Pharmacological Treatment of Schizophrenia

Joanna Bennett

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.

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

MODE OF ACTION OF TYPICALS Carlsson & Lundquist (1963)

• Chlorpromazine blocked dopamine receptors in all areas of the brain

nigrostriatal [movements]

mesolimbic [psychosis]

mesocortical [ negative symptoms]

tuberoinfundibular [prolactin]

Stahl, Essential Psychopharmacology;Cambridge University Press 1996

Important dopamine pathways

SOME COMMON GROUPS OF TYPICAL ANTIPSYCHOTICS PHENOTHIAZINES

• chlorpromazine

BUTYROPHENONES• haloperidol

THIOXANTHENES• Flupenthixol• ?? Caribbean context

DOPAMINE HYPOTHESIS

No certainty regarding the biochemical basis of schizophrenia, evidence suggest dopamine is involved to some degree (Dopamine hypothesis)

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

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

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

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

Atypical/Second Generation Antipsychotics (SGAs)

Clozapine, 1990 Remoxipride, 1991 Risperidone, 1993 Sertindole, 1996 Olanzapine, 1997 Quetiapine, 1998 Amisulpiride, 2000 Zotepine, 2000 Ziprasidone Aripiprazole

What does atypical mean? An antipsychotic that does not cause

EPS at therapeutic doses

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)

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

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

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.

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

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)

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

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

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

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

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

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.

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

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

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

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

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).

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

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.