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Los ensayos naturalistas sobre la efectividad de los antipsicóticos atípicos son necesarios para aportar una información más amplia sobre la eficacia, la seguridad y la tolerabilidad en pacientes con esquizofrenia tratados en un centro médico de la comunidad.
En este estudio multicéntrico abierto de 26 semanas, diversos pacientes con esquizofrenia, que necesitaron un cambio en la medicación antipsicótica porque no toleraban bien la medicación actual y/o porque los síntomas clínicos no estaban bien controlados, se aleatorizaron para recibir aripiprazol o un tratamiento estándar (TE) con un antipsicótico atípico (por ejemplo, olanzapina, quetiapina o risperidona en función del juicio del investigador sobre el tratamiento óptimo de cada paciente individual y la respuesta previa del paciente a la medicación antipsicótica). El objetivo principal fue comparar la efectividad de un tratamiento de 26 semanas con aripiprazol con el TE, medido por la puntuación total del Cuestionario de Evaluación del Investigador (IAQ) en la última observación arrastrada (UOA) de la semana 26 (variable primaria), una medida validada que controla el alivio o el empeoramiento de 10 síntomas clave asociados con la psicopatología de la esquizofrenia y los efectos secundarios del tratamiento antipsicótico. Los objetivos secundarios fueron evaluar la efectividad usando las escalas Impresión Clínica Global - Mejoría Global (CGI-I) e Impresión Clínica Global - Gravedad de la Enfermedad, para evaluar el tiempo transcurrido hasta la suspensión del tratamiento, la preferencia del paciente respecto a la medicación, y la calidad de vida y la tolerabilidad de aripiprazol comparado con el TE.
El tratamiento con aripiprazol (n=268) fue significativamente más eficaz que el TE (n = 254; P < 0,001; UOA de la semana 26), evidenciado por la puntuación IAQ total, desde la semana 4 (primera fase de evaluación) y se mantuvo hasta la semana 26. Una relación similar se demostró en los pacientes que terminaron el estudio (análisis de casos observados); aripiprazol se asoció con una efectividad significativamente mayor en todas las fases de evaluación con un mayor efecto diferencial de TE con el tiempo. Los pacientes tratados con aripiprazol también tuvieron mejorías significativamente mayores en la escala CGI-I (tasa de rspuesta, P = 0,009 en la UOA de la semana 26), y en la calidad de vida (puntuación total en la escala de Calidad de Vida; P < 0,001 en la semana 26). Además, una proporción significativamente mayor de pacientes que recibieron aripiprazol calificaron la medicación del estudio como “mucho mejor” en la escala del Cuestionario de Preferencias de Medicación (POM) que la medicación anterior al estudio comparados con los pacientes tratados con TE (P < 0,001; semana 26). El tiempo hasta la suspensión del tratamiento y las tasas de suspensión debidas a episodios adversos fueron similares en los dos grupos de tratamiento. La incidencia de pacientes con uno o varios síntomas extrapiramidales (por ejemplo, acatisia, distonía, episodios parkinsonianos y episodios residuales) fue mayor en los pacientes que recibieron aripiprazol comparados con los pacientes tratados con TE (13,5% frente a 5,6%); sin embargo, una proporción mayor de pacientes del grupo TE tuvo un aumento de peso clínicamente significativo (21,2% frente a 7,3% para aripiprazol) y de las concentraciones séricas (potencialmente importantes desde el punto de vista clínico) de colesterol total, colesterol de lipoproteínas de baja densidad, triglicéridos y prolactina comparados con los pacientes que recibieron aripiprazol.
Aripiprazol es un antipsicótico atípico eficaz para el tratamiento de la esquizofrenia, que ha demostrado más efectividad que los fármacos estándar usados en este estudio en pacientes que necesitaban un cambio en la medicación antipsicótica.
Naturalistic effectiveness trials of atypical antipsychotics are needed to provide broader information on efficacy, safety, and tolerability in patients with schizophrenia treated in a community practice setting.
in this 26-week, open-label, multicentre study, patients with schizophrenia requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled were randomized to receive aripiprazole or an atypical antipsychotic standard of care (SOC) treatment (i.e., olanzapine, quetiapine, or risperidone based on the investigator's judgment of the optimal treatment for the individual patient and the patient's prior response to antipsychotic medication). The primary objective was to compare the effectiveness of a 26-week treatment of aripiprazole versus SOC, as measured by the investigator Assessment Questionnaire (IAQ) total score at Week 26 last observation carried forward (LOCF) (primary endpoint), a validated measure that monitors relief or worsening of 10 key symptoms associated with the psychopathology of schizophrenia and side effects of antipsychotic treatment. Secondary objectives were to further assess effectiveness using the Clinical Global Impression – Global Improvement (CGI-I) and Clinical Global Impression – Severity of Illness scale, to assess time to treatment discontinuation, patient preference of medication, quality of life, and the tolerability of aripiprazole compared with SOC.
Aripiprazole treatment (n = 268) resulted in significantly better effectiveness than SOC treatment (n = 254; P < 0.001; Week 26 LOCF) as evidenced by the IAQ total score beginning at Week 4 (the first assessment point) and sustained through Week 26. A similar relationship was demonstrated among patients who completed the study (observed cases analysis); aripiprazole was associated with significantly better effectiveness at all time points with a greater differential effect from SOC over time. Patients treated with aripiprazole also demonstrated significantly greater improvements on the CGI-I scale (responder rate, P = 0.009 at Week 26 LOCF), as well as on quality of life (Quality of Life scale total score; P < 0.001 at Week 26). Furthermore, a significantly higher proportion of patients receiving aripiprazole rated their study medication as “much better” on the Preference of Medication Questionnaire (POM) scale than their pre-study medication compared with SOC patients (P < 0.001; Week 26). Time to treatment discontinuation and rates of discontinuation due to adverse events were similar in both treatment groups. The incidence of patients with one or more extrapyramidal symptom (e.g., akathisia, dystonia, parkinsonian events, and residual events) was higher in patients receiving aripiprazole compared with patients treated with SOC (13.5% vs. 5.6%); however, a higher proportion of patients in the SOC-treated group had clinically significant weight gain (21.2% vs. 7.3% for aripiprazole) and potentially clinically relevant elevated fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and serum prolactin compared with patients receiving aripiprazole.
Aripiprazole is an effective atypical antipsychotic for the treatment of schizophrenia, demonstrating better effectiveness than SOC agents used in this study in patients for whom a switch in antipsychotic medication was warranted.
Schizophrenia is a major cause of suicide, and symptoms characteristic of treatment-resistant disease are strong risk factors. Clozapine reduces symptoms in 60% of such patients and significantly decreases the risk of suicide.
To model the impact of increased clozapine prescribing on lives saved and resource utilisation.
A model was built to compare current levels of clozapine prescribing with a scenario in which all suitable patients with treatment-resistant schizophrenia received clozapine.
It was estimated that an average of 53 lives could be saved in the UK each year. If clozapine is cost-neutral, the cost per life-year saved is $.5108. If clozapine achieves a 10% reduction in annual support costs, the net saving is $8.7 million per annum. An average of 167 acute beds would be freed each year.
The use of clozapine in treatment-resistant schizophrenia saves lives, frees resources and is cost-effective.
Specific psychotropic drugs and disorders
David A. Collier, Section of Genetics Institute of Psychiatry, London, UK,
Maria J. Arranz, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK,
Sarah Osborne, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK,
Katherine J. Aitchison, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK,
Janet Munro, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK,
Dalu Mancama, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK,
Robert W. Kerwin, Section of Clinical Neuropharmacology Institute of Psychiatry, London, UK
Bernard Lerer, Hadassah-Hebrew Medical Center, Jerusalem
Clozapine is an atypical antipsychotic drug with unique clinical features, particularly in treatment resistant schizophrenia. This chapter concentrates on the genetics of response to the antipsychotic drug clozapine, focusing mainly on pharmacodynamic factors related to clozapine's receptor binding. It is important to note, however, that a pharmacogenetic effect is dependent on functional genetic variation; for some genes, there may be no genetic variation that affects clozapine's action. The use of neuropsychology to assess treatment response in schizophrenia is a new area of investigation. Genetic variation in clozapine's receptor targets is a potential source of pharmacodynamic influence on drug response, by altering drug action. Clozapine therapy has been used as a model system for pharmacogenetic research into antipsychotic drugs. This is largely for the historical reasons that it has high affinity for the dopamine D4 receptor, which shows extensive genetic variability, but also because its pharmacology is well understood.
To develop and introduce a drug treatment protocol for schizophrenia and to evaluate its effect on prescribing. Prescribing of antipsychotics was audited in January 1998. A prescribing protocol was then developed by a collaborative process involving all medical staff, and introduced in September1998. A second prescribing audit was conducted in February 1999.
The proportion of patients prescribed atypical drugs increased from 16.6% to 25.5%. Co-prescription of atypical and typical drugs was relatively uncommon compared with findings of other prescribing surveys. The use of anticholinergic medication was significantly more likely in patients receiving regular typical drugs alongside atypical agents than in those receiving atypicals alone.
Widely agreed prescribing protocols may promote improved prescribing practices. Co-prescription of atypical and typical drugs should be discouraged.
People prescribed clozapine for treatment-resistant schizophrenia have mandatory haematological monitoring through a case register for identifying reversible neutropenia.
To quantify risk factors for agranulocytosis in subjects receiving clozapine.
Data from 12 760 subjects registered to receive clozapine from January 1990 to April 1997 were analysed. Risk factors for agranulocytosis were quantified using a Cox proportional-hazards regression analysis.
The risk for agranulocytosis in Asian subjects was 2.4 times that in Caucasians (P=0.03). There was an age-related increase in risk of 53% per decade (P=0.0001).
The case register yielded valuable information for guiding research into the causes of the haematological reactions.
The dopamine hypothesis proposes that antipsychotic drugs act primarily through limbic cortical D2/D2-like dopamine receptor blockade.
To evaluate this hypothesis with the D2/D3-selective SPET probe [123I]-epidepride.
[123I]-epidepride SPETscans were performed on 12 patients with schizophrenia treated with antipsychotics and 11 age-matched healthy controls. [123I]-epidepride specific binding to D2/D3 dopamine receptors was estimated, and relative percentage D2/D3 receptor occupancy by typical antipsychotic drugs determined.
Mean (s.d.) daily dose was 669.12 (516.8) mg chlorpromazine equivalents. Mean percentage D2/D3 receptor occupancy was 81.6 (8.1) and 73.2 (13.9) in the temporal cortex and striatum respectively.
Typical antipsychotic drug treatment is associated with substantial temporal cortical D2/D3 receptor occupancy. The relationship between this and efficacy is poor in patients with treatment-resistant schizophrenia.
5-HT2A receptor antagonism may be crucial to the action of atypical antipsychotics. Previous work has related 5-HT2A receptor blockade to clinical efficacy and protection from extrapyramidal side-effects.
We developed a SPET imaging protocol for assessing 5-HT2A receptor binding using the selective ligand 1231-5-1-R91150. Six healthy volunteers, five clozapine- and five risperidone-treated subjects with DSM–IV schizophrenia were studied. Multi-slice SPET was performed on each subject.
Cortex: cerebellum ratios were significantly lower in both clozapine-and risperidone-treated subjects compared with the healthy volunteers in all cortical regions. There was no difference in occupancy between the two drug-treated groups. No correlation was found between the percentage change in the Global Assessment Scale (GAS) and 5-HT2A receptor binding indices in the drug-treated groups.
Clozapine and risperidone potently block 5-HT2A receptors in vivo. The lack of relationship between receptor binding indices and change in GAS suggests that 5-HT2A receptor blockade may be unrelated to clinical improvement. Future studies will substantiate this finding by studying 5-HT2A receptor binding in large groups of patients treated with both typical and novel atypical antipsychotics.
The early treatment of newly diagnosed schizophrenia has ramifications for the future psychiatric and social well-being of the patient. Changes in care structures and care delivery mechanisms, in addition to financial constraints and outcome targets, provide an additional incentive to ensuring that any intervention is both successful and cost-effective.
We compared regional cerebral blood flow (rCBF) in three groups of patients with DSM–III–R anxiety disorders.
Fifteen patients with obsessive–compulsive disorder (OCD), 15 with panic disorder with agoraphobia (PA), and 16 with post-traumatic stress disorder (PTSD) and a similar group of healthy controls were assessed on brain-dedicated high-resolution SPET.
MANOVA revealed significant rCBF differences between diagnostic groups (F=4.4; d.f.=3, 57; P=0.007) and between cerebral regions (F=6.4; d.f.=1, 57; P=0.01) in OCD and PTSD compared with PA and healthy controls, limited to bilateral superior frontal cortices and right caudate nuclei. Whole brain blood flow correlated positively with anxiety (r=0.24, n=46, P=0.05). Beck depression scores correlated significantly negatively with left caudate rCBF (r= –0.24, n=46, P=0.05) and right caudate rCBF (r= –0.31, n=46, P=0.02). PTSD syndrome severity correlated significantly negatively with the left caudate (r=-0.49, n=16. P=0.03) and with right caudate rCBF (r=-0.7, n=16, P=0.001)
Functional rCBF differences in anxiety disorders could relate to repetitive, intrusive, distressing mental activity, prominent in both OCD and PTSD.
Schizophrenia is highly expensive in calculable and incalculable costs. Measures which impact the cost in the most severely affected are likely to produce the greatest cost reductions. Studies regarding clozapine in the USA have demonstrated clear cost-effectiveness, despite the high prescription costs. There are no prior UK studies.
We performed a cost-effectiveness analysis comparing the three years prior to commencing clozapine to the period following establishment of clozapine treatment (mean 36.4 months) for 26 patients with chronic schizophrenia or schizoaffective disorder.
There was a significant improvement in all clinical ratings applied (and a mean net saving of £3768 per annum). The cost-effectiveness of clozapine was double that of conventional neuroleptics (15.2 pre-, 33.0 post-clozapine, P < 0.005).
As a naturalistic study our data provide valuable information on the cost-effectiveness of clozapine in the UK. Our methodology could be applied in a community setting or in the study of another atypical neuroleptic.
Numerous studies have attempted to relate brain morphology to treatment outcome in schizophrenia in an attempt to define subtypes of schizophrenia that may respond well to antipsychotic treatment (Brown & Herz, 1989). This has potential clinical significance since, if we can predict outcome based on brain structure, it would then influence treatment.
In a textbook of psychopharmacology published as recently as 1990, Hollister and Csernansky wrote about antipsychotics “It is most discouraging that more effective pharmacotherapy has not been developed. Present drugs have many deficiences: they are not curative; their ameliorative effects are often limited, many patients remain totally unresponsive; they are unpleasant to take so that many patients are less than fully compliant; they produce major side effects such as tardive dyskinesia whose full implications are still uncertain”.
We tested whether cortical and subcortical regional cerebral blood flow (rCBF) differs between patients with obsessive-compulsive disorder (OCD) and healthy controls. We then explored the relationship between rCBF and OCD mental state.
Thirty out-patients from the Maudsley Hospital with OCD as defined in DSM–III–R were scanned at rest using brain-dedicated, high-resolution, single photon emission tomography. RCBF was measured as uptake of 99mTc-HMPAO in 15 regions of interest and compared with rCBF data in 30 healthy people matched for age, sex and handedness. Symptom ratings were obtained using standard measures on the scanning day. Principal components factor analysis identified two distinct clinical dimensions: obsessive–compulsive (OC) and anxious–avoidant (AA). These were correlated with patients' rCBF measurements, using Spearman's rank correlation coefficient, and multiple regression coefficients calculated.
We found significant reductions in rCBF measurements of OCD patients compared with resting, healthy controls (F = 1.92, P = 0.04) in seven brain regions: the right and left superior frontal cortex, right inferior frontal cortex, left temporal cortex, left parietal cortex, right caudate nucleus and right thalamus. Regional differences were not secondary to generalised reduction in patients' brain perfusion. Reduced blood flow to the right inferior frontal cortex correlated significantly with illness severity (r = 0.37, P = 0.02). There was no relationship with age, age-of-onset, sex, handedness, depression or medication status. OC clinical dimension, concerning obsessions, compulsions and low mood, was significantly negatively correlated with left inferior frontal, medial frontal and right parietal rCBF. AA dimension, concerning anxiety and avoidance, was significantly positively associated with left and right superior frontal, right inferior frontal, medial frontal cortical, and right and left caudate and thalamic rCBF.
rCBF differs significantly between resting OCD patients and healthy controls, and separate clinical dimensions are associated with functionally distinct rCBF patterns.
Clozapine is an effective antipsychotic that has high affinity for serotonin type 2 (5-HT2) receptors. The importance of 5-HT antagonism in the overall clinical efficacy of clozapine is unclear. Using a neuroendocrine strategy we tested the hypothesis that clinical response to clozapine is related to alteration in 5-HT function.
Ten treatment-resistant schizophrenic subjects were treated with clozapine for a mean of 10.3 (s.e. 0.9) weeks; d-fenfluramine (DFEN) challenge tests were performed before and after treatment with concurrent clinical ratings (BPRS, SAPS, SANS) made at the time of testing.
All patients showed clinical improvement following treatment with clozapine. In addition, clozapine produced a significant attenuation of prolactin (PRL) and cortisol (CRT) response to DFEN challenge. Change in symptom ratings correlated significantly with reduction in PRL response to DFEN challenge.
These data show that functional alterations occur in the 5-HT system following response to clozapine and lend support to studies suggesting that 5-HT is an important component to the spectrum of action of clozapine.