Treatment approach to treatment resistant schizophrenia

1. Dr Rakesh Mehta

2.  Treatment-resistant schizophrenia
(TRS) has been defined as the
persistence of symptoms despite ≥2
trials of antipsychotic medications of
adequate dose and duration with
documented adherence.¹

3.  Three key elements define the concept of
treatment resistant schizophrenia:
1. a confirmed diagnosis of
schizophrenia based on validated criteria,
2. adequate pharmacological treatment,
and
3. persistence of significant symptoms
despite adequate treatment.

4.  TRS occurs in up to 34% of patients with
schizophrenia.
 Although persistent symptoms may be
negative or cognitive, persistence of positive
symptoms is generally one of the defining
features of TRS.

5.  TRS results from lack of response to adequate
exposure to medication with no confounding
factors,
 whereas Pseudo-resistance may occur as a
result of medication nonadherence,
◦ ↓ plasma levels of a medication,
◦ inadequate dosage or duration of treatment,
◦ misdiagnosis,
◦ adverse events of a treatment masking a response,
◦ the presence of confounding psychiatric or medical
comorbidities.

6.  Outcomes for patients with treatment
resistance may be improved if identification
of TRS occurs earlier in the course of disease
rather than after a long duration of untreated
psychosis

7. Number
of Failed
AP Trials
Specified
Antipsychotic
Adequate
Treatment Episode
Duration
APA 2 At least one of which
is a second generation
antipsychotic”
>6 weeks
Maudsley 2 Consider use of either
first- or second
generation
antipsychotic
2–3 weeks for trial of first
Antipsychotic in First
episode psychosis;
6-week trial for a
subsequent Antipsychotic
NICE 2 “One of the drugs
should be a
nonclozapine second
generation
antipsychotic
Not specified

8.  The DSP hypothesis was first proposed by
Chouinard et al. in 1978.
 The main known mechanism of action for
antipsychotic medication is dopamine D2
receptor (DRD2) blockade
 The dopaminergic changes following
continuous receptor blockade with an
antipsychotic medication are proposed to
involve increases in DRD2 receptor density

9.  In turn, increases in antipsychotic medication
doses to control breakthrough symptoms are
thought to lead to further increases in DRD2
density, resulting in increased dopamine
supersensitivity, and consequently, the
reemergence of symptoms

10.  Hyperdopaminergic
◦ Increased striatal dopamine synthesis and release
capacity in vivo are linked to psychotic relapse and
the development of the first psychotic episode.
 Normodopaminergic
◦ Positron Emission Tomography studies showing
that dopamine synthesis capacity in the striatum is
significantly higher in vivo in patients with
treatment-responsive schizophrenia relative to
patients with TRS, who, in turn, have a dopamine
synthesis capacity similar to healthy controls

11.  A combination of dopamine transporter
[DAT-VNTR]) and serotonin transporter
[SERT-in2] polymorphisms has been
associated with TRS.⁴
 A study of two single-nucleotide polymorphisms
(SNPs) in the dopamine-degrading enzyme
catechol-O-methyltransferase (COMT)
demonstrated that a higher-activity haplotype was
protective against TRS in women but not men.

12.  Notably, these genes were not all related to
dopaminergic receptors, indicating that
development of TRS may occur through
multiple pathways

13.  According to the glutamate hypothesis,
NMDA receptor dysfunction on GABA
interneurons causes hyperactivation of
glutamate neurons,
 In turn, stimulates activity of dopaminergic
projections from the midbrain to the
striatum, resulting in the positive symptoms
of schizophrenia.

14.  some patients with schizophrenia have a loss
of GABAergic neurons in the hippocampus.
 GABA has a regulatory effect on dopamine
activity,
 the loss of inhibitory GABAergic neurons
could lead to the hyperactivity of
dopaminergic neurons

15.  Current hypotheses posit serotonin excess as
a cause of both positive and negative
symptoms in schizophrenia.
 Serotonin antagonist activity of clozapine and
other SGA
 Decrease positive symptoms in chronic
patients has contributed to the validity of this
hypothesis

16.  Postmortem studies in schizophrenia have
demonstrated decreased muscarinic and
nicotinic receptors in the caudate-putamen,
hippocampus, and selected regions of the
prefrontal cortex.
 These receptors play a role in the regulation
of neurotransmitter systems involved in
cognition, which is impaired in schizophrenia.

17.  Secondary Psychotic Disorders
◦ Substance induced- amphetamine, belladonna, alcohol,
barbiturate withdrawal, cocaine, phencyclidine
◦ Epilepsy-especially temporal lobe epilepsy
◦ Neoplasm, cerebrovascular disease, or trauma-especially frontal
or limbic
 Other conditions
◦ Acute intermittent porphyria
◦ AIDS
◦ Vitamin B12 deficiency
◦ Carbon monoxide poisoning
◦ Heavy metal poisoning
◦ Herpes encephalitis, Homocystinuria, Huntington's disease
◦ Neurosyphilis
◦ Normal pressure hydrocephalus
◦ Pellagra
◦ Systemic lupus erythematosus
◦ Wernicke - Korsakoff syndrome
◦ Wilson's disease

18.  Other Psychotic Disorders
◦ Schizophreniform disorder differs from
schizophrenia in that the symptoms have a duration
of at least 1 month but less than 6 months.
◦ Brief psychotic disorder is the appropriate diagnosis
when the symptoms have lasted at least 1 day but
less than 1 month

19.  Schizoaffective disorder is the appropriate
diagnosis when a manic or depressive
syndrome develops concurrently with the
major symptoms of schizophrenia
 Nonbizarre delusions present for at least 1
month without other symptoms of
schizophrenia or a mood disorder warrant the
diagnosis of Delusional disorder.

20.  Delusions seen with Psychotic Depression are
typically mood congruent and involve themes
such as guilt, self-depreciation, deserved
punishment, and incurable illnesses.
 Delusions in Mania are most often mood
congruent and typically involve grandiose
themes.

21.  Personality Disorders:
◦ Schizotypal, schizoid, and borderline personality
disorders are the personality disorders with the
most similar symptoms. Severe obsessive-
compulsive personality disorder may mask an
underlying schizophrenic process.
 Malingering and Factitious Disorders
◦ falsification of psychotic symptoms
◦ have some obvious financial or legal reason

22.  On antipsychotic, approx 60 % will achieve a
complete remission or experience only mild
symptoms. ⁶
 the remaining 40 % of patients will improve
but still have some positive symptoms that
are resistant to the medications.

23.  2-3 week trial on an adequate dose no
improvement (FGA/SGA)
 Consider measuring drug level.
◦ Drug adherance Y/N
◦ Increase the dose to min effective therapeutic level
◦ Change drug
 If even a mild amount of improvement is seen
 wait 4 weeks before changing.

24.  If poor response to FGA it is highly unlikely
that another FGA will work
 Consider changing to SGA
 Wait for the response for at least 2-3weeks
 No improvement CONSIDER CLOZAPINE
 Studies has shown 60% of these patient show
improvement under clozapine when treated
for 6 months.

25.  A trial of clozapine should last at least 8
weeks at a dosage from 300 to 800 mg/day.
 If a person treated with clozapine has failed
to demonstrate an adequate response, then a
clozapine level should be obtained to
ascertain whether the clozapine level is above
350 ng/ml.
 If the blood level is less than 350 ng/ml, then
the dosage should be increased, to the extent
that side effects are tolerated, to achieve a
blood level above 350 ng/ml.

26.  Extra Pyramidal Side effects
◦ most commonly with FGA
◦ add an antiParkinson medication, or change the patient
to an SGA.
◦ Akathisa : B-blockers propranolol 30-90mg/day
 Tardive Dyskinesia
◦ use the lowest effective dose
◦ consider switching to a different drug.
◦ Clozapine has been shown to be effective in reducing
severe tardive dyskinesia or tardive dystonia.
 Excessive Sedation/ Weight gain:
◦ Consider switching to AP with better side effect profiles.

27. Drugs Sedation Weight
gain
Akathisia Parkinsonism Min/Max
dose
Olanzapine ++ +++ - - 5mg/20mg
Aripiprazole - - + - 10/30mg
Quetiapine ++ ++ - - 150/750mg
Clozapine +++ +++ - - 900mg
Amisulpride - + + + 300/1200mg
Risperidone + ++ + + 2/16mg
Trifluoperazine + + + +++ 10/30mg
Chlorpromazine +++ ++ + ++ 200/1000

29.  ECT is treatment of last resort.
◦ Effective for Acute Schizophrenia
◦ Marked positive symptoms, catatonia, or affective
symtoms.
◦ Improvement is rapid.
◦ Administered 2-3 times a week
◦ More than 15 sessions may be needed.
◦ If not improving after 6-10 sessions, bilateral
placement and high-density treatment should be
done before abandoning.

30. Goal is to develop social and vocational skills for
independent living.
 Social Skills Traning
 Family Oriented Therapy
 Group Therapy
 Congnitive Behavioral Therapy
 Individual Psychotherapy
 Personal Therapy
 Dialectical Behavior Therapy
 Vocational Therapy
 Art Therapy

31. REFERENCES
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