pharmacological treatment of schizophrenia
TRANSCRIPT
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Pharmacological Treatment of Schizophrenia
Joanna Bennett
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CLASSIFICATION & CLINICAL USE WHO Classification
• Antipsychotics: drugs with therapeutic effects on psychoses and other types of psychiatric disorder
• Referred to as Neuroleptics - ability to produce a state of ‘neurolepsis’ or calm indifference without loss of consciousness
Clinical use• schizophrenia, mania, delusional disorder,
mood/bipolar disorder.
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DEVELOPMENT OF ANTIPSYCHOTICS Chance finding
• Promethazine a phenothiazine derivative found to possess sedative & antihistamine effects – encouraged the synthesis of other compounds
• Chlorpromzine synthesised in 1950 found to have profound calmative effects on disturbed psychotic patients
• Introduced into clinical practice in 1952
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MODE OF ACTION OF TYPICALS Carlsson & Lundquist (1963)
• Chlorpromazine blocked dopamine receptors in all areas of the brain
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nigrostriatal [movements]
mesolimbic [psychosis]
mesocortical [ negative symptoms]
tuberoinfundibular [prolactin]
Stahl, Essential Psychopharmacology;Cambridge University Press 1996
Important dopamine pathways
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SOME COMMON GROUPS OF TYPICAL ANTIPSYCHOTICS PHENOTHIAZINES
• chlorpromazine
BUTYROPHENONES• haloperidol
THIOXANTHENES• Flupenthixol• ?? Caribbean context
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DOPAMINE HYPOTHESIS
No certainty regarding the biochemical basis of schizophrenia, evidence suggest dopamine is involved to some degree (Dopamine hypothesis)
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EVIDENCE FOR DOPAMINE HYPOTHESIS
• Amphetamine, cocaine increase dopamine levels and can cause psychosis
• All antipsychotics block dopamine D2 receptors
• PET studies shows close correlation between the degree of D2 blockade and clinical improvement
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EVIDENCE AGAINST DOPAMINE HYPOTHESIS
• Only a proportion of patients respond to treatment with antipsychotics
• Atypical antipsychotics are just as effective but have more affinity to serotonin than dopamine
• Developing evidence suggesting functional and structural anomalies in the brain
• Other evidence suggest social and environmental factors important in explaining the trigger for psychosis or specific episodes
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EFFECTIVENESS OF TYPICALS/First Generation (FGAs) Effective in acute phase and as
maintenance therapy 80% Respond Positive symptoms (hallucinations,
delusions, thought disorder) No effect on negative symptoms 20 % treatment-resistant 50%-80% non-compliance
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SIDE EFFECTS OF TYPICALS Dopamine blockade –EPS (TD), raised
prolactin levels (sexual side effects, menstural problems, galactorrhoea)
Anticholinergic – dry mouth, urinary etc Postural hypotension Sedation Weight gain
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Atypical/Second Generation Antipsychotics (SGAs)
Clozapine, 1990 Remoxipride, 1991 Risperidone, 1993 Sertindole, 1996 Olanzapine, 1997 Quetiapine, 1998 Amisulpiride, 2000 Zotepine, 2000 Ziprasidone Aripiprazole
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What does atypical mean? An antipsychotic that does not cause
EPS at therapeutic doses
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Pharmacology of Atypicals All atypical antipsychotics (clozapine,
rispiridone, olanzapine, quetiapine) show high occupancy of 5HT2a receptors and low occupancy of D2
D2 binding variable – low for clozapine & quetipapine and higher for rispiridone & olanzapine and is dose dependent
Degree of D2 occupancy (72-78%) = EPS, elevation of prolactin levels (sexual side effects)
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Receptor Binding AffinitiesHaloperidol Clozapine Risperidone Olanzapine Sertindole Quetiapine
D1 +++ ++ ++ +++ +++ +D2 ++++ ++ ++++ +++ +++++ ++D3 +++++ ++ ++++ +++ ++++ +D4 ++++ ++ ++++ +++ +++ -5HT1a - + ++ - ++ -5HT2a + +++ +++++ ++++ ++++ +5HT2c - +++++ +++ ++++ +++++ ++5HT3 - ++ - ++ - +
1 ++ +++ +++ +++ +++ ++++
2 - +++ +++ - - +H1 - ++++ ++ ++++ + ++++M1 - +++++ - +++++ + +++M2 - ++++ - ++++ +M3 - ++++ - ++++ -M4 - ++++ - ++++ +
Pickar. Lancet (1995) 345, 557-562Seeman et al. Curr.Opin.Neurol.Neurosurg. (1993) 6, 602-608Bymaster et al. Neuropsychopharmacology (1996) 14, 87-96Schotte et al. Psychopharmacology (1996) 124, 57-73Moore et al. Curr.Opin.Invest.Drugs. (1993) 2 (4), 281-293
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EFFECTIVENESS of Atypicals There is no clear evidence that atypical
antipsychotics are more effective or are better tolerated than conventional antipsychotics.
Apart from clozapine none of the other atypical are superior to typical antipsychotics in reducing pos. or neg. symptoms
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EFFECTIVENESS of Atypicals All are less likely to cause movement
disorder (good prescribing) Only clozapine has proven efficacy in
treatment-resistant schizophrenia Olanzapine is associated with greatest
weight gain and increases in measures
of glucose and lipid metabolism.
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Metabolic side effects Evidence of association between metabolic
disturbances and the use of atypical antipsychoitics
The ‘metabolic syndrome’ include:• Obesity• Diabetes • Dyslipidemia
Metabolic syndrome significantly accelerates risk for premature CHD
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Metabolic side effects Differences between the atypicals with respect
to relative risk of metabolic disturbances Agent Weight gain Risk for Diabetes Worsening lipid
profile Clozapine +++ + +
Olanzapine +++ + + Risperidone ++ D D Quetiapine ++ D D Aripiprazole* +/- - - Zaprasidone* +/- - -
+ Increased effect; - no effect D discrepant results* Newer drugs with limited long term data
American Diabetes Society (2004)
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2009 PORT treatment recommendations
Evidence Review Group (ERG)
Extensive literature review
Since the last PORT (2004) over 600 studies published on the pharmacological treatment of schizophrenia
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Key studies: Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE)(2005)
Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS)(2006)
2 largest, non-industry sponsored comparisons (FGA) and (SGA) medications in people with multi-episode schizophrenia
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PORT Recommendations muli-episode Schizophrenia
Treatment of acute positive symptoms• antipsychotic medications other than
clozapine
• choice of antipsychotic should include:• individual preference• prior treatment response• side effect & adherence history• relevant medical history
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PORT Recommendations cont… Daily dosage FGAs 300–1000 chlorpromazine
equivalents (CPZ) T
dosage of SGAs - acute symptom episode• aripiprazole: 10–30 mg• olanzapine:10–20 mg• paliperidone: 3–15 mg • quetiapine: 300–750mg• risperidone: 2–8 mg• ziprasidone: 80–160 mg
Treatment trials should be at least 2 - 6 weeks
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PORT Recommendations 1st episode Schizophrenia Antipsychotic medications, other than clozapine
and olanzapine
No significant short-term efficacy differences between FGAs and SGAs
Significant differences in adverse effects, including drug-induced movement disorders and metabolic side effects, between and among FGAs and SGAs
These should be considered in shared decision making around selection of initial antipsychotic treatment
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PORT Recommendations 1st episode Schizophrenia: Dosage Antipsychotic should be started with
doses lower
Lowest effective doses is especially important in people with first-episode schizophrenia in order to establish treatment acceptance and reduce the severity of adverse effects.
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Maintenance Treatment maintenance therapy with FGA or SGA
reduces the risk of symptom relapse during the first to second year following an acute symptom episode.
the lowest effective dose should be used for maintenance treatment
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Long-acting antipsychotics (LAI) Offered as an alternative to oral
medication for maintenance treatment when the LAI formulation is preferred to oral preparations.
current evidence is insufficient to recommend a specific LAI antipsychotic agent
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Soteria Paradigm (Mosher et al 2004)
1960s /1970s- attempts to create therapeutic community alternatives to hospitalization for people diagnosed with schizophrenia.
Attempts to understand schizophrenia not as an illness needing medical intervention but rather as an important aspect of an individual’s life history
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Soteria Paradigm Rather than use of antipsychotic
medication as a first course of treatment, such initiatives emphasized the need to allow individuals to go through their experience of psychosis with minimal interference and high levels of support
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Soteria Paradigm Soteria critical elements:
• provision of a small, community-based therapeutic milieu -lay person staffing
• preservation of personal power, social networks, and communal responsibilities,
• no or low dose antipsychotic medication (choice and without coercion).
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Soteria Paradigm: Effectiveness Calton et al (2008) review of controlled studies
• Suggest that the Soteria paradigm yields equal, and in certain specific areas, better results in the treatment of people diagnosed with first- or second-episode schizophrenia compared with conventional, medication-based approaches.
• Achieving with considerably lower use of medication
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ReferencesBuchana et al (2010) The 2009 Schizophrenia PORT Psychopharmacological Treatment Recommendations and Summary Statements. Schizophrenia Bulletin vol. 36 no. 1 pp. 71–93,doi:10.1093/schbul/sbp116
Calton, T, Ferriter, M, Huband, Spandler, H (2008) A Systematic Review of the Soteria Paradigm for the Treatment of People Diagnosed With Schizophrenia. Schizophrenia Bulletin vol. 34 no. 1 pp. 181–192, doi:10.1093/schbul/sbm047
Jones PB, Barnes TR, Davies L, et al.(2006) Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1).Arch Gen Psychiatry.63:1079–1087.
Lieberman JA, Stroup TS, McEvoy JP, et al. (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med.353:1209–1223.