Antipsychotic medication is the first port of call when treating schizophrenia, and patients are often maintained on these drugs for many years due to the chronic nature of the illness. The term ‘antipsychotic’ is a bit of a misnomer, however. In medical parlance, these drugs are more commonly known as dopamine antagonists. This is because the principal mechanism of all antipsychotics is to block certain types of dopamine receptors across the brain.

The dopamine hypothesis of schizophrenia states that excess release of dopamine in the mesolimbic pathway of the brain gives rise to the ‘positive’ symptoms of schizophrenia such as hallucinations and delusions (Carlsson & Lindqvist, 1963). By blocking said receptors, a reduction in symptoms should ensue.

While this is not the only prominent hypothesis of schizophrenia, it is the most well established, with a recent landmark genetics study lending it weight by finding a variant in a dopamine receptor gene to be common in schizophrenia. Nonetheless, putting aside the potential efficacy of antipsychotics as a whole, what about the relative efficacy of one antipsychotic over another?

Antipsychotics for schizophrenia

It is important to know that antipsychotics are split into different groups:

• ‘Typical’ or first generation antipsychotics
• ‘Atypical’ or second generation antipsychotics

Typical and atypical antipsychotics differ in their side effects, and atypicals have broader applications as mood stabilisers for other illnesses such as bipolar disorder (Taylor et al., 2007). Atypicals are newer, but not necessarily superior, as recent studies have begun to find (Leucht et al., 2009). These newer drugs are also more expensive, hence many countries tend to prescribe typical antipsychotics. Even in richer countries like Germany, typical antipsychotics still form a significant proportion of the market share (Lohse et al., 2004).

High-potency versus low-potency

Each first-generation antipsychotic is classified according to its potency, with low-potency antipsychotics requiring higher doses to achieve the same effect as high-potency ones, but with different side effects (Rijcken et al., 2003). Interestingly, the potency of an antipsychotic may not be related to its efficacy, as is often perceived by clinicians. Currently, there is little evidence to indicate as much, meaning that treatment guidelines (at least in Europe) recommend typical antipsychotics equivalently regardless of potency (Gaebel et al., 2006).

This may have important consequences regarding side effects, as high-potency antipsychotics are more likely to produce Parkinsons-like movement disorders, while low-potency antipsychotics tend to produce sedation (Arana, 2000).

New Cochrane reviews

In three separate meta-analytic reviews published earlier this year in the Cochrane Library (Tardy et al, 2014a; Tardy et al, 2014b; Tardy et al, 2014c), Tardy and colleagues attempted to determine whether the evidence corroborates the treatment guidelines.

The authors summarise that:

Systematic reviews on the comparative efficacy of high-potency versus low-potency antipsychotic drugs are not available. Cochrane reviews on the effects of specific conventional antipsychotic drugs have been published, but they compared the effects of one antipsychotic drug versus any other antipsychotic drugs and thus did not consider the important classification in high-potency and low-potency antipsychotics.

Methods

Each paper evaluated the efficacy of a high-potency first generation antipsychotic (Trifluoperazine, Fluphenazine, and Haloperidol, respectively) against all low-potency antipsychotics. All three reviews searched available literature in the Cochrane Schizophrenia Group’s comprehensive Trials Register, selecting for randomised controlled trials (RCTs) regardless of duration.

The principal outcome measure was clinical response as reported in each study, with the following secondary outcome measures: symptoms of schizophrenia, change in global state, leaving the study due to inefficacy or side effects, relapse rates, rehospitalisation, side effects, death, quality of life, and satisfaction with care.

Two of the authors extracted and examined the data independently. For continuous data, mean differences (MD) between groups were estimated. For categorical (e.g. yes/no) data, risk ratios (RR) and their 95% confidence intervals (CI) were calculated, based on a random-effects model (i.e. a way of accounting for unobserved randomness).

Results

Here are the highlights of the findings from the three reviews:

Trifluoperazine

• 7 RCTs involving 422 participants were included, (range in sample sizes: 20 and 157 participants, study length range: 4 and 52 weeks)
• Overall, randomisation and blinding procedures were poorly reported
• Trifluoperazine was not significantly different from low-potency antipsychotic drugs regarding response to treatment (3 RCTs, RR 0.96 CI 0.59 to 1.56, moderate quality evidence)
• No significant difference in acceptability of treatment (3 RCTs, RR 1.25, CI 0.72 to 2.17, low quality evidence)
• At least one movement disorder was significantly more frequent in the trifluoperazine group, as well as incoordination, and rigor, although both groups experienced at least one adverse effect
• No data were available for other outcomes of interest death, sedation and quality of life

Fluphenazine

• 7 RCTs and 1,567 participants were included (sample sizes ranged between 40 and 438 participants)
• Overall, randomisation and blinding procedures were poorly reported
• No significant difference in terms of response to treatment (2 RCTs, RR 1.06 CI 0.75 to 1.50, moderate quality evidence)
• No significant difference in acceptability of treatment (fluphenazine 36%, low-potency antipsychotics 36%, 6 RCTs, RR 1.00 CI 0.88 to 1.14, moderate quality evidence)
• At least one movement disorder occurred more frequently in the fluphenazine group (low quality of evidence). In contrast, low-potency antipsychotics produced significantly more sedation (high quality evidence)
• No data were available for the outcomes of death and quality of life
• Adverse effects such as akathisia (restlessness), dystonia (muscle spasms and contractions), loss of associated movement, rigor, and tremor occurred significantly more in the fluphenazine group
• Other adverse effects such as dizziness, drowsiness, dry mouth, nausea, and vomiting occurred significantly more in the low-potency group

Haloperidol

• 17 RCTs and 877 participants were included (sample sizes ranged between 16 and 109 participants, and study length between two and 12 weeks)
• Overall, randomisation and blinding procedures were poorly reported
• No clear evidence that haloperidol was superior to low-potency antipsychotics in terms of clinical response (14 RCTs, n = 574, RR 1.11, CI 0.86 to 1.44 low quality evidence)
• No clear differences in acceptability of treatment (11 RCTs, RR 0.82, CI 0.38 to 1.77, low quality evidence)
• More participants from the low-potency drug group experienced sedation, orthostasis problems (not being able to stand for long) and weight gain
• In contrast, movement disorders were more frequent in the haloperidol group
• No data were available for death or quality of life

The authors state that:

For people with schizophrenia it is important to know that there is low/moderate quality evidence that Trifluoperazine/Haloperidol/Fluphenazine and low-potency antipsychotics are approximately equal in their effects on treatment response, and that there is evidence of a lower quality that they clearly differ in side-effects (such as movement disorders). They might tell their doctors that they want to be involved in the choice of the antipsychotic that is best for them.

Discussion

All three reviews found little difference in efficacy between the high-potency antipsychotics Trifluoperazine, Haloperidol, Fluphenazine, and low-potency typical antipsychotics.

Regarding adverse side effects, the general conclusion across all three papers is that high-potency antipsychotics produce greater movement disorders, while low-potency antipsychotics produce more varied effects such as sedation, dizziness, nausea, and weight gain.

This reinforces the view, echoed by the authors, that patients should be involved in the choice of prescribed antipsychotic. If efficacy is more or less equivalent from one antipsychotic to another, then it would surely come down to which side effects were the most tolerable, or presented a greater health-risk to the individual.

It is worth noting that both the quality of how the trials were reported and the data they gathered was mostly of low and/or medium quality. The only high-quality finding was from one RCT of Fluphenazine against low-potency antipsychotics, showing that the latter were significantly more responsible for sedation.

Conclusions

With the current evidence being limited in terms of quality, it is difficult to draw firm conclusions about the relative efficacy of high vs low-potency first generation antipsychotics. Nonetheless, what evidence is available points to a lack of a difference in efficacy, but clear differences in adverse side effects, making it crucial that patients be involved in deciding which antipsychotic is right for them, as the authors make clear in their conclusions.

Speaking more broadly, mental healthcare is perhaps unique within medicine, with regards to the impact that patient involvement can have on outcomes, such as treatment adherence (Thompson & McCabe, 2012). It is dispiriting to learn from recent reviews that shared decision-making in the treatment of schizophrenia occurs less often than in general practice, despite both patients and clinicians acknowledging its desirability (Beitinger et al., 2014).

Limitations

• The generally low quality of available data, and the lack of data for certain outcome measures like sedation, death, or quality of life
• There is a broader limitation beyond the confines of these reviews, which the authors articulate: “the classification of high- and low-potency antipsychotics is not clear cut”
• The authors also explain that many low-potency antipsychotics were missing from the available data
• Two of the authors received consultancy or lecture fees from pharmaceutical companies. Nonetheless, the two authors who actually conducted the data extraction had no conflicts of interest to declare

Links

Tardy, M., Dold, M., Engel Rolf, R., & Leucht, S. (2014a). Trifluoperazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews, (7). Retrieved from http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009396.pub2/abstract doi:10.1002/14651858.CD009396.pub2

Tardy, M., Huhn, M., Engel Rolf, R., & Leucht, S. (2014b). Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews, (8). Retrieved from http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009230.pub2/abstract doi:10.1002/14651858.CD009230.pub2

Tardy, M., Huhn, M., Kissling, W., Engel Rolf, R., & Leucht, S. (2014c). Haloperidol versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database of Systematic Reviews, (7). Retrieved from http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009268.pub2/abstract doi:10.1002/14651858.CD009268.pub2

Arana, G. W. (2000). An overview of side effects caused by typical antipsychotics (PDF). Journal of Clinical Psychiatry, 61(Suppl 8), 5-11.

Beitinger, R., Kissling, W., & Hamann, J. (2014). Trends and perspectives of shared decision-making in schizophrenia and related disorders. Current opinion in psychiatry, 27(3), 222-229. [PubMed abstract]

Carlsson, A., & Lindqvist, M. (1963). Effect of chlorpromazine or haloperidol on formation of 3‐methoxytyramine and normetanephrine in mouse brain. Acta pharmacologica et toxicologica, 20(2), 140-144. [Abstract]

Gaebel, W., Falkai, P., Weinmann, S., & Wobrock, T. (2006). Deutsche Gesellschaft für Psychiatrie PuNH (Hrsg) S3-Praxisleitlinien in Psychiatrie und Psychotherapie, Bd 1: Behandlungsleitlinie Schizophrenie. Steinkopff, Darmstadt.

Leucht, S., Corves, C., Arbter, D., Engel, R. R., Li, C., & Davis, J. M. (2009). Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. The Lancet, 373(9657), 31-41. [PubMed abstract]

Lohse, M. J., Lorenzen, A., & Müller-Oerlinghausen, B. (2004). Psychopharmaka Arzneiverordnungs-Report 2003 (pp. 704-749): Springer.

Rijcken, C. A., Monster, T. B., & Brouwers, J. R. (2003). Chlorpromazine equivalents versus defined daily doses: how to compare antipsychotic drug doses? Journal of clinical psychopharmacology, 23(6), 657-659. [PubMed abstract]

Taylor, D., Paton, C., & Kerwin, R. (2007). The Maudsley prescribing guidelines: CRC Press.

Thompson, L., & McCabe, R. (2012). The effect of clinician-patient alliance and communication on treatment adherence in mental health care: a systematic review. BMC psychiatry, 12(1), 87. [PubMed abstract]