Recent Developments in the Treatment of Schizophrenia
Third Generation Antipsychotic Medicines
Although there is now better access to the talking therapies in the UK, antipsychotics remain the mainstay of treatment in the NHS. (See our information sheet on Modern Treatments for a broader discussion of the treatments available) This is because we know that they are effective in controlling positive symptoms like hallucinations and delusions. In this piece Rob Foster looks at some recent developments in the use of antipsychotic medicines in schizophrenia and particularly at the new drugs which have come to be known as the third-generation antipsychotics.
In the decades of study and research into the complex disorder of schizophrenia, science has continued its development of treatments that aim to out-perform their predecessors in the control of the varied symptoms of the disorder. To most relatives and carers of patients with schizophrenia, the categories of symptoms are well known in terms of positive, negative and cognitive effects and medical/pharmacological science has endeavoured to find a comprehensive treatment for all. Our information sheet on Symptoms has more detail about this subject.
Before we can discuss the recent and potential drug discoveries, we must indulge in a brief history lesson. The first generation of antipsychotics such as chlorpromazine and haloperidol are known as dopamine D2 receptor blockers as they block a receptor in the brain triggered by the chemical messenger dopamine, discovered to be involved in causing the positive symptoms. This blockade prevents dopamine from binding with the D2 receptor and switching it on, thus reducing the manifestation of the positive symptoms.
The second-generation drugs such as olanzapine and quetiapine, expanded the scope of drug therapy to include another type of receptor triggered by the chemical messenger serotonin, in an attempt to affect the negative and cognitive symptoms. The most recent development is the so-called third generation drugs such as aripiprazole, brexpiprazole and cariprazine. These drugs are also known as ‘D2/D3 partial agonists’ or dopamine-serotonin stabilisers’. The novel mode of action of these drugs is that in areas where dopamine and serotonin activity is low, they increase signals and in areas where it is high, they reduce it. This correcting of the imbalances in certain signal pathways of the brain believed to be the biological basis for the symptoms of schizophrenia. Aripiprazole was the first third-generation antipsychotic to be approved for the treatment of schizophrenia followed by brexpiprazole and then cariprazine.
Effectiveness and Safety of Third Generation DrugsA
Since its development and licensing, aripiprazole has become a popular choice of treatment of first episode schizophrenia and the subject of study. Although effective at lower doses, aripiprazole’s usual therapeutic dose range is from 10-15mg a day with a maximum dose of 30mg. (Please note that recommended dosages do vary over time and in different countries. This information is only a guide and reflects prescribing practice in the UK at the time of publication. For detailed information on medication dosages it would be best to speak to your health care professional.) It is best taken on a morning, once a day and is started on a dose of 5mg and increased depending on response after 2-4 week intervals however it can take up to six weeks to have an effect.
Aripiprazole is also available as a fast-acting injection for the rapid treatment of agitation and as a long acting injection given deep into the muscle. The dose is usually from 300mg-400mg given monthly but only after the patient has been stabilised on oral aripiprazole and must remain on 10mg to 20mg orally for 14 consecutive days following injection, to maintain therapeutic blood levels.
In terms of the effect of the drug on the body and on those considered a ‘risk’ group, the news is relatively good compared to first generation drugs. Elderly patients i.e. those over 65, showed no increased presentation of serious side effects. This may be due to the lack of study of this group but in comparison to previous generation drugs, aripiprazole’s lack of significant side effects such as potentially serious and irreversible movement disorders known as ‘extra-pyramidal symptoms’’ such as tardive dyskinesia (involuntary pursing of the lips, tongue movements, jaw clenching) and sedation, is a good sign it is well tolerated by the elderly. For more information about side effects see our information sheet Coping with Side Effects. With regards to children and adolescents (15-17), the drug should be started low at 2mg a day for two days, then up to 5mg for two days, then 10mg for two days then, if required, it should be increased in doses of 5mg to a maximum of 30mg a day. This of course, must be done under expert medical supervision.
The side effect profile of aripiprazole is promising for this new generation of antipsychotics. There are no major changes in the function of bodily systems that require extremely close monitoring as with some previous generations drugs however, as with any long-term antipsychotic use, annual or six-monthly bloods, baseline observations (pulse, BP, temperature etc) and ECG (trace of the hearts electrical rhythm) is prudent. The most common side effects are headache, insomnia, anxiety, restlessness and a movement disorder called ‘akathisia’ which literally means ‘inability to sit still’. This can be very problematic to some patients typified by an irresistible urge to constantly shift their weight from one foot to the other. On the bright side, this is easily reversed with antidote drugs called ‘anti-muscarinics’, the most commonly used in practice is procyclidine. Studies have shown however, that aripiprazole can also cause tremors associated with ‘drug induced Parkinsonism (DIP)’
Another new kid on the block is related drug brexpiprazole which is still only newly licensed in the UK under its trade name Rexulti. Brexpiprazole is available in oral doses of 0.25mg, 0.5mg, 1mg, 2mg, 3mg and 4mg tablets. The recommended starting dose for schizophrenia is 1mg per day for days 1-4 with a target dose of 2mg-4mg a day.
In terms of its mechanism of action, it is very similar to aripiprazole in that it works at the same dopamine and serotonin receptors in the brain, making it also referred to as a ‘D2/D3 partial agonist’ and a ‘dopamine-serotonin stabiliser’. There are slight differences in terms of effect compared to aripiprazole due to the strength of effect at the same receptors. It is generally held that it is very well tolerated with a low number of test subjects stopping treatment due to side effects. It is safe in the elderly and children with the same level of medical supervision required in the potential risk groups however there is much less research data available compared to aripiprazole. The different level of effect on receptors means that brexpiprazole causes less incidence of movement disorders and akathisia. There is also a reduction in headache and insomnia. There have however, been some side effects not akin to aripiprazole such as hyperglycaemia (high blood sugar) and increased triglycerides (related to cholesterol level) however, both usually fall within routine blood screening completed as part of 6 monthly MOT carried out on long term antipsychotic users. In conclusion, the overall side effect profile of brexpiprazole is less than aripiprazole but cost of treatment is currently, substantially higher.
Finally, the most recent development in this emerging class of drugs is cariprazine, which has the same novel chemical properties as its predecessors. Although also a ‘D2/D3 partial agonist’, it differs as it is broken down by the body into two very active drugs in their own right, one of which has an unusually long chemical life span, impacting greatly on the length of its therapeutic action. Its strength of acting on the same receptors as the other two has an effect on its side effect profile and tolerability. Cariprazine is licensed for the treatment of schizophrenia and is available in capsules with a dose range of 1.5mg, 3mg, 4.5mg and 6mg. The starting dose is 1.5mg and should be increased in increments of 1.5mg to a maximum of 6mg a day depending on response. Safety wise, there is no established regime for use in children or adolescents. Safety in the elderly is lacking in sufficient studies to identify specific concerns and the level of potential harm. There are some cautions associated with cariprazine such as the possibility of suicidal ideation (suicidal thinking), seizures and a serious movement disorder called tardive dyskinesia. Suicidal ideation has been noted in both patients with schizophrenia and bipolar disorder. It has been advised to monitor patients closely and limit the number of tablets prescribed to those at risk in case of overdose. It is also advised caution be used when given to patients with a diagnosed seizure disorder, a history of seizures or some condition that causes a susceptibility to seizures.
In conclusion, the new emergent antipsychotics with several synonyms relating to their sequence of development in the great antipsychotic story, their pharmacological action or the resultant state they induce, have one other major aspect in common, they signal a change in science’s approach in addressing the multilateral nature of schizophrenia by assuming current theory in the biological basis for schizophrenia is an accurate, modern model that has finally ended the academic graveyard that has historically been the study of its complex pathology. They are rapidly becoming the first drug of choice in new first episode patients and first alternative in first relapse patients on older antipsychotics however, we still see an under-current of treatment resistance that defies this medical model and requires psychiatry’s last resorts, clozapine, high-dose antipsychotic (above maximum dose) or dual therapy.
The comparatively new field of pharmacogenetics and its role in the treatment of schizophrenia is becoming a very promising but controversial tool in the long battle against the variety of symptoms in schizophrenia and the avoidance of side effects related to drugs necessary to achieve adequate response and ultimately benefit quality of life. In terms of drug therapy, there is a large arsenal available to medics when encountering first episode schizophrenia and pharmacogenetics aims to help better prescribing by trying to predict which patients will do well on each type of medicine.
In relation to potential application, it can be broken down into two aspects: a drug’s targets and side effects and how a drug is broken down. Most drugs which act on the brain are broken down in the liver by the same family of enzymes but the level of activity of these enzymes can vary in individual patients thus affecting the dosage regime necessary to achieve therapeutic levels. This must also be balanced against side effects as a dose is increased and therefore can be crucial in selecting the most appropriate and safest treatment.
Genetic studies relating to the activity of the enzymes in the liver that break down most antipsychotics have shown moderate clinical usefulness in selecting a drug and dosage plus potentially the level of its effect. The activity of these enzymes determines how fast a particular drug is broken down therefore affecting whether a therapeutic level can be reached and maintained. There are however, non-genetic reasons for the activity if these enzymes such as the side effects of other substances that cause either inhibition of or induce the activity of particular enzymes. For example, chemicals in cigarette smoke induce the activity of the main enzyme responsible for breaking down the antipsychotic clozapine thus requiring substantially higher doses to reach constant therapeutic blood levels.
Perhaps one of the most important genetic indicator is the likelihood of susceptibility to potentially dangerous or irreversible side effects. In this area of study, the focus has been on particular receptor numbers, types and their ability to respond to chemical triggers. Studies show that the prevalence of certain dopamine receptors are linked to the likelihood of developing classic side effects of antipsychotics. For example, the activity of one subtype has been linked to a tendency for movement disorders and another for weight gain and obesity. The use of patient’s genetics to precisely identify the perfect drug of choice is not so conclusive. The most pertinent studies have failed to produce data of clinical use however, the lack of research is partly to blame and more studies are needed. The most likely cause of this area of study failing to produce clinically useful data is more to do with the complex mechanism of action of antipsychotics and our lack of complete understanding.
In conclusion, the identification of a person’s metabolism of various drugs can be of help in identifying treatment options, dosing and possibly effectiveness, however in terms of using genetics of patients to produce clinically useful data to identify the ideal therapy, this area still requires a lot more research.
A.Important Foot Note: Shortly after this piece was published, the United Kingdom left the European Union. This change was accompanied by a wide range of legislative changes, some of which have affected the availability of medicines in the UK. This particularly applies to some of the newer antipsychotics. The situation concerning some medicines remains very fluid and so we would urge any reader interested in these medicines to seek further advice from their doctor regarding availability in their area.
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Author: Rob Foster.
Copyright © November 2019 Rob Foster.