Medication for

Psychoses. The Risks

versus Benefits
Prof Dr Philip George
Principles Of Drug Treatment
In Psychiatry

 Potential benefits outweigh any side

effects
 Keep in mind dangerous side effects and
interactions with other drugs and food
 Problems associated with certain groups
of patients
– elderly, pregnant, breast feeding
mothers and those with suicidal risk
 Cost of the drug and compliance of the
patient

 If treatment fails
– review the diagnosis
– review the drug dosage and / or
duration
– subjects compliance
 Incomplete response and/or poor
prognosis
– Adjust doses
– Long-term medication
– (consider depot if compliance poor)
 Counseling and support for family (reduce
EE)
 Assess needs for sheltered work or
housing
Since all drugs within a class are
equally effective, the choice of a
drug often depends on it’s side-
effects
Psychoses
 Schizophrenia is one of the most severe
and debilitating of forms of mental
disorder with a lifetime prevalence across
all populations of around 1%.
 Thought disturbances, hallucinations,
delusions, disturbances in emotion and
feelings
 Cognitive impairments – memory,
attention and perception.
 10% die by suicide
 Commonly starts during early adulthood,
can be lifelong resulting in considerable
social, functional and economic
impairments.
 Other illnesses a/w psychoses incl;
 MDP
 PsychoticDepression
 Organic Psychotic Disorder
 Drug-induced Psychoses
Management
 Hospitalization
 Pharmacological
 Physical
 Social
 Psychological
Antipsychotics
 Bother some side-effects

 Patients need to be properly educated

 Unpleasant side-effects can lead to

refusal to take medication
General Pharmacology
strategies

Indication: Establish a diagnosis and

identify the target symptoms that will be
used to monitor therapy response.
Choice of agent and dosage: Select an
agent with an acceptable side effect
profile and use the lowest effective dose.
Remember the delayed response for
many psych meds and drug-drug
interactions.
 The patient should understand the
benefits and risks of the medication.
Make sure to document this discussion.

 Implement a monitoring program: Track

and document compliance, side effects,
target symptom response, blood levels
and blood tests as appropriate.
The Dopamine Hypothesis:
Two Components

 Psychosis due to a functional excess of

dopamine
 Antipsychotic effects due to a blockade of
dopamine receptors
MESOCORTICAL

 Projects from the ventral tegmentum

(brain stem) to the cerebral cortex.
 This pathway is where the negative
symptoms and cognitive disorders (lack
of executive function) arise.
 Problem here for a psychotic patient, is
too little dopamine.
MESOLIMBIC
 Projects from the dopaminergic cell
bodies in the ventral tegmentum to the
limbic system.
 This pathway is where the positive
symptoms come from (hallucinations,
delusions, and thought disorders).
 Problem here in a psychotic patient is
there is too much dopamine.
NIGROSTRIATAL
 Projects from the dopaminergic cell
bodies in the substantia nigra to the
basal ganglia.
 This pathway is involved in movement
regulation.
 Dopamine suppresses acetylcholine
activity. Dopamine hypoactivity can
cause Parkinsonian movements i.e.
rigidity, bradykinesia, tremors),
akathisia and dystonia.
TUBEROINFUNDIBULAR
 Projects from the hypothalamus to the
anterior pituitary.
 Dopamine release here
inhibits/regulates prolactin release.
 Blocking dopamine in this pathway will
cause hyperprolactinemia
(gynecomastia/galactorrhea/decreased
libido/menstrual dysfunction).
Typical antipsychotics

 Dopamine receptor antagonists D2

 Effective for treating positive symptoms
 Positive points
– Inexpensive
– As effective as atypicals for positive
symptoms
– Have intramuscular forms for acute or
depot use.
Dopamine receptor
antagonist
Shortcomings include;
Side-effects
 E.P.S.
Psuedoparkinsonism Dystonias
Tardive dyskinesia Akathesia
Cognitive impairments
Anticholinergic effects ……….. Dry
mouth, constipation,
Weight gain blurred vision, urinary sx.
Sedation
Orthostatic hypotension
Galactorrhea/amenorrhea
Sexual dysfunction
Neuromalignant Syndrome
Compounds Available

Phenothiazines
1.Aliphatic side chain Chlorpromazine
2.Piperidine side chain Thioridazine
3.Piperizine side chain Trifluoperazine, Fluphenazine
Thioxanthines Flupenthixol, Clopenthixol
Butyrophenones Haloperidol
Diphenylbutylpiperidines Pimozide
 Sedation Anti- E.P.S.
Cholinergic

low potency
• Chlorpromazine +++ ++ ++
(100mg)
• Thioridazine ++ +++ +

high potency
• Haloperidol + + +++
(5mg)
• Trifluperazine + + +++
Antipsychotics: Atypicals
 The Atypical Antipsychotics - atypical
agents are serotonin-dopamine 2
antagonists (SDAs)
 They are considered atypical in the way
they affect dopamine and serotonin
neurotransmission in the four key
dopamine pathways in the brain.
Atypical antipsychotics
 As effective as the typical antipsychotics
 Effective for negative symptoms
 Less if any extrapyramidal side-effects
 SDA – serotonin-dopamine antagonists
 Serotonin opposes the release of dopamine in two
pathways –tuberoinfundibular & nigrostriatal

 Clozapine, Risperidone, Olanzepine, Quetiapine,

Asenapine, Paliperidone, Aripriprazole

 Metabolic Syndrome, sedation and EPS

Clozapine
 Most efficacious but with most lethal side-
effect – reserved for treatment resistant
Schizophrenia
 Agranulocytosis in 0.5 to 2%
 Need blood monitoring weekly for 18
weeks & then monthly
 Sedation & sialorrhea
 Increase risk of seizures
 300 to 600mg/day. Start slow and go slow
Risperidone
 Bipolar disorders & Schizophrenia
 Can elevate prolactin levels
 Reports of use in children
 Higher doses can cause EPS /
hyperprolactinemia
 Less weight gain
 3 to 6mg/day
Olanzepine
 Both Bipolar Disorders & Schizophrenia
 Reports of use in children & treatment of
refractory cases
 EPS unusual at recommended doses
 Once daily dose 10mg to 20mg nocte
 Cause sedation so useful for insomnia commonly
associated with Psychoses.
 Causes considerable weight gain in about 15% of
patients
 Watch for metabolic syndrome
Aripiprazole (Abilify)
 Available in regular tabs and depo form
 Unique mechanism of action as a D2
partial agonist
 Low EPS, no QT prolongation, low
sedation
 Could cause potential intolerability due to
akathisia / activation.
 Not associated with weight gain
 10 to 20mg/day
 Asenapine (Saphris)
 Sublingual (no food or liquid for 10 min)
 BID dosing required 5-10mg
 Can start at therapeutic dose
 Low weight gain and metabolic disturbances
 Sedation, somnolence, akathisia
 Not recommended for patients with severe
hepatic impairment
 Be careful with co-administration of
(CYP1A2 inhibitor)
Leucht S, et al. Lancet 2009; 373(9657):31-41. Slide courtesy of Dick Miyoshi
Antipsychotic adverse
effects
 Tardive Dyskinesia (TD)-involuntary
muscle movements that may not resolve
with drug discontinuation- risk approx. 5%
per year
 Neuroleptic Malignant Syndrome (NMS):
Characterized by severe muscle rigidity,
fever, altered mental status, autonomic
instability, elevated WBC, CPK and lfts.
Potentially fatal.
 Extrapyramidal side effects (EPS): Acute
dystonia, Parkinson syndrome, Akathisia
Agents for EPS
 Anticholinergics such as benztropine,
trihexyphenidyl, diphenhydramine
 Dopamine facilitators such as Amantadine
 Beta-blockers such as propranolol
 Need to watch for anticholinergic SE
particularly if taken with other meds with
anticholinergic activity ie TCAs
Case
 21 yo AA male with symptoms consistent
with schizophrenia is admitted because
of profound psychotic sx. He is treatment
naïve. You plan to start an antipsychotic-
what baseline blood work would you
obtain?
 Many atypical antipsychotics can cause
dyslipidemia, transaminitis and elevated
blood sugars and there is a class risk of
diabetes unrelated to weight gain so you
need the following:
 Fasting lipid profile
 Fasting blood sugar
 Lfts
 CBC
 FDA approved indications in Bipolar disorder

Generic Trade name Manic Mixed Maintenance Depressed

name

Aripiprazole Abilify
x x x
Ziprasidone Geodon
x x X*
Risperdone Risperdal
x x
Asenapine Saphris
x x
Quetiapine Seroquel
x X*
Quetiapine XR Seroquel XR
x X* x
Chlorpromazin Thorazine
e
x
Olanzapine Zyprexa
x x x
Olanzapine Symbyax
fluoxetine
x
comb

*denotes FDA approval for adjunct therapy not mono-therapy

 Antipsychotic or
Anti-Schizophrenic Agents?

 The Northwick Park “Functional Psychosis” Trial

compared pimozide and lithium to placebo
 Reduction of psychotic symptoms was equally
great in patients with elevated or depressed
mood and euthymic psychotic patients
 Suggested that neuroleptics may be general
antipsychotics, rather than specific for a
particular type of psychosis (e.g. schizophrenic
or affective)