IzBen C. Williams, MD, MPH Lecturer. Biological Therapies and ECT OVERVIEW A. Neurotransmitter abnormalities are implicated in the etiology of most

BEHAVIORAL SCIENCE

IzBen C. Williams, MD, MPHLecturer

Biological Therapies and ECT

OVERVIEWA. 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


OVERVIEW: Pharmacokinetic principlesPlease 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.


OVERVIEW: Pharmacokinetic principlesC. 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.


OVERVIEW: 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)

Biological Therapies and ECTPharmacologic properties and side

effects of psychotropic medicationPharmacologic Property Side Effects

Dopamine D2 receptor blockade

Extrapyramidal movement disorders

Serotonin 5-HT2 receptor blockade

Organic and ejaculatory disturbances, hypotension

Histamine H1 receptor blockade

Sedation, drowsiness, weight gain

Muscarinic receptor blockade Dry mouth, blurred vision, constipation, urinary retention, sinus tachycardia, memory disturbances

Biological Therapies and ECTPharmacologic properties and side

effects of psychotropic medication (cont’d)Pharmacologic Property Side Effects

Adrenergic α₁ receptor blockade

Postural hypotension, dizziness, reflex tachycardia, ejaculatory disturbances

Adrenergic α₂ receptor blockade

priapism

Dopamine reuptake inhibition Psychomotor activation, aggravation of psychosis

Serotonin reuptake inhibition Gastrointestinal disturbances, insomnia, restlessness, orgasmic disturbances

Norepinephrine reuptake inhibition

Tremor, tachycardia

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ANTIPSYCHOTICAGENTS

Antipsychotic AgentsANTIPSYCHOTICS General considerationsA. 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.

Antipsychotic AgentsANTIPSYCHOTICS General considerationsC. 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

Antipsychotic AgentsANTIPSYCHOTICS Traditional antipsychotic agentTraditional 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,

Antipsychotic AgentsANTIPSYCHOTICS Traditional antipsychotic agentTraditional 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

Antipsychotic Agents ANTIPSYCHOTICS Atypical antipsychotic agent include

Clozapine - clozarilOlanzapine - zyprexaQuetiapine – SeroquelResperidone - ResperidolZiprasidone – GeodonAripiprazole - Abilify

Antipsychotic AgentsANTIPSYCHOTICS 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


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


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

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ANTIDEPRESSANT AGENTS

Antidepressant AgentsOverview: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

Antidepressant AgentsOverview: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

Antidepressant AgentsOverview: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

Antidepressant AgentsOverview: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

elderlyAlso 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

Antidepressant AgentsHeterocyclic AgentsHeterocyclic antidepressants block reuptake

of norepinephrine and serotonin at the synapse. Some also block reuptake of dopamineHeterocyclics 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)

Antidepressant AgentsHeterocyclic AgentsOther 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

Antidepressant AgentsSSRIs and SSNRIsSSRIs: selective serotonin reuptake blockade; SSNRIs: serotonin and norepinephrine reuptake

blockadeSSRI 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

Antidepressant AgentsMAOIsMAOIs inhibit the breakdown of

neurotransmitters by monoamine oxidase A (MAOA) 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

Antidepressant AgentsMAOIsA major drawback to the use of MAOIs is its potential

for lethality when taken in conjunction with certain foods. This reaction occurs becausea. MAO metabolizes tyramine, a pressor in the GI tractb. If MAO is inhibited, ingestion of tyramine-rich foods or

sympatomimetic drugs can increase tyramine levelsc. 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

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MOOD STABILIZERS

Mood StabilizersMood Stabilizers: Used to treat Bipolar Disorder Lithium (carbonate or citrate) Anticonvulsants

Carbamazepine (Tegretol) Oxycarbamazepine (Trileptal) Valproic Acid (Depakote)

Mood StabilizersMood 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

Mood StabilizersMood 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

Mood StabilizersMood Stabilizers: Used to treat Bipolar DisorderAnticonvulsants 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

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ANTIANXIETY AGENTS

Antianxiety AgentsAntianxiety AgentsA. Benzodiazepines

BZs activate binding sites on the GABAA 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

Antianxiety AgentsAntianxiety AgentsA. 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

Antianxiety AgentsAntianxiety AgentsB. Non-benzodiazepinesI. Buspirone (BuSpar) is an azaspirodecanedione. It

is not related to the benzodiazepinesa. 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

Antianxiety AgentsAntianxiety AgentsNon-benzodiazepinesII. 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

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ElectroconvulsiveTherapy (ECT)

Electroconvulsive Therapy

A. Uses of ECT1. ECT provides rapid, safe treatment for some

psychiatric disturbancesa. 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


A. Uses of ECTECT 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


B. Administration of ECT1. 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


B. Administration of ECT5. Bifrontal ECT: one electrode placed above

the end of each eyebrow6. 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


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.


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

Documents

IzBen C. Williams, MD, MPH Lecturer. Biological Therapies and ECT OVERVIEW A. Neurotransmitter abnormalities are implicated in the etiology of most