Schizophrenia and The Arugs Available To Treat It

Introduction

This essay will consider schizophrenia and the various pharmaceutical treatments available, in particular the newer antipsychotic drugs and how, on occasion, these can be used in combination and why this is necessary.

What is schizophrenia?

Schizophrenia is a complex subject, not one condition, but a useful umbrella term for a number of psychotic conditions. It usually, though by no always, manifests itself in the third decade of life as it can occur in quite young people too or be late in onset. Acute episodes can last as long as 6 months  and so it can be seen that it has a huge negative effect on the life of those concerned,  as well as on society in general when one takes into consideration loss of work hours, effects on family life, the cost of treatment etc. Drew Western in ‘Psychology, Mind, Brain and Culture’ defines it is his glossary as:-

Psychotic disorders characterized by disturbances in thought, perception, behaviour, language, communication and emotion.

Because sufferer’s have a different perception of the world to that of the majority population they tend to respond in what is perceived as an unusual way of behaving.

Those with this disorder may develop apathy, a significant loss of interest or pleasure in life. This affects such things as their appetite and general interest in food. In some there are mood abnormalities such as inappropriate smiling, face pulling or laughing, or, at the other extreme, depression, anxiety or unreasonable anger may predominate. Often normal day and night activities will be reversed i.e. the person stays up very late at night and then counteracts this by sleeping late in the morning. Often abnormal movements such as  constant pacing, rocking, or long periods of immobility will occur. There may be are noticeable cognitive impairments such as poor concentration, memory problems and an impaired ability to solve even simple problems. Although there are many theories regarding the possible causes including stress factors, the fact that there is no one known causative agent has made it difficult to arrive at one particular treatment.  Genetics are considered to play a large part, and it is certain that it runs in families.

The immediate biological relatives of those with schizophrenia are 10 times more likely to develop symptoms than the population in general, with some patients developing the disease, whatever their environment and life situation, while a second group will only become psychotic under certain moderate changes to their circumstances, and yet others require substantial impetus before symptoms develop according to D.C. Fowles ‘Schizophrenia,: Diathesis –stress revisited’ in 1992. Drew Weston in ‘Psychology, Mind, Brain and Culture cites ( page 595) a number of researchers who consider genetics to be the root cause, but whether one gene or several are involved remains uncertain. The fact that the condition can be aided by the use of chemical agents gives credence to the other main idea, that it is caused by an imbalance in body chemistry, in particular that of the brain. Diagnosis is usually done on a clinical basis, but there is research into blood tests, eye tracking etc as described at Schizophrenia .com

Drug Treatments Available

From the earliest times there have been attempts to treat the mind with drugs of various kinds  – alcohol, opium, marijuana and even ‘magic mushrooms’ ( fly agaric). Despite this really effective drugs that restore normal mental function is a very modern concept, only really starting in the 1950’s.

Drugs are not the only way to treat schizophrenia. There are various therapies that help a patient and his family better deal with the results of his condition such as social and vocational training and family therapy. Such efforts though are complementary to drug therapy.

The pharmatalogical treatments available are thought to affect the neurotransmitters, dopamine and serotonin, within the brain., inhibiting over sensitive or over active neuro transmitters and receptors.  Some treatments for this complicated condition work in diagrammatically opposite way, increasing the  active life of neurotransmitters that are relatively dormant.

 Those antipsychotic drugs described as typical or conventional are those that have been in use longest. They could be said to be traditional treatments and include relatively inexpensive drugs such as Haloperidol (Haldol) Thioridazine and Fluphenazine   This relatively cheapness can be an important consideration when drugs are going to be required life long. Unfortunately this group can produce negative side effects such as involuntary jerking. ( tardive dyskenesia)

The newer medications are usually referred to as new generation or atypical antipsychotics. They are effective at managing and balancing both positive and negative symptoms. They include: Clozapine (Clozaril), Olanzapine (Zyprexa) ,Quetiapine (Seroquel) Ziprasidone (Geodon),Aripiprazole (Abilify) and Paliperidone (Invega) together with  Risperidone (Risperdal), the only drug approved by the American Food and Drug Administration for the treatment of  young people aged from 13 to 17. The use of any of these medications also can result in side effects. These include higher levels of cholesterol, weight gain, raised blood pressure and the onset of diabetes. As the drugs can take many weeks before producing positive effects it is important to convince patients of their ultimate effectiveness, .especially if their administration is associated with side effects. This leads psychiatrists to try and effectively control any psychotic symptoms using the lowest possible dosage of any medication. These may in some cases be combined with the use of anti-depressants or drugs designed to lower anxiety levels. If side effects prove to be intolerable or the medication doesn’t seem as efficacious as it might be, then doctors will consider either exchanging it for another drug or using it in combination with something else. In these cases dosages of any antipsychotic drug must be tapered off quite slowly or withdrawal symptoms will occur.

The article ‘How is Schizophrenia Treated’ on the web page of the National Institute of Mental Health tells us that, from the 1950’s onwards, antipsychotic medications became widely accessible to treat  the disturbances of thought, perception, behavior and so on which characterize this overwhelming disorder. In 1956 chlorpromazine (Thorazine®) changed the whole treatment regime. Patients, except when having acute episodes, were able to live  for the first time outside the mental hospitals. When attacks did occur hospital treatment was only used for short periods, and once the acute phases of the condition was over they were able to leave. Clozapine (Clozaril®) was already in use and this treatment had led to huge improvements in many previously intractable cases who had not responded positively  to earlier treatment with chlorpromazine and similar medications as described by Kane, Honigfield et al in the 1988 article ‘Clozapine for the treatment-resistant schizophrenic: A double blind comparison with chlorpromazine’,

Such treatments, in the majority of cases, greatly improved the course of the disease, reducing any psychotic symptoms enough to allow normal functioning and appropriate behavior, though there are a minority who will not be aided by these medications. It is very difficult for physicians to predict in advance which patients will be helped and which not, and indeed, which are the very few patients who will improve without medication. Other factors can affect someone’s medication needs, for instance, if a patient also become depressed, then his psychotic symptoms worsen and when the depression is treated effectively the psychotic symptoms may also improve.

Antipsychotic drugs are not a total cure and do not prevent future psychotic experiences, but merely reduce the psychotic effects of the condition. Dosage is complicated and must be in the hands of someone experienced in dealing with this particular condition. He will choose not only the dosage, but also the particular drug required to meet individual need. Patients will be found to vary considerably in the dosage required in order to reduce any symptoms, without at the same time forcing them to endure unpleasant side effects.  New  treatments, the so-called “atypical antipsychotics” have been in use since about 1990. First came clozapine (Clozaril®),  which, though it has been shown to be more effective than earlier antipsychotics, carries with it the possibility of serious side effects. These include the development of agranulocytosis, that is a loss of the white blood cells that the body needs in order to fight infection. This means that patients for whom this drug was prescribed were in a precarious position, and frequent blood tests were necessary in order to monitor the state of their blood.

The newer antipsychotic drugs, such as risperidone (Risperdal®) and olanzapine (Zyprexa®), are considered to be safer than the older antipsychotics or the newer clozapine. They are usually better tolerated by the majority of people, but may or may not be as effective in their ability to overcome psychotic symptoms. Several antipsychotics are being researched at present in order to find possible treatments that are effective as well as being safe.

The various antipsychotic drugs can be very effective in treating certain kinds schizophrenic symptoms, especially hallucinations and delusions, but they do not necessarily work as effectively with other symptoms, in particular those connected to the emotions, such as a reduction in motivation and the patient’s ability to express emotions.

Indeed, the older antipsychotics, at one time referred to as neuroleptics, drugs such as haloperidol (Haldol®) or chlorpromazine (Thorazine®),  may even have the effect  of creating side effects which resemble schizophrenic symptoms of the more difficult to treat type. Such negative effects can however be reduced by a reduction in the dose, or in some case by switching to another medicine. These, the newer medicines such as  olanzapine (Zyprexa®), quetiapine (Seroquel®), and risperidone (Risperdal®), appear to produce less unpleasant side effects. There are also ongoing efforts to produce effective medications in long acting forms, thus eliminating the need for confused people to remember daily tablets. Quetiapin (Seroquel®), produced by Astra Zeneca, is an antipsychotic used since 1993  for the treatment of schizophrenia as well for the treatment of the  acute manic episodes that are part of bipolar disorder.

Misconceptions

Both patients and their relatives worry about taking antipsychotic medications such as those used to treat schizophrenia. They may be over concerned about possible side effects or about the possibility of addiction, despite the fact that such medications do not lead to addictive behavior in those who use them.

Another misconception about antipsychotic drugs is that they over control the mind, taking away people’s free will. They do have a sedative effect, but used at the correct dosage do not prevent patients from making their own decisions in life. The sedation is rather to reduce agitation and to diminish the likelihood of symptoms such as hallucinations and delusions and so enable the person concerned to once again live in a rational world.

Length of time for which medication will be required

The use of antipsychotic medications is necessary life long in order to reduce the risk of future psychotic episodes in patients who no longer have acute psychotic episodes. However, even with continued treatment, there are some people who will always have relapses. In those who discontinue taking their medication, or take it haphazardly, there will be higher relapse rates.  In the majority cases it cannot be said that continued drug treatment serves to totally prevent the possibility of relapse. Instead it reduces both their intensity and the frequency with which such psychotic episodes are likely to happen. The treatment of severe psychotic periods will in general need higher doses of the chosen medication than when these are used  for maintenance treatment. If symptoms reappear when someone is taking a lower dosage, it may be found that a temporary increase in medication may control the situation and prevent it worsening.

Helping Patients Take the Correct Dosage

Because of the nature of the condition patients may have great difficulty in maintaining correct dosages. Many of those with schizophrenia seem to be unaware that they have a psychotic illness. Such poor insight is not just a way of coping with the abnormality but  is caused by the illness. They may be so confused in their thinking  that they refuse medication and any available help. Others may simply forget to take the medication. In some case substance abuse, both in the form of drugs and /or alcohol will interfere with the effectiveness of the prescribed medication. In some cases the patient decides that the accompanying side effects make the taking of the drug too difficult.

There are a number of ways in which adherence to the correct dosages can be enhanced. Some drugs are available in long term injectable form for instance. These include haloperidol (Haldol®), fluphenazine (Prolixin®), perphenazine (Trilafon®.) Otherwise , relatively simple methods can be used such as the use of  medication calendars or pill boxes which carry the names of the days of the week . These allow patients, their carers and family members to check easily whether or not necessary medications have been taken. Using watches with electronic timers that beep when medications should be taken and the establishment of routine such as taking pills with meals, can help patients to partake of the correct dosage.

These and other methods will be effective if the patient and his family are properly educated as to what schizophrenia is and how the medications can help. This will help their self motivation and so encourage correct dosage and the keeping of clinic appointments.

Possible Outcomes

The best outcomes are linked to early and persistent treatment with suitable antipsychotic medication soon after the onset of symptoms, but other factors are also important such as the acuteness of the original onset, and this occurring at a greater age than average. Women who were well adjusted before becoming ill, with only a brief period of illness, who exhibit normal neurological function and an absence of both residual symptoms and who have a normal brain structure are those most likely to make the best recovery, especially if there is no history of either schizophrenia or mood disorders in the immediate family.

Drug Details

Aripiprazole ( Abilify®) is used alone, or alongside other medications in cases of schizophrenia. It is counter-indicated in the elderly with dementia. It is available in tablet form, as a liquid and also as a slow dissolving tablet to be kept in the mouth. As with many other treatments for schizophrenia dosage begins at a low level and is adjusted according to need. MedlinePlus has a very long list of conditions that a physician needs to be aware of when prescribing this drug including the misuse of drugs. It also reports that at the beginning of treatment suicidal thoughts are possible. It can also causes problems with the bodies ability to cool down if it gets over heated. It is made by the  Otsuka Pharmacutical Company Ltd.

 Chlorpromazine ( Thorazine®) is a phenothiazine antipsychotic once widely used to treat schizophrenia, but also useful in the treatment of anxiety, nausea and of hiccoughs. It is available as syrup, tablet and in controlled release form. Dosage varies considerably and must be decided according to the patient’s condition from 25 mg 8 hourly up to a maximum of 800mg or more as a maximum. It is available as an injection. The lowest possible effective dosage should be aimed at, especially if the patient is likely to walk about, because it can have a sudden hypotensive effect upon standing.

Patients receiving chlorpromazine long term need careful monitoring with blood pressure checks, pulse counts, and laboratory tests such as those for liver function, blood cell counts and renal counts. ECGs and EEGs are also needed. There are a number of possible  side effects, some  of which are more likley to manifest themselves in the early stages of treatment e.g.sedation and liver damage. If and when treatment needs to be discontinued this must be done at a gradual rate over about 4 weeks in order to avoid withdrawal symptoms i.e. anxiety and insomnia.

Today chlorpromazine, though it still has a place in the treatment of acute anxiety, has in most cases been superseded by newer drugs as it has potentially fatal side effects in the rare onset of neuroleptic malignant syndrome – a rigidity of the  accompanied by fever, delirium and a rise in creatine levels. In other cases use can produce constipation, hypotension and sedation. There may also be restlessness and a mild, Parkinson like tremor. If jerking movements develop in some cases there are irreversible.

Dosage – in acute conditions it is often given as a syrup because this has a speedier action than when given in other forms. Its exact mode of operation is uncertain.It is contra-indicated in cases of allergy to other  phenothiazines and damage to the brain, liver, blood or bone marrow or when the patient has recently taken any medications or alchohol which might depress the central nervous system. Care must be taken in the case of pregnancy or in nursing mothers.It may interact with astemizole, pergolide, or terfenadine

Clozapine ( Clozapril®) is an atypical anti-psychotic available in tablet form in sizes from 25 mg to 200mg. It is derived from dibenzodiazepine

Although very effective in many cases its use is limited because of the possibility of agranulocytosis and regular blood tests need to be carried out inpatients taking this drug. Also positive response rates to its use vary somewhat according to Doctors Miriam Naheed and Ben Green in their article ‘Focus on Clozapine’. They point out that despite the severity and frequency rates of possible side effects these are outweighed by the rate of suicide in patients not treated with Clozapine. Manufactured by Novartis.

Haloperidol ( Haldol Deconate®) an antipsychotic used as a sedative and for a number of conditions including as a pre-anesthetic sedative and available in a number of forms. For injection in 3 strengths –5 mg per ml 50 mg per ml and 100 mg per ml. It is also available as tablets in doses of 5mg and 10mg.  Haldol Oral Liquid in 2 strengths, 2mg per ml, and 10 mg per ml.

Dosage is 50mg-300mg as a monthly deep intramuscular injection for adults. Orally it can be taken  in doses of 0.5mg  to 5 mg 2 or 3 times a day depending upon condition being treated. The dosage can be increased regularly up to a total of 200mg per day after which it is gradually reduced to a maintenance dose. The oral preparations are used for children at a dosage of 0,05mg per kilogram of body weight per day, given in doses which are equally divided throughout the day. Special care must be taken in cases of Parkinsonism and epilepsy, in nursing or pregnant women, or when there is a diagnosis of serious heart or other circulatory condition. Made by Janssen.

Olanzapine (Zyprexa®), an atypical antipsychotic, is considered to be superior to several other drugs used  for schizophrenia , both because of its efficacy and because of  fewer side effects. According to Nutt in 1994 the effects of this and similar medications is because of its alpha-2 adrenergic antagonist effects. Side effects include weight gain, but this may be because those treated regain their appetite. Drowsiness is also common says Dr Ben Green in his article ‘Focus on Olanazine’. It is made by Lilley and Co

Paliperidone ( Invega®) is one of the atypical antipsychotic drugs  whose exact action is unclear, but it seems to affect chemicals in the brain. It is contraindicated in cases of heart disease as it has an effect of the QT interval. The tablets must be taken whole so those with swallowing problems might be better served by another medication. Physicians need to be aware of pregnancy, but also a number of other conditions as noted on the web page Paliperidone, from Drugs.com including the family history of diabetes and  also a very long list of medications with whom it can interact. Its use can cause fatalities in the elderly, mainly from heart problems or from overwhelming infections. Th emakers are Janssen.

Quetiapine (Seroquel®) is an antipsychotic used to treat both schizophrenia and bipolar disorder. It does this by blocking neurotransmitters. It is given as tablets of between 25 and 400 mg and is taken 2 or 3 times daily in gradually increasing dosages. In schizophrenia dosage usually begins at 25mg twice daily. Phenytoin and thioridazine may prevent proper absorption in the gut. Use can increase the sedative action of other drugs taken and also any hypotensive actions. Its action in pregnancy is uncertain and it should not be combined with breast feeding. Headaches and tiredness are common, but rarer side effects include seizures and hypothyroidism according to Jay Marks on the web page ‘Generic name: quetiapine. It should also be mentioned that it can cause  extreme hyperglycaemia and other dysfunctional events such as ketoacidosis  which are usually associated with untreated and severe Diabetes type 1.The manufacturers as AstraZeneca who were recently admonished by the Food and Drug Administration in America for minimizing its risks in information to health professionals according to the web article ‘Seroquel maker warned by FDA for misleading material’ of November 2006.

Risperidene (Risperdal®), antipsychotic used for schizophrenia and other psychoses. It is a benzisoxazole derivative, available in tablets of 1 to 4 mg. The dosage is gradually increased from 1 mg twice on the first day up to 3mg twice on the third day, with a maximum dosage of 8mg per day. I t is not suitable for use in children and in the cases of the elderly dosage is reduced to 0.5 mg going up to 1 or 2 mg daily.

Special care should be taken if there is a history of epilepsy, renal, hepatic or cardiac disease, or if the patient is pregnant or a nursing mother, has Parkinsonism. Patients should be warned about operating machinery. If jerking and other extrapyramidal symptoms appear then this medication should be stopped.

There is the possibility of interaction with levadopa, dopamine antagonists and drugs acting centrally. This drug has a long list of possible side effects such as hypotension, tachycardia, sexual disorders, anxiety and insomnia, headaches, dizzy spells, tiredness and poor concentration, gastro-intestinal problems, runny noses, weight gain, rashes, and changes to the vision. The manufacturer is Jannsen/Organon.

Thioridazine is a piperidine antipsychotic manufactured by various companies under a number of names, though in several cases production has been discontinued due to the associated problems. It works by central adrenergic-blocking, has a dopamine blocking action. It also has a use  in cases of tuberculosis that are resistant to other drugs. It is only used when other treatments for schizophrenia are unsuccessful as it can produce a dangerously irregularity of the heart. Aganulocytosis is also commoner with this drug than with others. It needs to be taken accompanied by food in order to avoid stomach problems. It can adversely affect sexual function. According to Medline Drug Information this is used to ‘treat schizophrenia and symptoms such as hallucinations, delusions, and hostility.’ It can be taken in tablet form or in a liquid suspension or as a liquid concentrate which must first be diluted.Dosage is  50mg per day in milder cases up to 600–800 mg per day in the most  severely disturbed patients Before prescribing it is necessay to discover what other medications the patient is taking e.g. any antacids, vitamins,cold medicines, sedatives, antidepressants, diet pills and antihistamines The page also lists a long list of prescibed drugs  that it is necessary to take into consideration. These are :- benztropine (Cogentin), bromocriptine (Parlodel), carbamazepine (Tegretol), dicyclomine (Bentyl), fluoxetine (Prozac), fluvoxamine (Luvox), guanethidine (Ismelin), lithium, meperidine (Demerol), methyldopa (Aldomet), paroxetine (Paxil), phenytoin (Dilantin), pindolol (Visken), propranolol (Inderal), trihexyphenidyl Artane) and  valproic acid (Depakane)

Physicians also need to take into account any history depression, epilepsy, respiratory conditions, urinary or prostate problems, glaucoma, alcohol abuse; thyroid problems, a  bad reaction to insulin, circulatory and cardiac problems, or renal and hepatic disease and the possiblity of pregnancy or  the cases of nursing mothers.

Side effects can include excessive reaction to sunlight and drowsiness, especially when acccompanied by the intake of alchohol.

Ziprasidone ( Geodon®) An antipsychotic used for schzophrenia and available in injectable form in 20 mg size needing the addition of 1.2 mls of sterile water  or as capsules from 20mgs to 80 mgs in size.Usually dosage starts with 20mg twice daily and grows until optimal levels are reached.Taking it with food increases the rate of absorption. Geodon has a mild effect on the heart, affectign the QT interval as reported by Emmanuel Saltiel in 2003,’ Generic name:ziprasidone’  but can enhance the negative actions of other drugs which do the same. The same web site also has a list of drugs which can block its effectiveness. It may cause birth defects if given in pregnancy and there alsomay be an effect on blood sugar levels.It is a Pfizer product.

Conclusion

Schizophrenia falls into three main types – paranoid, catatonic and disorganized, each of which has their own set of symptoms. It affects as many as 1 in a 100 people. Because of the complexity of this condition, combined with the different way in which various patients react to treatment, for a number of reasons including their personal and family medical histories, and any other drugs they are taking, treatment must be personalized. There are a number of checks that should be made both before treatment begins and as long as it continues including blood pressure checks , bloodlevels of various things, ECG’s and EEG’s. Dosages in most cases will start low and gradually climb to an adequate dosage. Possible adverse reactions can be countered by using the lowest possible  optimal dose and by choosing the correct drug to suit a particualar person’s needs in order to maintain them at optimal health. The possibility of any serious side effects must be balanced against the likely outcome if treatment is withheld. Care must be taken to ensure that the patient take obtains the correct treatment and that they and their families are educated about the condition and its treatment and that they know they must inform the doctor concerned of any changes, whether these consist of changes in their circumstances,  other medication taken, the onset of any side effects and so on.

In many cases , although the drug can be observed to be effective, how this occurs is unknown, though there are a number of hypotheses. This uncertainty makes it difficult to come up with new and effective drugs or to assess the likely effects in a particular case which are all the more reasons for the gradual introduction of the drugs, careful monitering and a response when there is a need for alteration. In certain cases such as patients who also have dementia of the elderly,  who are pregnant, or who have other serious conditions the choice of possible drugs is very limited. It is in  cases such as these perhaps where combining drugs is necessary so as to achieve the best outcome with low doses, without puttting the patient at unnecessary  risk. Consideration also must be given to the stage at which the condition is, as prolonged administration of many of these drugs at high doses is so likely to cause devestating side effects, some of them irreversible.This means that higher doses are given during acute episodes and that once these more severe  periods are over gradually lower doses can be given. Another point is tha the drug companies have the interests of their shareholders as a priority, and though they may spend huge amounts in research and provide a valuable service, they can sometimes be found wanting when it comes to revealing negative aspects of their products as was seen in the case of Seraquel and AstaZeneca.

References

Books

Prescription Drugs and Medical Terms, Brockhampton Reference, (1995) London, Geddes and Grosser Ltd

Western,D. (1999) Psychology, Mind, Brain and Culture. New York, John Wiley and Sons Inc.

Journals

Fowles, D.C.,(1992), ‘Schizophrenia,: Diathesis –stress revisited’, Annual Review of Psychology, 43, pages 303-336

Kane,J., Honigfield,G. et al, ( 1988)‘Clozapine for the treatment-resistant schizophrenic: A double blind comparison with  chlorpromazine’, Archives of General Psychiatry, 45, 489-496

Nutt, D J (1994) Putting the ‘A’ in atypical: does alpha-2 adrenoceptor antagonism account for the therapeutic advantage of new antipsychotics? J Psychopharmacol., 8, 193-5.

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