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Efficacy and side effects of drugs used in schizophrenia treatment

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The treatment of schizophrenia is often complex and difficult. In recent years there has been a large increase in the drugs available to treat the condition. Newer second generation anti-psychotic drugs have now replaced older first generation medication as the gold standard treatment for schizophrenia. These newer drugs have fewer side effects (most notably reduced extrapyramidal side effects) and are more effective at treating the negative symptoms of schizophrenia. In comparing the second generation anti-psychotics, all appear to be equally effective in symptom control and differ only in their side effect profiles. Each drugs’ major side effects are outlined below and summarized in Table 3.

Over the last decade there has been considerable development of newer, and presumably better, anti-psychotic medications. Older, typical or first generation anti-psychotics (FGAs) have been largely replaced by newer, atypical, second generation anti-psychotics (SGAs) due to significantly reduced serious side effects. However, with the release of ever more second generation agents it has become unclear as to which drugs, if any, are superior to others.

To objectively compare drugs it is important to look at two aspects, how effective a drug is at controlling the patient’s symptoms and what side effects the drug has. However, this is often difficult as the situation is confused by the competing interests of drug manufactures who continually publish studies that support their specific drugs.1

First generation anti-psychotic medication had the considerable problem of extra-pyramidal side effects after long term use. These include tremor, slurred speech and eventually crippling tardive dyskinesia. The result is that FGAs are no longer considered to be the best treatment for schizophrenia.2 The other advantage of SGAs is their ability to improve the negative symptoms of schizophrenia, including self neglect, decreased cognition and social withdrawal.3 As a result of the obvious benefits of SGAs, only SGA medication will be reviewed below.

Efficacy

The efficacy of SGAs have been investigated by numerous studies. Many studies have tried to show that one drug has superior efficacy compared to the others, but if all the studies are looked at objectively all the SGAs (risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole) have the same ability to control both the positive (delusions and hallucinations) and negative symptoms of schizophrenia.1-5

Only clozapine has been shown to be more potent in controlling symptoms.2 It has consistently been shown that clozapine is more potent than both FGAs and the other SGAs, and must be considered for all treatment resistant patients. Treatment resistance is defined as a failure of two different antipsychotics to control the symptoms of schizophrenia.


Side effects

As all the SGAs (except clozapine) have been shown to have equal efficacies, the choice of which medication to start with will largely depend on their individual side effect profiles.

The main side effects of all SGAs are:2

  • Weight gain
  • Metabolic syndrome (glucose insensitivity, lipid abnormalities).
  • Sedation
  • Hypotension
  • Prolactin elevation

Other side effects include anti-cholinergic side effects (blurred vision, dry mouth, and urinary retention), cardiac conduction changes, nausea and headache. 

Each SGA has a slightly different side effect profile and is therefore more or less likely to cause the above side effects.  Below are the side effects of the specific drugs.

Olanzapine (Zyprexa)

Olanzapine has a high risk of weight gain, and most patients will experience the metabolic syndrome. A high degree of glucose insensitivity is caused, and diabetes mellitus can result.6 Somnolence (sleepiness) and asthenia (lack of strength) are also common adverse reactions.17 There is also a moderate risk of orthostatic hypotension. However, olanzapine rarely produces sexual dysfunction or anti-cholinergic side effects.6


Risperidone (Risperdal Oral)

Risperidone has low to moderate risks of weight gain and metabolic syndrome. There is a low risk of sedation and anticholinergic side effects and a moderate risk of orthostatic hypotension. Risperidone does, however, cause prolactin elevation and this can result in sexual dysfunction. Risperidone is also associated with extrapyramidal side effects if taken at a high dose.6

Long acting injectable form risperidone (Risperdal Consta)

Over the long term, the long acting form has a slightly lower risk of extrapyramidal side effects, nausea and symptom-causing prolactin elevation compared to the oral form. The long acting injections are associated with little on no injection site pain.7, 8 Overall the side effects of the injectable version are similar, if somewhat less frequent, to that of the oral version.6 A recent article compared the side effects of long acting risperidone to oral Olanzapine and found that long acting Risperidone had considerably less weight gain then oral Olanzapine.9

Apart from just side effects there are other benefits to long term injectable risperidone. Other benefits include:10

  • Improved compliance rates
  • Improved relapse prevention and reduced rehospitalisation rate
  • Enhanced efficacy due to reduced peak-trough dose variation and improved compliance
  • Minimal gastro-intestinal absorption problems 
  • Reduced first pass metabolism
  • Staff time saving due to reduced need to reinforce compliance issues.

There are however some disadvantages to long acting medications and these include:

  • Side effects may remain for a longer time after discontinuation of medication
  • Patient feelings of "being controlled"
  • Social Stigma
  • Fear of injections. Although injections are usually associated with only minimal pain and discomfort.

There is now new data coming through for a new use of long acting Risperidone. Traditionally this was reserved as a second line treatment for patients who where either already stable on other medication or who where repeatedly noncompliant with medication. However two recently published studies suggest that long acting Risperidone may be useful as a first line treatment for newly diagnosed patients.11, 12 Newly diagnosed patients often have the best response to treatment but suffer from high relapse rates due to poor compliance to medication. To help reduce relapse rates long acting Risperidone was trialed as the first treatment. Both studies found that long acting Risperidone had similar efficacy and side effects of oral risperidone but much higher long term compliance rates. In one study compliance after 2 years was as high as 72% and only 11% of patients had suffered a relpse.11 It is important to note that these are only small studies and more research is needed before long acting Risperidone can be confidently recommended as a first line treatment of newly diagnosed patients but the early results seem to be promising.    


Quetiapine (Seroquel)

Quetiapine has only moderate weight gain and metabolic syndrome side effects. Quetiapine also has only moderate hypotension but is associated with higher rates of sedation and dry mouth. There is a theoretical increased risk of cataracts but this has not been shown in human studies.6

Ziprasidone (Zeldox)

Ziprasidone has a milder side effect profile. The drug is only occasionally associated with weight gain and the metabolic syndrome and only rarely gives the other common side effects (such as sedation, hypotension or anti-cholinergic effects). However, it is associated with insomnia (although this is often transient), dry mouth and constipation. Ziprasidone is also associated with a moderate risk of cardiac conduction abnormalities (prolonged QT time) although the implication of this for clinical outcomes remains unclear.6

Aripiprazole (Abilify)

Aripiprazole, a new drug, differs in its mechanism of action and has shown itself to have few side effects. It is not associated with significant weight gain or metabolic syndrome, sexual dysfunction or anti-cholinergic effects. Aripiprazole is associated with restlessness, nausea and vomiting, insomnia and headache. However, the medication has only recently been released, and further post-marketing research is needed to clearly identify all side effects.6,13  

Clozapine (Clopine, CloSyn, Clozaril)

Clozapine is again a special case due to its side effect of agranulocytosis. Although agranulocytosis occurs in less than 1% of patients who take clozapine, it is a potentially life threatening condition. As a result all patients on clozapine require ongoing monitoring with regular blood tests (Full Blood Picture).14

The other main side effects of clozapine are:

  • High risk of weight gain and glucose and lipid abnormalities
  • Sedation
  • Orthostatic hypotension
  • Anti-cholinergic side effects

The metabolic syndrome

Almost as soon as SGAs were introduced, it was found that patients who took them experienced significant weight gain, changes in glucose metabolism and lipid abnormalities. About 50% of all patients who take SGA will experience this to some extent.3 In the long term, metabolic syndrome is a critical side effect due to the risks of diabetes and lipid abnormalities. These risks include:

  • Coronary artery disease
  • Cerebral vascular disease
  • Peripheral vascular disease
  • Kidney disease
  • Eye disease

The rates of cardiovascular disease are around 2 times higher in the population taking anti-psychotic medication than in the general population. There are three reasons suggested for this increased rate:

  • The illness itself changing glucose and lipid metabolism
  • Lifestyle factors (this population is usually more sedentary, has a poorer diet and higher rate of smoking)
  • Medication factors

Because of the high risk of long term general health complications, identification of the metabolic complications is of the uttermost importance. Therefore all patients started on anti-psychotic medication should be screened both at the start of treatment and then at regular intervals. Screening should include:

  • Body Mass Index and waist to hip ratio measurements
  • Personal and family history of diabetes, heart disease or hypertension
  • Measurement of fasting blood glucose, blood pressure and lipid profile.

For patients in which this becomes a problem, there should be a comprehensive approach of diet, exercise and medication review to help prevent the complications of metabolic syndrome.15

Compliance rate

An interesting way to view the different side effect profiles is to look at patient compliance figures. Although compliance may be influenced by many factors, the side effects that a patient experiences play a very important role in compliance. It has been suggested that excessive weight gain is a significant reason for noncompliance to medication. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study, first published in 2005 showed that noncompliance rates among antipsychotic medications are very high. At 18 months the noncompliance rates were: 16

  • Olanzapine 64%
  • Risperidone oral 74%
  • Ziprasidone 79% 
  • Quetiapine 82%

One of the strategies to help improve compliance is the use of long act injectable forms of antipsychotic medication, such as Risperdal Consta. Compared to oral Olanzapine Risperdal Consta has a higher compliance rate. In the patients recieving Risperdal Consta half of those who stopped their medication did so with the consent of their doctor, while only a quarter of patients who stopped their oral Olanzapine did so with their doctors consent.9

Conclusion

Second generation anti-psychotics are the mainstay of treatment for patients with schizophrenia. However, each of the drugs has a different side effect profile and thus some are more suited to some patients than others.  Below are a series of tables that summarise the use of SGA. Table 1 summarises the basic treatment pathway for patients with schizophrenia, Table 2 summarises which SGA should be used with specific patients and Table 3 compares the major side effects of SGA.

It can be seen that different drugs will find uses in different patients and while it is easy to compare different drugs on paper, it is much harder to implement effective treatment programs. Ultimately it will always be the patient’s individual response to the medication that will dictate which drug is most suitable for that particular patient.


Table 1: Basic treatment pathway for patients with schizophrenia14

 Situation

Treatment 

 1st episode schizophrenia

 SGA (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole)
 Some evidence for use of long acting injectable forms of SGA (Risperdal Consta)11,12  

 Treatment resistant schizophrenia Clozapine
 Noncompliant patient Long acting injectable forms of SGA (Risperdal Consta)

Table 2: Drug of choice based on patient characteristics2

 Patient characteristics

 Drugs to use 

 Sensitivity to weight gain Ziprasidone or anpiprazole
 Past history of lipid abnormalities Ziprasidone or anpiprazole 
 Sensitivity to extrapyramidal side effects All SGAs except risperidone
 Sensitivity to prolactin secretion All SGAs except risperidone
 Persistent suicidal behaviour or aggression Clozapine

Table 3: Summary of major side effects of SGAs2,17

Drug

Weight
gain

Glucose
abnormalities

Lipid
changes

Sedation

Hypotension

Prolactin
elevation

 Clozapine

***

***

***

***

***

– 

 Risperidone oral

**

**

**

*

*

***

 LA Risperidone consta injection

 *

***

 Olanzapine

***

***

***

***

*

*

 Quetiapine

**

**

**

**

**

 Ziprasidone

*

 Aripiprazole

*

    –   = rarely causes this side effect
   *    = occasionally causes this side effect
  **   = sometimes causes this side effect
 ***  = frequently causes this side effect

 

Reference:

  1. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: An exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006; 163:185-94.
  2. Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, et al. Practice guideline for the treatment of patients with schizophrenia. 2nd Ed. American Psychiatric Association; 2004.
  3. Serretti A, De Ronchi D, Lorenzi C, Berardi D. New antipsychotics and schizophrenia: A review on efficacy and side effects. Cur Med Chem 2004; 11: 343-58.
  4. Tandon R. Comparing antipsychotic efficacy. Am J Psychiatry 2006; 163(9): 1645.
  5. Tandon R, Fleischhacker W. Comparative efficacy of antipsychotics in the treatment of schizophrenia: A critical assessment. Schizophrenia Research 2005; 79: 145- 55.
  6. CMPMedica Australia. eMIMS. Version 5.01.0088. St Leonards: CMPMedica Australia; 2007.
  7. Fleischhacker W, Eerdekens M, Karcher K, Remington G, etal. Treatment of Schizophrenia With Long Acting Injectable Risperidone: A 12-Month Open Label Trail of the First Long Acting Second Generation Antipsychotic. J Clin Psych 2003; 64(10): 1250-8.
  8. Lasser R, Bossie C, Gharabawi G, Turner M. Patients with schizophrenia previously stabilized on conventional depto antipsychotics experience significant clinical improvements following treatment with long acting risperidone. European Psychiatry 2004; 19: 219-25.
  9. Keks N, Ingham M, Khan A, Karcher K. Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. British J Psych 2007; 191: 131-9.
  10. Nasrallah H. The case for long-acting antipsychotic agents in the post-CATIE era. Acta Psych Scand 2007; 1-8.
  11. Emsley R, Medori R, Koen L, Paulus P etal. Long-Acting Injectable Risperidone in the Treatment of Subjects With recent-onset PsychosiS A Preliminary study. J Clin Psychopharmacology 2008; 28(2):210-4.
  12. Chue P, Emsley R. Long-Acting Formulations of Atypical Antipsychotics Time to Reconsider When to Introduce Depot Antipsychotics. CNS Drugs 2007; 21(6): 441-8.
  13. El-Sayeh HG, Morganti C. Aripiprazole for schizophrenia. Cochrane Database of Systematic Reviews 2006, Issue 2. Art.No.: CD004578.
  14. Picchioni MM, Murray RM. Schizophrenia. BMJ 2007; 335: 91-5.
  15. Komeda J. Metabolic syndrome and psychosis. Medical Forum Magazine 2007; 5: 34.
  16. Mortimer A, Williams P, Meddis D. Impact of side-effects of atypical antipsychotics on non-compliance, relapse and cost. Journal of International Medical Research 2003; 31: 188-96.
  17. MIMS Australia. [online] Zyprexa (Olanzipine). 2006. Available at URL: http://www.mims.com.au (last accessed 2/5/08)

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Dates

Posted On: 15 February, 2008
Modified On: 16 January, 2014

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