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Published on 3 April 2012

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Antipsychotic evolution: past to present

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David Taylor BSc MSc PhD MRPharmS
Director of Pharmacy and Pathology,
South London and Maudsley NHS Trust,
London, UK

I graduated in 1986 with a BSc in Pharmacy. I later obtained a Masters in Clinical Pharmacy in 1991 and a PhD in Clinical Psychopharmacology in 2003. My current positions include the Director of Pharmacy and Pathology at South London and Maudsley NHS Foundation Trust and Professor of Psychopharmacology at King’s College London.

I am also the Pharmaceutical Sciences Clinical Academic Group Head at King’s Health Partners, (which comprises three of the UK’s leading trust pharmacy departments – Guy’s and St. Thomas’ NHS Foundation Trust, King’s College Hospital NHS Foundation Trust and South London and Maudsley NHS Foundation Trust). I became the Editor-in-Chief for Therapeutic Advances in Psychopharmacology in 2010.

How has treatment for psychotic disorders, including schizophrenia, and the development of antipsychotics evolved over the past decade?
In my view, we have seen the introduction of two incremental improvements. The first is the approval of metabolically neutral antipsychotics, like aripiprazole, ziprasidone and asenapine. The second is the introduction of atypical depots, such as risperidone, olanzapine and paliperidone.

What are the benefits of the new, long-acting formulations of antipsychotics?
The benefits are practical: we can now assure compliance and assure therapeutic plasma levels. For the first time we can be certain that the patient is receiving the atypical antipsychotic prescribed to them.

There are also potential cost benefits. Approximately 50% of patients given oral treatment do not take their medicines as directed. If the prescription is filled and the patient doesn’t take the medicine, it is completely wasted. In addition, the cost of readmission is much greater than the cost of lengthy treatment with any drug. The key to cost-effectiveness is to keep the patient out of hospital and in work.

Regarding safety, the latest formulations of atypicals are new preparations of well-established oral drugs. We can’t say that they (the corresponding depot formulations) are absolutely safe but their adverse effect profile is well known. It is not expected that depot formulations will provoke any hitherto unrecognised adverse effects.

Tolerability is probably slightly better with depot preparations because of lower peak–trough variation in plasma levels. This has recently been demonstrated by a comparison of risperidone oral and depot preparations.

How should pharmacists be involved to optimise clinical outcomes?
The pharmacist often advises on drug choice. This is mainly done on the ward round where the pharmacist is a member of the multi-disciplinary team. It’s also undertaken in policy making, for example at the hospital or national level.

Has the introduction of new agents benefited patients?
There aren’t yet data to prove this, but it’s anticipated that long-acting formulations will give lower rates of relapse than oral medication. We might say it would be expected that long-acting atypical depots will be more effective than typical depots, given that oral atypicals are usually better tolerated than conventional oral drugs.

Would you like to say anything specific to the readers of Hospital Pharmacy Europe?
I suppose it’s worth observing that the development of schizophrenia products is rather unevenly piecemeal. We had the first effective drug (chlorpromazine) in 1952 and didn’t see its wider impact on outcome in psychosis for several years. The introduction of an old drug, clozapine, in 1990 marked the beginning of the decade of atypicals, which improved tolerability but not clinical outcome.(1) We then saw a long gap before introduction of the atypical aripiprazole in the early ‘noughties’ and asenapine nearly 10 years later. Things have slowed down somewhat. We’re waiting for the next generation of antipsychotic drugs to emerge. If you look at the recent introduction of new drugs in schizophrenia (as opposed to formulations), there were seven in the 1990s, just one in the ‘noughties’ and one so far in the 10s.

What new treatment approaches are being researched?
Dopamine receptor antagonists remain the basis for drug development, but glutamatergic drugs are under investigation, including drugs with agonist action on the NMDA receptor. It seems that NMDA agonists or co-agonists are able to improve negative and cognitive symptoms in schizophrenia. l

References

  1. www.primarypsychiatry.com/aspx/articledetail.aspx?articleid=422

 

Xeplion: the most recent addition to the range of LAI anti-psychotics

Paliperidone palmitate (PP) or 9-hydroxyrisperidone is the most recent addition to the range of long-acting injectable (LAI) antipsychotics. PP is licensed in Europe for the maintenance treatment of schizophrenia. Paliperidone binds strongly to dopaminergic D2 and serotonergic 5-HT2 receptors(1) and also exerts adrenergic α1,2 and histaminergic H1 blockade.(2)

In order to achieve therapeutic levels of paliperidone quickly, PP is administered as 150 mg on day 1 in the deltoid muscle followed by 100 mg on day 8, also in the deltoid muscle. Maintenance doses thereafter can be administered into either the deltoid or gluteal muscle at the patient’s discretion. Switching to PP from another LAI does not require this loading dose regimen. The PP maintenance dose should be initiated at the next due depot date and continue thereafter at monthly intervals. However, should a deterioration in mental state be observed, or the monthly date be jeopardised, PP may be administered up to seven days early or late.

PP has been shown to be non-inferior to risperidone LAI (RLAI), with similar response rates; 53% and 48.5% respectfully.(3) PP has also been shown to be clinically effective with significant delays in time to relapse.4 The safety and tolerability of risperidone is widely documented and provides a platform to predict how PP will be tolerated.(3) Weight gain is often a common side effect with antipsychotic treatment but the mean weight increase for PP is 0.9 kg.5 In the same study, 13% of patients displayed weight gain of >7% of their body weight.

Unlike RLAI, PP provides rapid antipsychotic plasma levels without oral supplementation, the licensed dose range is higher, administration intervals are longer and PP does not require cold storage. PP is approximately the same price as RLAI without the possibility of wastage due to a 7 day expiry (RLAI) once stored above 8 ºC. PP is therefore a promising new agent for the maintenance treatment of schizophrenia.

References

  1. Janssen Pharmaceuticals. INVEGA® SUSTENNA® (paliperidone palmitate) Extended-Release Injectable Suspension for intramuscular use. Full Prescribing Information. http://www.janssencns.com/sustenna-prescribing-information; 2011.
  2. Owen RT. Paliperidone palmitate injection: Its efficacy, safety and tolerability in schizophrenia. Drugs Today (Barc ) 2010;46:463-71.
  3. Pandina G et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:218-26.
  4. Hough D et al. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2010;116:107-17.
  5. Gopal S et al. A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol 2011;25(5):685-97.

 

Treatment journey to typical antipsychotics
By Cher Thornhill

Treatment for psychosis progressed out of recognition over the twentieth century, from invasive physical therapies including lobotomy, to a growing range of antipsychotic drugs.
During this time, increasing numbers of patients considered psychotic began to receive medical interventions, rather than become committed to asylums, as they were in the late 1800s.(1)

In the first half of the twentieth century, invasive physical therapies were developed in Europe. In 1927, the Viennese psychiatrist Julius Wagner-Kauregg received a Nobel prize for identification of malaria treatment of general paresis.(2) Barbiturate-induced, deep sleep therapy was practised in the 1920’s by the Swiss psychiatrist Jakob Kläsi.(3) In 1933, Manfred Sakel began using insulin coma therapy for psychosis,4 a discovery that was closely followed by the use of cardiazol shock therapy in 1934.(4)

The 1940’s brought electroconvulsive therapy (ECT) for schizophrenia, which is much better recognised, and is still used today in certain parts of the world. ECT acts through passage of an electric current between electrodes placed on the patient’s temples. Recommendation of ECT for the general management of schizophrenia has been stopped since 2003.5

Lobotomy
Brain surgery was first introduced as a possible medical treatment at the end of the 1800s after Swiss physician Gottlieb Burkhardt attempted to create calm in schizophrenia patients by severing the usual nerve pathways in a lobe of the brain.6 It was considered a radical treatment for schizophrenia patients exhibiting severe disturbances. Even though a 1937 study revealed a concerning range of responses, the practice became widely adopted, largely owing to the then shortage of treatment options.

Emergence of drug therapy
The first generation of antipsychotics, known as the typical antipsychotics, were first discovered in 1950 and subsequently introduced into medical practice in the 1970s. While the arrival of oral therapy – in the form of clozapine – brought a welcome alternative to the unpredictable and severe results seen with earlier management, it brought its own adverse-effects, including headache,  fever and extrapyramidal side-effects.

References

  1. Mental illness and the late Victorians: a study of patients admitted to three asylums in York, from 1880–1884. http://www.ncbi.nlm.nih.gov/pubmed/2657829.
  2. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1927/wagner-jauregg-lecture.html.
  3. A critical review. Narcosis therapy. Gillespie RD. J Neurol Psychiatry 1939; 2: 1945–65.
  4. Kragh JV. Shock therapy in Danish psychiatry. Med Hist 2010; 54: 341–64.
  5. Electroconvulsive therapy (ECT) (TA59). National Institute for Health and Clinical Excellence.
  6. Lobotomy. Encyclopedia Britannica. http://www.britannica.com/EBchecked/topic/345502/lobotomy.lobotomy

 

 



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