The effect of vortioxetine on anhedonia in patients with schizophrenia

Abstract

Objective

Anhedonia is a common symptom of depression, but is also a negative symptom of schizophrenia. The purpose of this study was to examine the effects of vortioxetine on anhedonia in patients with schizophrenia.

Methods

A total of 120 patients with schizophrenia in remission who met inclusion criteria were randomized 1:1 by the envelope method into intervention and control groups. All participants in both groups were divided into three subgroups based on the antipsychotic therapy they were receiving (olanzapine, risperidone, or aripiprazole). Vortioxetine was administered to those in the intervention group at a fixed dose of 10 mg per day. The Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), and Chapman Scale for Social and Physical Anhedonia (CSPA) were administered. The study lasted 12 weeks. Participants were assessed twice: At baseline and at the end of the study. Six participants dropped out, with 114 completing the trial.

Findings

Vortioxetine treatment had a significant effect on level of physical anhedonia. The treatment interaction was also statistically significant, but with a relatively small effect (F = 3.17, P < .05; η2 = .061). Vortioxetine treatment had a particularly strong effect on the level of social anhedonia. The interaction between the treatment and the type of antipsychotics was also statistically significant with a small effect (F = 5.04, P < 0. 01; η2 = .091).

Conclusion

The combination of olanzapine and vortioxetine was found to be the best option to reduce symptoms of social and physical anhedonia in these patients with remitted schizophrenia.

Keywords

schizophrenia physical anhedonia social anhedonia vortioxetine antipsychotics

Introduction

Schizophrenia

Schizophrenia is one of the most severe and generally chronic disabling mental health conditions¹ associated with positive (psychotic symptoms such as hallucinations and delusions), negative (such as anhedonia and asociality) and cognitive symptoms (such as impaired working memory and executive function).² Schizophrenia affects approximately 1% of the world's population.³ There is a clear link between negative symptoms and the functional incapacity of patients.⁴ Antipsychotics are fundamental for the treatment of schizophrenia.⁵ However, they have some limitations, including poor efficacy against negative and cognitive symptoms as well as different adverse events.⁶ Anhedonia can be induced by dopamine D2 receptor blocking agents such as antipsychotics and, in turn, attenuated by activating dopamine D2/D3 receptors and/or by increasing dopamine sensitivity in the reward pathway.⁷ The relationship between antipsychotics and anhedonia is incompletely understood.⁸ The prevailing view is that a combination of antipsychotics and psychosocial treatments is the optimal approach to functional recovery.⁹

Anhedonia

Anhedonia is a decreased ability to experience pleasant emotions and is considered a transdiagnostic symptom.¹⁰ It is present across different psychiatric disorders, including major depressive disorder (MDD) and schizophrenia.¹¹ In schizophrenia, anhedonia is strongly associated with poorer global functioning and is a strong predictor of reduced quality of life, social and physical functional outcomes.¹²

In depression, there is a lack of satisfaction for everything that was pleasant before.¹³ In schizophrenia, the usually pleasant satisfaction becomes unattainable.¹⁴ Anhedonia is a negative symptom of schizophrenia and a symptom of depression. It is also present in personality disorders, addiction and post-traumatic stress disorder.¹⁵ Anhedonia also occurs in healthy people and is more expressed in the chronic phase of schizophrenia.¹⁶ It is associated with neurotransmission dysfunction in the mesolimbic dopamine reward system.¹⁷ There are two types of anhedonia: physical and social anhedonia.⁴ Patients with schizophrenia have greater physical and social anhedonia than the healthy population.¹⁸ A study on first relatives of patients with schizophrenia shows greater physical anhedonia compared to the control group (healthy participants),¹⁹ while patients with schizophrenia have anhedonia more often than healthy people but less often than patients with depression.²⁰ The concept of anhedonia is now divided into two aspects: consummatory and anticipatory anhedonia.²¹ The latest meta-analysis shows that in schizophrenia, there is a greater impairment of consummatory than anticipatory anhedonia,²² and unlike depression, both components were equally presented. Anhedonia is associated with suicidality regardless of the presence of depression.^23,24

Vortioxetine

Vortioxetine, a novel multimodal serotonergic antidepressant,²⁵ is a 5-HT3, 5-HT1D and 5-HT7 antagonist, 5-HT1A agonist and 5-HT1B partial agonist. It is also a 5-hydroxytryptamine (5-HT) transporter inhibitor, depending on the dose.^26,27 The antidepressant has also demonstrated improvements in both depression and cognitive symptoms.²⁸ Unlike selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), vortioxetine enhances excitatory synaptic neurotransmission and neuroplasticity.²⁹

Purpose of the study

The purpose of the study is to examine the effects of vortioxetine on anhedonia in patients with schizophrenia.

Method

In all, 120 patients with schizophrenia in remission, and diagnosed according to the diagnostic and the Statistical Manual of Mental Disorders (DSM- 5),³⁰ who fulfilled inclusion criteria, were randomized on a 1:1 envelope method basis. All participants were in either the intervention or control groups. Both groups, comprising 60 patients, were divided into three subgroups for the purpose of antipsychotic monotherapy: 20 patients received olanzapine (≤ 10 mg per day), 20 patients received risperidone (≤6 mg per day), and 20 patients received aripiprazole (≤20 mg per day). Vortioxetine was administered to those in the intervention group at a fixed dose of 10 mg per day. The Positive and Negative Syndrome Scale (PANSS),³¹ Calgary Depression Scale for Schizophrenia (CDSS)³² and Chapman Scales for Social and Physical Anhedonia (CSPA)³³ were performed. The study lasted 12 weeks. The patients were assessed twice: at baseline and at the end of the study. There were no major adverse events during the study. Six patients dropped out of the study. Two patients dropped out due to personal reasons, and another four patients were infected with COVID-19 and subsequently admitted to intensive care. At the end of the study, 114 participants remained.

Inclusion criteria

Patients in stable remission were included, which was defined as those having a total score ≤ 70 on the Positive and Negative Syndrome Scale (PANSS)³¹ and those not having significant depressive symptoms, as reflected in scores ≤ 6 on the Calgary Depression Scale (CDSS).³² The patients were enrolled after they provided the written informed consent, approved by the Local Ethics Committee. The study was conducted in full compliance with the Helsinki Declaration.

Exclusion criteria

Patients were excluded if receiving diazepam equivalent in doses ≥ 10 mg daily, or if they took mood stabilizers, antidepressants in the past three months, abused substances in the past three months, attempted suicide in the past six months, were presented with suicidal, hetero-aggressive, or other similar behavior in the past six months, or had somatic comorbidities (such as intellectual disabilities, significant neurological disease, or head trauma). Pregnant or lactating individuals were also excluded.

Data collection tools

The Positive and Negative Syndrome Scale (PANSS) measures two types of symptoms in schizophrenia, as defined by the American Psychiatric Association. Positive symptoms are the excess or impairment of normal functions (e.g., hallucinations and delusions), whereas negative symptoms represent a reduction or loss of normal psychological functions and general symptoms. Some functions that can be lost include normal thoughts, actions, the ability to make fantasies come true, and the ability to accurately express emotions. The PANSS is a relatively brief interview, requiring 45 to 50 minutes to administer.³¹

The Calgary Depression Scale for Schizophrenia (CDSS) assesses the severity of depressive symptoms in patients with schizophrenia. It is the only depression scale devised for assessing depression in schizophrenia and differentiates depression from negative and positive symptoms of schizophrenia. It is used both in relapsed and remitted patients and is sensitive to changes.³²

The Chapman Scale for Social Anhedonia (CSAS) assesses the ability to experience pleasure in social activities such as socializing, talking, sharing experiences and feelings. It contains 40 true or false questions. Women scoring 16 or more points and men scoring 20 or more points are considered anhedonic.³³

The Chapman Scale for Physical Anhedonia (CPAS) assesses the feeling and ability to experience typically pleasant from physical stimuli. It consists of 61 true or false questions. Patients are considered to be anhedonic when scoring 20 or more points.³³

Statistical analysis

The statistical methods used for data analysis in this prospective study were descriptive statistical methods (frequencies, percentages, arithmetic mean, standard deviations, minimum, maximum, skewness and curvature, kurtosis and flatness), general linear models, factorial analysis of covariance, draft 2 × 3 plus covariate. The SPSS21 program was used for data analysis. The graphs were created in MS Excel. Initially, the descriptive characteristics of the included scales were calculated. Due to the small sample, the normality of the distributions was checked using skewness and kurtosis statistics, and it turned out that most of the results do not deviate significantly from the normal distribution.

Results

Sociodemography

In all, 120 participants with schizophrenia initially participated in the study: 70 (58%) men and 50 (42%) women. The age range of the participants was 21 to 50 years old, with an average age of 37 years (sd = 7.88). The average age of the disease was M = 21.8 years (sd = 3.54), and all participants were diagnosed between the ages of 15 and 33. The participants were hospitalized between 1 and 11 times, and the average number of hospitalizations per participant is M = 5 (sd = 2.25). The majority of participants (63%) have completed secondary education, 26% have a college or university degree, and the remaining 12% have completed primary school or less. In all, 63% of participants were unemployed, 74% were not married, and 77% had no children. In addition, 61% of participants had a positive family history of psychiatric disorders, and 22% of participants had attempted suicide at least once (Tables 1 and 2).

Table 1.

Sociodemographic Characteristics of Participants.

		N	%
In total		120	100
Group	Intervetion	60	50
Group	Control	60	50
Antipsychotic	Olanzapine	40	33
	Risperidone	40	33
	Aripiprazole	40	33
Gender	Male	70	58
Gender	Female	50	42
Education	Primary education and below	14	12
	Secondary education	75	62
	High education	31	26
Marriage status	Single	89	74
	Married	14	12
	Divorced	17	14
Number of children	0	92	77
	1	14	12
	2	13	10
	3	1	1
Suicide attempts	0	93	78
	1	17	14
	2	9	7
	3	1	1
Family inheritance	No	47	39
Family inheritance	Yes	73	61
Working status	Unemployed	74	63
	Employed	34	29
	Retired	12	8

Table 2.

Descriptive Statistics: Indicators of Schizophrenia and Depressive Symptoms (PANSS and CDSS) First and Second Measurement.

Scale:		N	Min	Max	M	SD
PANSS	Positive symptoms, 1^st meas	120	7	11	7.7	.96
	Negative symptoms, 1^st meas	120	15	29	22.4	2.80
	General symptoms, 1^st meas	120	20	38	26.9	3.33
	Positive symptoms, 2^rd meas	114	7	11	7.5	.87
	Negative symptoms, 2^rd meas	114	12	27	20.1	3.00
	General symptoms, 2^rd meas	114	19	39	26.8	3.53
	PANSS Total, 1^st meas	120	45	70	57.1	5.01
	PANSS Total, 2^rd meas	114	42	70	54.4	5.32
CDSS	1. measurement	120	2	6	4.7	.95
CDSS	2. measurement	114	2	6	4.7	1.11

Table 3.

Descriptive Statistics on the Total Sample: Chapman Scale for Physical and Social Anhedonia (CSPA).

		N	Min	Max	M	SD	Skewness	Kurtosis
Physical Anhedonia	1. meas	120	34	55	48.0	4.36	-.342	-.098
Physical Anhedonia	2. meas	114	29	56	44.8	6.45	-.235	-.912
Social Anhedonia	1. meas	120	22	36	28.5	2.71	.266	-.051
Social Anhedonia	2. meas	114	17	34	26.4	4.11	-.442	-.449

The total range of results in Chapman Scale for Physical Anhedonia (CPAS) varies from 34 to 55 in the first measurement and from 29 to 56 in the second measurement. The arithmetic mean is M = 48 (sd = 4.36) for the first measurement and M = 44.8 (sd = 6.45) for the second measurement. The distributions do not deviate from the normal (Table 3).

The results from the Chapman Scale for Social Anhedonia (CSAS) range between 22 and 36 in the first measurement, 17 and 34 in the second measurement. The arithmetic means are M1 = 28.5 (sd1 = 2.71) and M2 = 26.4 (sd2 = 4.11). The distributions do not deviate from the normal (Table 3).

According to the results in Table 4 relating to Chapman Scale for Physical and Social anhedonia (CSPA), the arithmetic means were equalized for the intervention and control groups in the first measurement, while in the second measurement there was a drop in the average result for both variables in the intervention group.

Table 4.

Descriptive Statistics of the Used Scales Depending on the Group and Measurement.

	N		M		SD
	Intervention	Control	Intervention	Control	Intervention	Control
Physical Anhedonia, 1. meas	60	60	47.6	48.4	4.30	4.43
Physical Anhedonia, 2. meas	57	57	41.6	48.4	5.89	5.06
Social Anhedonia, 1. meas	60	60	28.5	28.4	2.98	2.42
Social Anhedonia, 2. meas	57	57	24.2	28.6	4.08	2.76

Table 5 shows the arithmetic means and standard deviations measured at the second measurement, for all three variables, depending on the group and the antipsychotic taken by the participants.

Table 5.

Arithmetic Means and Standard Deviations on the Scales of anhedonia Depending on the Group and the Used antipsychotic (second Measurement).

		Physical Anhedonia			Social Anhedonia
Group		M	SD	N	M	SD	N
Intervention	Olanzapin	35.4	2.79	18	20.5	2.94	18
	Risperidon	48.5	1.97	19	28.9	1.64	19
	Aripiprazol	41.0	2.32	20	23.6	1.57	20
	Total	41.5	5.75	57	24.3	3.99	57
Control	Olanzapin	42.6	2.66	19	26.4	1.36	19
	Risperidon	53.5	1.17	19	31.6	1.12	19
	Aripiprazol	47.9	2.28	19	28.2	1.90	19
	Total	48.7	4.84	57	28.9	2.62	57

Table 6 shows that there is a statistically significant main effect of treatment with vortioxetine (F = 266.668, p < .001) and the type of antipsychotic (F = 30.704, p < .001) on the level of physical anhedonia for the second measurement. The main effect of antipsychotics (η2 = .388) is much smaller than the main effect of vortioxetine treatment (η2 = .733). According to the arithmetic means in Table 5, we can see that the intervention group, in the second measurement (M = 41.5), achieved significantly lower results on the scale of physical anhedonia than the control group (M = 48.7). Therefore, treatment with vortioxetine has a significant effect on the level of physical anhedonia in participants. The effect of antipsychotics, although weaker than the effect of vortioxetine treatment, is also moderately strong, and according to the arithmetic means (Table 5), we can see that the lowest level of physical anhedonia is shown by participants on olanzapine (M = 38.5), and the highest by participants on risperidone (M = 51.1). The interaction of intervention is also statistically significant but with a very slight effect (F = 3.168, p < .05; η2 = .061).

Table 6.

Analysis of Covariance - Testing the Main Effect of Treatment With vortioxetine, Type of antipsychotic, and their Interaction on Physical anhedonia.

	SS	df	MS	F	p	Parc. Eta square
Physical anhedonia, 1^st meas	134.409	1	134.409	36,723	.000	.275
Vortioxetine	976.021	1	976.021	266,668	.000	.733
Antipsychotic	224,759	2	112,380	30,704	.000	.388
Group * Antipsychotic	23.191	2	11,596	3.168	.046	.061
Error	355,026	97	3660
In total	213780.00	104
Adjusted total	4258.615	103

Table 7 shows a statistically significant main effect of intervention with vortioxetine (F = 163.516, p < .001) as well as the type of antipsychotic (F = 17.928, p < .001) on the level of social anhedonia in the second measurement. As with physical anhedonia, the main effect of antipsychotics (η2 = .262) is much smaller than the main effect of vortioxetine intervention (η2 = .618). According to the arithmetic means in Table 5, we see that the intervention group in the second measurement (M = 24.3) achieves significantly lower results on the scale of social anhedonia than the control group (M = 28.9). Therefore, treatment with vortioxetine has a significant effect on the level of social anhedonia in participants. The main effect of the type of antipsychotic is mild, and according to the arithmetic means (Table 5) it shows that the lowest levels of social anhedonia are shown by participants on olanzapine (M = 23.4) and the highest by participants on risperidone (M = 30.3). The interaction of intervention and type of antipsychotic is statistically significant but with a slight effect (F = 5.040, p < .01; η2 = .091).

Table 7.

Analysis of Covariance - Testing the Main Effects of Intervention With vortioxetine, Type of antipsychotic, and their Interaction on Social anhedonia.

	SS	df	MS	F	p	Parc. Eta square
Soc. anhedonia, 1^st meas	21,507	1	21,507	6746	.011	.063
Group	521.322	1	521.322	163,516	.000	.618
Antipsychotic	114.319	2	57.159	17,928	.000	.262
Group * Antipsychotic	32,140	2	16,070	5040	.008	.091
Error	322.009	101	3.188
In total	78085.00	108
Adjusted total	1764.250	107

Discussion

Anhedonia is a common symptom of depression and a negative symptom of schizophrenia that reduces the ability of patients to feel positive emotions.¹⁰ Anhedonia, as a transdiagnostic concept, is important both in depression and in schizophrenia because it reduces the capacity to feel pleasant emotions.¹¹ It has multiple effects on the patient's recovery, most often as reduced motivation for recovery and impaired general functioning.³⁴ It has even been stated that anhedonia is a risk factor for the onset of schizophrenia, while also indicating high physical and social anhedonia in people with a high risk of developing psychosis.^35,36

The results obtained using analysis of covariance in this study show a statistically significant and high effect of vortioxetine treatment on physical anhedonia. Also, between the first and second measurements, there was an improvement in symptoms associated with physical anhedonia in the intervention group, whereas there was almost no change in the control group.

In social anhedonia, the change in the intervention group between the first and second measurements was slightly higher and indicated an improvement in symptoms, while the control group also showed very similar results in both measurements, even though there was a slight worsening of symptoms. The difference between the groups that did not receive vortioxetine and the intervention group at the second measurement is statistically significant, with a relatively large main treatment effect.

As mentioned above, there is almost no research on the effectiveness of vortioxetine on various symptoms in patients with schizophrenia, but previous research on the effects of vortioxetine on anhedonia in depressive disorders shows that vortioxetine leads to a significant improvement in symptoms. For example, in the study of 95 Canadian participants with diagnosed depression, a significant improvement in anhedonia symptoms was noted after eight weeks of vortioxetine use.³⁷ Similar results were obtained in an extensive study that included a placebo group and was conducted on as many as 4988 people with a depressive disorder. Their results show a significant short-term improvement in symptoms of anhedonia in patients with depression.³⁸ Since they are similar mechanisms of anhedonia in patients with schizophrenia and depression, the expectation is that the results are similar due to vortioxetine treatment improving anhedonic symptoms in these patients as well.³⁹ Previous studies have produced multiple results. Some have found that different antipsychotics do not have significantly different effects on symptoms of anhedonia, while some find slight differences in effects between different antipsychotics and the prescribed dose.^6,40

In our study, statistically significant and predominantly mild main effects of the type of antipsychotic on physical anhedonia and social anhedonia were found. In both measures, the participants who took olanzapine showed the lowest results, that is, weak anhedonic symptoms, whereas the participants who used risperidone showed the highest results, that is, the most anhedonic symptoms. Statistically significant interactions between the type of antipsychotic and treatment with vortioxetine are found in physical and social anhedonia, but in both cases, the effects are mild.

In general, we can say that the results showed high main effects on the reduction of physical and social anhedonia in patients with schizophrenia. Interestingly, patients on olanzapine showed the lowest severity of both physical and social anhedonia, both at the beginning and at the end of the follow-up period, regardless of the intervention. The combination of olanzapine and vortioxetine shows the highest effect in reducing either physical or social anhedonia. Based on the literature data, this finding does not seem accidental. However, olanzapine therapy has been shown to have different biological effects in the area of the ventral striatum (nucleus accumbens), which is considered the origin of anhedonia. However, while patients treated with typical reward antipsychotics had reduced activation of this region, switching to olanzapine therapy normalized this deficit.⁴¹ In an animal model of depression-anhedonia, olanzapine therapy resulted in complete recovery, faster than amitriptyline.⁴² If olanzapine leads to such changes, it understandably alleviates anhedonia. Studies on the effect of olanzapine, specifically on anhedonia, are rare. One study found an equal effect of olanzapine and risperidone on global anhedonia-asociality in negative symptoms in cannabis users with a first psychotic episode,⁴³ but it is important to emphasize that this population is difficult to compare with ours. However, our patients had chronic schizophrenia for whom taking cannabis was an exclusive criterion.

Moreover, these results should be seen in the context of high scores for both anhedonias in our patients. However, while the initial scores in our patients were approximately 48 for physical and 28 for social anhedonia, in an earlier study that was also conducted at our clinic, patients with schizophrenia had more than twice the anhedonia scores, where the average severity of physical anhedonia was 19 for men and 17 for women, while the average severity of social anhedonia was 12 in both sexes.⁴⁴ However, this situation can also be explained by the new circumstances at the time of our study – the pandemic and the earthquake that happened. The connection between anhedonia and stress is well-known. Chronic stress has been used to induce anhedonia in preclinical studies.⁴⁵ However, care is necessary in interpreting results because this effect is used in models of depression. Our patients had schizophrenia without significant depressive symptoms. However, we cannot claim that the high level of anhedonia in our patients is a consequence of stressful circumstances because we do not know their scores in the period before the pandemic and the earthquake. In any case, our preliminary results indicate that the combination of olanzapine and vortioxetine is the therapy of choice in patients with schizophrenia who have very pronounced physical and social anhedonia.

Study limitations

This research was an open design study. The subjectivity of the examiner and participants cannot be excluded in this design. Therefore, double-blind research should be used to confirm our results.

Vortioxetine was administered at a fixed dose of 10 mg per day. Higher doses were not applied.

The concentrations of antipsychotics and vortioxetine in serum were not determined. Therefore, we cannot be sure that all participants took the drugs nor that the concentrations of the drugs were within therapeutic limits. The comparative effects of other antidepressants were not tried.

Since a follow-up of the participants took place only for up to 12 weeks, the long-term effects of vortioxetine on anhedonia in patients with schizophrenia remain unknown, and the side effects of the drug vortioxetine were not monitored in a systematic manner.

Conclusion

The purpose of the study was to examine the relationship between vortioxetine treatment and the presence of physical and social anhedonia in patients with remitted schizophrenia. The study presents that participants treated with additional vortioxetine therapy showed statistically significantly lower levels of physical and social anhedonia. The strength of the effect was strong (Cohen’s d = 76) on physical and social anhedonia.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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