Somatic Therapies: Psychopharmacology Electroconvulsive Therapy Vicente Soria Cabuquit MD, FPPA, FPCPsych, DPBP, DPM (Lond.) Professor, Department of Psychiatry UERMMMC

Objectives To learn the principles of rational drug use To use the STEPS approach as the paradigm for rational drug use To understand the mechanisms of drug actions and side effects

Outline of Talk Principles of Psychopharmacology Antipsychotics Antidepressants Mood Stabilizers Anxiolytics Electroconvulsive Therapy (ECT)

Principles of Psychopharmacology Psychopharmacology is the main form of treatment in psychiatry Psychotropic drugs are used as first choice in virtually all types of psychoses and mood disorders ( except in mild cases) Drugs combined with psychotherapy increase success rates Drugs, psychotherapy, and psychosocial interventions provide the best results

Principles of Psychopharmacology Avoid polypharmacy as much as possible All drugs cause side-effects; advise patients about the most common adverse events Psychiatric disorders are mainly chronic in duration and require long-term treatment Drug adherence a primary concern Involve family the earliest possible time

The STEPS Approach (PCPsych 2006) Learning the right STEPS S afety T olerability E fficacy P rice S implicity (in dosing)

Antipsychotics Classical (Typicals; 1st generation) Serotonin/Dopamine Antagonists (Atypicals; 2nd generation) Dopamine Partial Agonist (Atypical; 3rd generation?)

Typical Antipsychotics Chlorpromazine – typical prototype -profound impact on the treatment of mental illness Haloperidol- another typical standard developed later -until lately (mid -1990s) typicals the main/core treatments for schizophrenia

Clinical Indications of Antipsychotics Schizophrenias (all phases) Mood disorders (with psychotic features) Delusional disorders Psychoses due to substance abuse or medical conditions Control of challenging behaviours among patients with learning disabilities/dementias (off label use)

Mechanisms of Action of Typicals Potent D2 blockers, minimal 5HT2a blockers Various dopamine pathways influenced; determine clinical effects like efficacy and tolerability Also block NA, Ach, H2

Safety/ Tolerability of Typicals Main problem: EPS(40-70%); a form of brain damage with loss 3% of cortical matter Most troublesome is tardive dyskinesia ( 5-30% per year); usually permanent PETscans: below 78% D2 occupancy → no EPS; above 78% → with EPS

Efficacy of Typicals Effective in control of positive symptoms and prevention of relapse 70% respond; 50% partial response Poor response on negative symptoms and cognitive deficits

Optimal Doses of Typicals Optimal dose = maximum efficacy + minimum adverse events + lowest therapeutic dose For CPZ: between 300-1000 mg Lower/higher than the above: not recommended

Optimal Dose of Haloperidol Routine high dose not recommended PETscans - Haloperidol 2 mg/day induce levels of D2 receptor occupancy rates (53-74%) with significant clinical improvement - Is it the optimal dose for haloperidol?

Typicals in Maintenance Treatment Can medications be stopped after a few years of remission? Could be tricky Six (6) studies on patients on remission for 1-5 years showed 75% relapsed over a 15-month period No reliable criteria who could be good risks for stoppage Rule : maintain at lowest effective dose

Typicals in Chronic Treatment About 1/5 to 1/3 derive little benefit; a smaller proportion totally resistant Nearly 40% partial responders Could be endogenous trait?

Price and Simplicity (in dosing) Very affordable. Less than 20 pesos/day Given 2-4x a day. Problem of adherence a worry

Atypical Antipsychotics Currently the drugs of choice for psychoses Used as adjunct treatment for mood disorders; latest studies suggest (not very convincingly) use for GAD With tolerability problems like weight gain, type 2 diabetes Expensive (some generics are now available)

Atypical Antipsychotics Clozapine- the first, the best, the dangerous Risperidone- only atypical that elevates prolactin Olanzapine- produces greatest weight gain Quetiapine- sedation, somnolence common Aripiprazole- akathisia could be a problem Others: Paliperidone and sertindole

Mechanism of Action of Atypicals Serotonin/Dopamine Antagonism Blockade of 5HT2a and D2 receptors 5HT2a prevents release of D2 in the NS and TI dopamine pathways → less EPS and prolactin side effects D2 release and 5HT2a blockade in MC pathways → improved (–) symptoms D2 blockade in ML pathway → reduced (+) s/s

Safety/Tolerability of Atypicals Less EPS, including tardive dyskinesia (none in clozapine) Less prolactin elevation Less worsening of (-) symptoms Less cognitive deficits But with different problems : weight gain, type 2 diabetes, QT prolongation

Efficacy of Atypicals More efficacy for (-) symptoms, cognitive, and depressive features than typicals More ‘broad spectrum’, e.g. bipolar disorders (quetiapine and aripiprazole)

Price and Simplicity (in dosing) Quite expensive. About 200-300 pesos/day Generics more affordable. Less than 100 pesos a day

Rational Use of Antipsychotics With price a concern, haloperidol is a good first choice; otherwise, any atypical would do (e.g. risperidone, aripiprazole, quetiapine) Start low and gradually increase dose Drug trial for 4-6 weeks; switch if needed Clozapine usually reserved for treatment-resistant cases; caution: agranulocytosis First episode: at least 6 mos. Chronic: at least 2 years

Choice of Antipsychotics: Summary Using the STEPS approach Safety – toss up between the two Tolerability – atypicals Efficacy – atypicals Price – typicals Simplicity - atypicals

Antidepressants Tricyclic Antidepressants (TCAs) Monoamine Oxidase Inhibitors (MAOIs) Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonergic and Noradrenergic (SNRIs) Noradrenergic and Specific Serotonergic Antidepressant (NaSSA)

Indications for Antidepressants Major Depression Other depressions (dysthymia) Bipolar Disorder (depressed phase) Anxiety disorders

Efficacy of Antidepressants Major depression – 70% response rate - 30% no response Bipolar disorders - at least 60%; monotherapy may cause mania; mood stabilizers may be preferred Anxiety disorders – 80% respond; can be combined with benzodiazepines

Rational Use of Antidepressants SSRIs drugs of choice (e.g. sertraline, fluoxetine) SNRIs and NaSSA are also good choices Drug trial for 4-8 weeks Therapeutic lag of about 10-14 days SSRIs, SNRIs, and NaSSA safe in overdose; TCAs unsafe First episode- give for 3-6 months; repeat episodes at least 12 months

Mood Stabilizers Drugs of choice for bipolar disorders (both phases) Mood disorders are believed essentially caused by synaptic and circuitry abnormalities Use of anticonvulsants based on so-called ‘kindling effect’

Mood Stabilizers Lithium carbonate- the first; very effective prophylactic Valproate- anticonvulsant; first line for mania; better tolerated than lithium Carbamazepine- alternative to lithium and valproate Others- lamotrigine Quetiapine and aripiprazole – atypicals with mood stabilizing effects (as combined Rx)

Rational Use of Mood Stabilizers Lithium or Valproate as first choices for acute mania; carbamazepine as second choice Quetiapine for combined therapy Drug trial for 3-4 weeks Lithium level assay needed (0.5-1.0 meq/L) For rapid cyclers (3-4x/year)- lithium and valproate or carbamazepine Renal and liver functions monitored for lithium and valproate respectively

Anxiolytics Most widely prescribed psychotropic drugs Potential for abuse Usually prescribed for short duration (2 -4 weeks); most patients do not abuse them Quick-acting (reason for being preferred)

Benzodiazepines High therapeutic index, little toxicity, (except with alcohol) and few drug-drug interactions Bind with specific benzodiazepine receptors in the brain; potentiate actions of GABA (major inhibitory neurotransmitter) → anxiolytic effect on the limbic system

Indications for Benzodiazepines Anxiety disorders Insomnia (short-term treatment) Alcohol/drug withdrawal

Commonly Used Benzodiazepines Alprazolam – excellent in short-term therapy Clonazepam- potent sedative/hypnotic Clorazepate- quick-acting; popular with GPs Diazepam- ‘therapeutic gold’; can cause paradoxical reaction (agitation, aggression rather than sedation) Flurazepam- long-acting hypnotic

Rational Use of Anxiolytics Limited period of use (3-6 weeks) Only a few would benefit from long-term use Knowledge of half-life of drugs useful: short (alprazolam); intermediate (clonazepam); long (flurazepam) Sudden stoppage after long use may cause withdrawal symptoms; gradual stoppage recommended

ECT as a choice First choice in patients who are actively suicidal, severely depressed and mute Given to drug-resistant cases of psychoses and mood disorders Should be combined with drug treatment Patient and family need to be reassured about the procedure Maintenance ECT of dubious value

Summary Psychopharmacology is the first line of treatment of psychiatric disorders Use of STEPS approach an essential way to rational drug treatment First choices: atypicals for psychoses, SSRIs for depression and anxiety disorders, lithium carbonate and anticonvulsants for mood disorders ECT usually as alternative choice