Non-benzodiazepines II. Zolpiden (Ambien) and zaleplon are short-acting agents unrelated to the BZs and used primarily to treat insomnia III. Carbamates (eg. Meprobamate) are used only rarely because they have a greater potential for abuse and a lower therapeutic index than BZs

37. . Electroconvulsive Therapy (ECT)

38. Electroconvulsive Therapy A. Uses of ECT 1. ECT provides rapid, safe treatment for some psychiatric disturbances a. Most commonly used to treat major depressive disorder that is refractory to antidepressants b. Indicated for serious depressive symptoms of any type (eg. psychotic depression) particularly when rapid resolution is imperative as in suicide risk c. Particularly useful for treating depression in the elderly

39. Electroconvulsive Therapy A. Uses of ECT ECT provides rapid, safe treatment for some psychiatric disturbances (perhaps through alteration of neurotransmitter function, as with neuroleptics) a. Most commonly used to treat major depressive disorder that is refractory to antidepressants b. Indicated for serious depressive symptoms of any type (eg. psychotic depression) particularly when rapid resolution is imperative as in suicide risk c. Particularly useful for treating depression in the elderly

40. Electroconvulsive Therapy B. Administration of ECT 1. ECT involves inducing a general seizure, lasting 25- 60 seconds, by passing an electric current across the brain 2. Firstly, premedication; then administration of a short acting general anesthetic and a muscle relaxant to prevent injury during seizure 3. Unilateral ECT: two electrodes on the non- dominant hemisphere 4. Bilateral ECT: one electrode placed on each temple

41. Electroconvulsive Therapy B. Administration of ECT 5. Bifrontal ECT: one electrode placed above the end of each eyebrow 6. With unilateral and bifrontal ECT, there are fewer side effects but less efficacy than with bilateral ECT 7. Improvement in mood typically begins after a few ECT treatments. A maximum response to ECT treatments is usually seen after 5-10 treatments given over 2-3 weeks

42. Electroconvulsive Therapy C. Problems associated with ECT 1. Memory problems is the major adverse effect of ECT. These problems include  an acute confusional state,which lasts about 30 minutes and then remits  Anterograde amnesia, which resolves within a few weeks  Retrograde amnesia (inability to remember events occurring up to two months prior to the ECT course; These memories rarely return.

43. Electroconvulsive Therapy C. Problems associated with ECT 2. Major contraindications for ECT are…..  Increased intracranial pressure  Recent (within 2 weeks) myocardial infarction 3. Mortality rate associated with ECT is very low and is comparable with that associated with induction of general anesthesia