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

2. 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

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

4. 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

5. 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

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

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

8. 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

9. 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)

10. 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

11. 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

12. 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

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

14. 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?

15. 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

16. 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?

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

18. 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)

19. 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

20. 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

21. 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

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

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

24. 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

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

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

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

28. 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

29. 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 days
SSRIs, SNRIs, and NaSSA safe in overdose; TCAs unsafe
First episode- give for 3-6 months; repeat episodes at least 12 months

30. 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’

31. 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)

32. 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 ( meq/L)
For rapid cyclers (3-4x/year)- lithium and valproate or carbamazepine
Renal and liver functions monitored for lithium and valproate respectively

33. 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)

34. 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

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

36. 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

37. 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

38. 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

39. 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