Treatment of depression in schizophrenia – can antidepressants be used?

Despite multiple scientific publications on depression in schizophrenia, the main provisions regarding this problem remain controversial today. The only aspect on which a certain consensus has been reached is that depression is an integral part of schizophrenia and it can develop in any form and at any stage of the disease.

Short information about depression in schizophrenia

There are indications of a “mitigating” effect of depression on the manifestations of schizophrenia, most researchers consider depression as an unfavorable prognostic factor that decreases the quality of patients’ lives, aggravates impairments in their psychosocial functioning, and increases the risk of suicide.

The incidence of depression in schizophrenia ranges from 7 to 70%. Such a wide range of numbers may be due to the examination of patients at different stages of the disease and the lack of generally accepted methodological approaches to the assessment of separate depressive symptoms and the extensive depressive syndrome.

The findings of the study by J. Sands and M. Harrow, who observed 70 schizophrenic patients for 7.5 years, showed that in 24% of cases depression signs were not observed, in 26% some depressive symptoms were detected, in 14% -condition close to depression, and 36% had depression meeting the clinical criteria for major depressive disorder.

Diagnosing depression in schizophrenia

Modern classifications for the identification of depression in schizophrenia (in particular, post-attack depression) use the same diagnostic guidelines as for a depressive episode within the framework of an affective disorder. This approach reduces the detection of depressive disorders in schizophrenia. This is not an optimal system of diagnosis. Criteria which to a greater extent reflect the specific features of depression in schizophrenia are still to be developed.

Causes and types of depression in schizophrenia

There are different concepts regarding the causes of depression in schizophrenia:

- In accordance with the personality-reactive hypotheses, the formation of depression is related mainly to the psychological reaction of the patient to the existence of a mental disorder and the social maladjustment caused by it. But within the framework of these hypotheses, there is another view: it is the depression in schizophrenia that causes psychological discomfort and social adaptation problems.

- The pharmacogenic theory of the onset of depression in schizophrenia emphasizes the role of neuroleptic therapy in the formation of depression. The hypothesis of pseudoparkinsonian depression is widely discussed, suggesting its relationship with the extrapyramidal syndrome (EPS). This does not exclude the direct effect of antipsychotic drugs on dopamine transmission. Antidopamine activity of antipsychotics entails the onset of not only EPS, but also hyperprolactinemia. The latter attracts attention due to the fact that scientific literature contains data on the occurence of affective disorders with an elevated level of prolactin both in individuals with endocrine disorders and in mentally ill patients. But in this case, it is also underestimated that the increase in prolactin may be related to thyroid hormones, which play an essential role in the development of affective pathology. We can add that when using atypical antipsychotics, which are significantly less conducive to the occurrence of neurological adverse reactions, depressive symptoms develop during therapy in 10-13% of cases. Thes, the concept of the link between depression and antipsychotic therapy requires further development.
- There is also a hypothesis according to which depression is an integral part of schizophrenia (at least one of the variants of this disease) along with negative and positive symptom complexes. This point of view is supported by data on the existence of the depressive vulnerability in a number of schizophrenic patients.
- Among other things, in schizophrenia, depression can be caused by a somatic illness, taking certain medications (beta-blockers, calcium channel blockers, sleeping pills, indomethacin, corticosteroids), medicines and drug addiction, alcoholism.
Thus, we can talk about primary and secondary depression in schizophrenia. In practice, there seem to be depressive conditions, in the formation of which several factors are involved. And if a number of secondary depressions can be diagnosed in a timely manner, then in a number of cases it is sometimes difficult to determine the role of one mechanism or another in the formation of primary depression. It is all the more difficult to objectively assess the contribution of reactive mechanisms to the formation of depression, which are most often present to one degree or another in patients with chronic disease.

Therapy of depression in schizophrenia

Diagnostic uncertainty entails therapeutic uncertainty in relation to strategies of the therapy depression in schizophrenia. The most controversial issue concerns the advisability of using antidepressants. The main concerns are related to the risk of exacerbation of psychotic symptoms with the use of antidepressants, and the possible increase in adverse reactions due to medications interactions.
However, in recent years, a number of publications have appeared that confirm that the introduction of antidepressants into antipsychotic therapy not only does not cause exacerbation of psychotic manifestations, but, on the contrary, has additional advantages. Thus, in a double-blind, placebo-controlled study, data were obtained on the enhancement of the antipsychotic effect of medicines for schizophrenia when Mirtazapine (atypical antidepressant) or Anafranil (tricyclic antidepressant) were added in cases where there was resistance to therapy.

In accordance with the topic of this review, special consideration requires the effect on depression in schizophrenia of modern antidepressants - selective serotonin reuptake inhibitors (SSRIs), which have less potential adverse effects than tricyclic antidepressants.

The existing concerns of using SSRIs in combination with atypical antipsychotics due to pharmacokinetic interactions and the risk of enhanced side effects seem to us somewhat exaggerated. First, individual SSRIs differ in their ability to inhibit the cytochrome P450 system (Fluoxetine, Paroxetine are strong inhibitors, Fluvoxamine has a less pronounced inhibitory ability, Sertraline and Citalopram have practically no effect on the microsomal enzyme system). Secondly, pharmacokinetic studies show that all SSRIs in therapeutic dosages do not cause clinically significant changes in the concentration of antipsychotics in blood plasma and their combined use is acceptable. Moreover, from the point of view of evidence-based medicine, such a combination is one of the methods of choice in the therapy of psychotic and resistant depression. None of the studies with the combined use of antidepressants and antipsychotics have proved a higher rate of psychotic symptoms exacerbation. But there is clear evidence of the effective use of SSRIs in the therapy of an acute attack of schizophrenia.

As an example of the stated above, a placebo-controlled trial of the use of Fluvoxamine and Olanzapine for an acute attack of schizophrenia can be cited. The study included 20 patients, the duration of therapy was 6 weeks. It was found that in the group of patients receiving Olanzapine and Fluvoxamine, there was a more pronounced reduction in the total schizophrenia severity scale score compared with the group receiving Olanzapine and placebo. There were no differences in the frequency of adverse reactions between groups. This suggests that the combined use of SSRIs and antipsychotics is permissible in terms of efficacy and safety.

Treatment of depression in schizophrenia in medical practice

Of great interest is the point of view of practitioners on the problem under discussion, since the combination of antidepressants and antipsychotics is a fairly common variant of pharmacotherapy in psychiatric practice - in 41.5% of all courses of psycho-pharmacotherapy.

It was found that in paroxysmal schizophrenia, combined therapy with antidepressants and antipsychotics is prescribed in 50.6% of all courses of treatment, monotherapy with antipsychotics - in 41.4%, and antidepressants - in 2.3%.

It also turned out that 70-80% of inpatients and 30-40% of outpatients with schizophrenia receive antidepressants, while antidepressants are widely prescribed in an acute attack of the disease. In this regard, the data of D. Addington et al., Who interviewed more than 3000 psychiatrists from the USA, Canada, Australia, and Europe, are also of interest. Their results showed that antidepressants in combination with neuroleptics are prescribed to 33% of inpatients and 36% of outpatients with schizophrenia. At the same time, the addition of antidepressants as the first choice method is considered by 58% of doctors in the therapy of depression in the structure of an acute schizophrenic attack, 54% - postpsychotic depression and 73% - depression in stable chronic schizophrenia.

When antidepressants are appointed in schizophrenia?

The main clinical symptoms that necessitate the use of antidepressants, according to most of the doctors, are suicidal thoughts, a sharply reduced mood, a feeling of hopelessness, lost of interest in life, sleep disturbances, especially early awakenings, and ideas of guilt. At the same time, 33% of respondents indicated that they rarely or never use antidepressants in schizophrenia due to the risk of enhanced severity of productive symptoms.

A detailed assessment of the risk of a flare-up of acute psychotic episodes due to the use of antidepressants was also carried out. Only 2% assess this risk as high, 34% as average. More than half (55%) consider the likelihood of such an exacerbation insignificant, and 9% do not believe at all that the appointment of antidepressants can lead to an exacerbation of psychosis.

From the data provided in the article, it can be seen that the discussion in the scientific community, the ambiguity and contradictions of many provisions concerning depression in schizophrenia reflect the picture that has developed in practical health care. Despite the fact that in the scientific literature much attention is paid to justifying the restrictions on the use of antidepressants in schizophrenia, for practitioners, adding antidepressants to antipsychotics in the therapy of schizophrenic patients with depression has become almost the main strategy of therapy. Moreover, this approach is used by most doctors, regardless of the existing standards of therapy in different countries. And although the choice of practitioners cannot be assessed from the standpoint of evidence-based medicine, it is confirmed by daily clinical observations. This dictates the need for special studies that would make it possible to realistically assess the role of antidepressants in the therapy of depression in schizophrenia.

Post by: Elizabeth Agrer, clinical pshychiatrist, Copenhagen, Denmark