While antipsychotics do produce some reduction of negative symptoms in people with schizophrenia, the improvement is somewhat less than in other symptoms of the condition.

Negative symptoms reflect a deficit in two clusters of symptoms:

1. An expressive deficit (affective flattening, poverty of speech)
2. Amotivational state (asociality, amotivational and apathy)

Persistent negative symptoms are a clinically important problem for a subgroup of otherwise stable individuals despite adequate antipsychotic drug treatment, and, are correlated with social and clinical long term morbidity and poor functioning in many areas of life.

There is a body of evidence that antidepressants help individuals who are in an acute episode of a major depressive disorder comorbid with their schizophrenic illness or when used to prevent another episode (Janicak PG, et al, 1993). Some controlled studies find antidepressants have a beneficial effect for negative symptoms, but many do not. It is therefore important to explore the direct effect of antidepressants on negative symptoms that is not explained by comorbid major depressive disorder.

The recently published ACTIONS trial explores one antidepressant (Citalopram) versus placebo for the long term treatment of selected people with schizophrenia who have persistent negative symptoms, but who do not have a comorbid acute major depressive illness.

Methods

This is a double-blind, placebo-controlled, random-assignment, multisite study (15 UK sites), of Citalopram 20 mg flexible dose (20 or 40 mg) in patients with well-established schizophrenia, adequately treated with antipsychotics, and clinically stable for at least 3 months.

Participants had persistent negative symptoms, with a PANSS negative symptoms score of 20 or more, and with 3 individual item scores of 3 or more.

Individuals with a major depressive illness in the past three months were excluded.

Results

There were no significant differences on all outcomes at 3 or 12 months, including adverse effects, QT intervals and the health economic outcomes.

Primary Outcome
Heinrich Quality of Life Scale		Placebo		Citalopram		Adjusted Difference	Significance
		n	Mean	n	Mean
Baseline		30	43	29	50	-7	NS
3 Month		25	50	21	52	-6	NS
12 Month		20	55	17	63	-0.1	NS
PANNS Negative Symptoms Scale
Baseline		32	26	30	25	-0.4	NS
3 month		24	23	22	22	-1.3	NS
12 month		23	22	19	20	-1.4	NS

Conclusions

The results fail to find evidence not only in quality of life and negative symptoms, but also in both clusters of negative symptoms, nor in a wide variety of other symptoms. Since negative symptoms produce considerable morbidity, the failure of benefit seen long term and the effect on health economic outcome is consistent with the clinical outcome.

A recent comprehensive meta-analysis (Helfer B. et al. 2016) found evidence for an overall small benefit, but this could result from a small effect in all patients or a larger effect in some studies, and, no difference in others. Some individual studies find antidepressant augmentation produced benefits in people with schizophrenia, while others do not. The latter could occur because of four possibilities:

1. Bias in a few studies can be carried through to the final meta-analysis result. There are many possibilities for bias to creep into studies, despite the best efforts of investigators. Individual investigators seek verification of their hypotheses, with positive results useful in seeking public grants. Industry sponsors seek positive results, and such bias could exist for several trials of that specific drug. Publication bias is a result that positive studies are more likely to be published than negative studies, and this is particularly so for small studies.
2. It is possible that only a subtype of patients respond. For example, some of these might be people with schizophrenia who also have comorbid major depressive disorders.
3. It is possible there could be differences in the mechanisms of action of different subtypes of antidepressants.
4. It is possible the beneficial effect could develop slowly so that a longer term study is necessary to demonstrate efficacy.

Strengths and limitations

• This study is multisite, publicly supported, thus free of certain biases.
• It is a long term study, relevant if prolonged treatment is needed to demonstrate a positive outcome.
• It is important for its specificity of patient selection, to include only persistent negative symptoms and exclude patients in or just after an episode of depression.
• The pharmacological specificities of individual drug studies reside in the specificity of possible mechanisms of action, and, in this case, the blockade of serotonin update.
• The major limitation is that the study is small, with the 62 participants recruited falling well short of the target recruitment of 358.

Summary

Compared to placebo, Citalopram, a serotonin uptake inhibitor, produced no benefit in people with stable schizophrenia on long term antipsychotics, selected with persistent negative symptoms. Since the clinician is using an individual drug, this would be evidence that Citalopram or other SSRIs might not be useful, but other antidepressants might. Even though small, the specificity of patients recruited (just severe chronic persistent negative symptoms and the exclusion of current major depression) produce new evidence that practitioners should consider. Choosing not to use any antidepressant is a decision.

Research might consider investigating individual drugs which more consistently demonstrated efficacy on negative symptoms.

Links

Primary paper

Barnes TRE, Leeson VC, Paton C, Costelloe C, Simon J, Kiss N, et al. Antidepressant Controlled Trial for Negative Symptoms in Schizophrenia (ACTIONS): a double-blind, placebo-controlled, randomised clinical trial (PDF). Health Technol Assess (2016);20(29).

Other references

Helfer B, Samara MT et al (2016) Efficacy and Safety of Antidepressants Added to Antipsychotics for Schizophrenia: A Systematic Review and Meta-Analysis. Am J Psychiatry. Published online: June 10, 2016; http://dx.doi.org/10.1176/appi.ajp.2016.15081035.

Janicak P, Davis JM et al (1993). Principles and Practice of Psychopharmacotherapy. Baltimore MD: Williams and Wilkins.

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