Significant outcomes/take home message
• The current findings support an association between akathisia and suicidality in men that is not previously reported.
• One should therefore consider screening for suicidality when men present with symptoms of antipsychotic-induced akathisia.
• We found a positive association between akathisia and agitation for those previously unexposed to antipsychotics.
• Clinicians should include akathisia as differential diagnosis when new motor or psychiatric symptoms of restlessness emerge during antipsychotic treatment.
Limitations
• Our results are based on analyses of cross-sectional data.
• Analyses of causality are therefore not possible.
• Akathisia is limited to subjective sensations reported by one single item of the UKU Side Effect Self-Rating Scale.
• The suicidality assessments is based solely on one item in the Calgary Depression Scale for Schizophrenia.
Trial registration
ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529.
Introduction
Antipsychotic drugs (APs) represent a cornerstone in the treatment of schizophrenia and related psychotic disorders, both in acute psychotic episodes and in the maintenance phase (Ceraso et al., Reference Ceraso, Lin, Schneider-Thoma, Siafis, Tardy, Komossa, Heres, Kissling, Davis and Leucht2020; Kahn et al., Reference Kahn, Sommer, Murray, Meyer-Lindenberg, Weinberger, Cannon, O'Donovan, Correll, Kane, van Os and Insel2015). APs are however associated with troublesome side effects (Stroup & Gray, Reference Stroup and Gray2018) of which akathisia is regarded among the most debilitating (Kane et al., Reference Kane, Fleischhacker, Hansen, Perlis, Pikalov and Assunção-Talbott2009; Salem et al., Reference Salem, Nagpal, Pigott and Teixeira2017). Akathisia is characterized by subjective feelings of inner restlessness and mental distress, objective motor restlessness caused by an urge for continuous movement (Factor et al., Reference Factor, Burkhard, Caroff, Friedman, Marras, Tinazzi and Comella2019), and has been associated with intense dysphoria (Kane et al., Reference Kane, Fleischhacker, Hansen, Perlis, Pikalov and Assunção-Talbott2009), reduced quality of life and depression (Cem Atbasoglu et al., Reference Cem Atbasoglu, Schultz and Andreasen2001; Velligan et al., Reference Velligan, Sajatovic, Hatch, Kramata and Docherty2017). Given the sometimes intense discomfort experienced by the patient, it seems plausible that akathisia may increase both suicidal behaviour and agitation, and indeed a putative association between akathisia and suicidality was suggested already four decades ago (Van Putten, Reference Van Putten1975). However, due to the paucity of relevant data (Musco et al., Reference Musco, McAllister and Caudle2020), the association remains elusive (Aguilar & Siris, Reference Aguilar and Siris2007; Kane et al., Reference Kane, Fleischhacker, Hansen, Perlis, Pikalov and Assunção-Talbott2009) though some associations towards increased suicide risk has been indicated (Cem Atbasoglu et al., Reference Cem Atbasoglu, Schultz and Andreasen2001; Hansen, Reference Hansen2001; Reutfors et al., Reference Reutfors, Clapham, Bahmanyar, Brandt, Jonsson, Ekbom, Boden and Osby2016), especially among patients with first-episode psychosis (Seemuller et al., Reference Seemuller, Schennach, Mayr, Musil, Jager, Maier, Klingenberg, Heuser, Klosterkotter, Gastpar, Schmitt, Schlosser, Schneider, Ohmann, Lewitzka, Gaebel, Moller and Riedel2012; Seemüller et al., Reference Seemüller, Lewitzka, Bauer, Meyer, Musil, Schennach, Riedel, Doucette and Möller2012). Similar concerns have been raised about agitation related to akathisia (Cem Atbasoglu et al., Reference Cem Atbasoglu, Schultz and Andreasen2001), but the nature and magnitude of any associations still remains to be clarified at large.
Akathisia usually occurs within a few days to weeks after the administration of an AP or an increase in the dosage (Juncal-Ruiz et al., Reference Juncal-Ruiz, Ramirez-Bonilla, Gomez-Arnau, Ortiz-Garcia de la Foz, Suarez-Pinilla, Martinez-Garcia, Neergaard, Tabares-Seisdedos and Crespo-Facorro2017). Acute akathisia is less likely with atypical antipsychotics (AAPs) than with typical antipsychotics (Musco et al., Reference Musco, McAllister and Caudle2020) but the risk still remains substantial (Martino et al., Reference Martino, Karnik, Osland, Barnes and Pringsheim2018) and acute akathisia is a highly relevant clinical phenomenon (Factor et al., Reference Factor, Burkhard, Caroff, Friedman, Marras, Tinazzi and Comella2019; Yoshimura et al., Reference Yoshimura, Sato, Sakamoto, Tsukahara, Yoshimura and So2019). The incidence rates and prevalence of akathisia with AAP’s range between 1% and 27% (Musco et al., Reference Musco, McAllister and Caudle2020). Predictors of acute akathisia except antipsychotic treatment remains unclear (Yoshimura et al., Reference Yoshimura, Sato, Sakamoto, Tsukahara, Yoshimura and So2019), but male gender seems to increase the risk, together with lower age as adolescents and previously untreated patients experiencing their first episode of psychosis (FEP) are particularly vulnerable to the development of akathisia (Musco et al., Reference Musco, McAllister and Caudle2020; Poyurovsky & Weizman, Reference Poyurovsky and Weizman2020).
Assembling the evidence for antipsychotic-associated movement disorders remains a challenge due to methodological heterogeneities across clinical trials, limitations in existing systematic reviews, in meta-analyses and literature overviews (Martino et al., Reference Martino, Karnik, Osland, Barnes and Pringsheim2018). Thus, further research in akathisia is highly pertinent to clarify its potential roles related to suicidality, agitation and depression, to prevent unnecessary suffering and potentially fatal outcomes. Given the limited and equivocal literature on the potential associations between akathisia and these variables during treatment with AAP, a naturalistic exploratory study is needed to understand these phenomena as they occur in a real-life clinical settings and to guide clinical decisions and future research. Finally, most meta-analytical evidence is based on randomised, controlled trials with highly selected samples (Leucht et al., Reference Leucht, Heres, Hamann and Kane2008) estimated to represent only one-tenth of the population under investigation due to extensive exclusion criteria. Pragmatic and naturalistic studies have been called for to increase generalizability of the findings to routine clinical care (Leucht & Davis, Reference Leucht and Davis2020). The strength of pragmatic trials like ours is the wide variety of psychotic disorders included, exclusion criteria kept to a minimum and psychotropic drug use largely unrestricted by the trial design, thus mirroring real-world treatment conditions.
Aims of the study
The aims of this exploratory study were to investigate if akathisia is associated with suicidality, agitation and depression, while accounting for gender differences and previous AP use in patients treated for acute-phase psychosis.
Materials and Methods
Design
This study is a sub-study of the Bergen Psychosis Project (BPP), a naturalistic, rater-blind, randomised trial comparing four AAPs. Data on this sub-study comprises findings from the quality assurance part of the BPP, investigating all study drug groups collectively. The BPP was conducted at Haukeland University Hospital in Bergen, Norway, from March 2004 until February 2009. Johnsen et al. (Reference Johnsen, Kroken, Wentzel-Larsen and Jorgensen2010) has further described BPP’s rationale, methods and design in more detail.
Sample
The present paper reports data collected during the first phase of the BPP study. Eligible participants included all patients (aged ≥18) admitted to the emergency psychiatric ward with symptoms of psychosis as determined by a score of ≥4 on at least one of the items Delusions, Hallucinations, Grandiosity, Suspiciousness/Persecution or Unusual thought content on the Positive and Negative Syndrome Scale (PANSS) (Opler et al., Reference Opler, Kay, Lindenmayer and Fiszbein1999). Included patients fulfilled diagnostic criteria according to the International Classification of Diseases (ICD-10) (World Health Organization, 2007) for schizophrenia (F20), schizophreniform disorder (F20.8), schizotypal disorder (F21), persistent delusional disorders (F22), acute and transient psychotic disorders (F23), schizoaffective disorder (F25), other non-organic psychotic disorders (F28), unspecified non-organic psychosis (F29), drug-induced psychosis (F1x.5) and major depressive disorder with psychotic features (F31.5, F32.3, F33.3). Further, eligible participants were candidates for oral AP therapy with a first-line AP. Drug-induced psychoses were included when the condition remained unresolved within a few days and when AP therapy was deemed indicated. Exclusion criteria included manic psychosis (F30.1), other behavioral or mental problems resulting in inability to cooperate with assessments, including organic brain disorders (dementia), agitation, hostility or pronounced suspiciousness towards the assessor, inability to use oral antipsychotics or already medicated with clozapine upon admittance, history of head injury or mental retardation, not understanding spoken Norwegian or being candidates for electroconvulsive therapy.
Procedure
Diagnoses were determined at discharge by the hospital’s own psychiatrists or specialists in psychology. Data collection reported in the present study was undertaken at discharge/follow-up, maximally 11 weeks from baseline if still not discharged. Participants were determined antipsychotic naïve if they had never before used antipsychotic medications.
Measures
The patient-administered version of the UKU Side Effect Self-Rating Scale (UKU SERS Pat) was used to assess the presence and severity of akathisia (Lindstrom et al., Reference Lindstrom, Lewander, Malm, Malt, Lublin and Ahlfors2001; Lingjaerde et al., Reference Lingjaerde, Ahlfors, Bech, Dencker and Elgen1987). Akathisia is one (item 2.6) of 48 items of the scale with scoring option 0–3, where 0 indicates no symptom, and scores 1–3 indicate the presence of symptoms with increasing severity from mild to severe (0: Not at all, 1: I like to keep moving around, but have no difficulty sitting or standing still (mild), 2: I have to force myself to sit down or stand still (moderate), 3: I have to keep walking around all the time (severe)). The UKU SERS Pat was administered at discharge/follow-up only. The Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., Reference Addington, Addington and Schissel1990) was used for assessing symptoms of depression and suicidality. The CDSS is the recommended scale for assessing depression symptoms in schizophrenia (Hasan et al., Reference Hasan, Falkai, Wobrock, Lieberman, Glenthoj, Gattaz, Thibaut and Moller2015). The CDSS has demonstrated good predictive validity (Lako et al., Reference Lako, Bruggeman, Knegtering, Wiersma, Schoevers, Slooff and Taxis2012), and distinguishes it better than other depression scoring tools depressive symptoms from negative and extra-pyramidal phenomena (Addington et al., Reference Addington, Addington and Maticka-Tyndale1994). Both a modified version of the CDSS total score without the suicidality item (mCDSS) and the single suicidality item (CDSS item 8) were used in the analyses. Symptoms of psychosis were assessed by means of the PANSS which is a 30-item rating scale comprising seven items for positive symptoms, seven items for negative symptoms and 16 items for general psychopathology (Kay et al., Reference Kay, Fiszbein and Opler1987), which is validity and reliability tested (Kay et al., Reference Kay, Opler and Lindenmayer1988). The BPP used the Structured Clinical Interview for the PANSS (SCI-PANSS), which was developed to secure reliable information for the PANSS scoring (Opler et al., Reference Opler, Kay, Lindenmayer and Fiszbein1999). High interrater reliability was demonstrated among the raters for the PANSS with intra-class correlation coefficient 0.92. We further used the validated PANSS Excited Component (PANSS-EC) factor to assess agitation (Montoya et al., Reference Montoya, Valladares, Lizán, San, Escobar and Paz2011). The PANSS-EC consists of the five PANSS items: P4 Excitement, P7 Hostility, G4 Tension, G8 Uncooperativeness and G14 Poor impulse control (Lindenmayer et al., Reference Lindenmayer, Brown, Baker, Schuh, Shao, Tohen, Ahmed and Stauffer2004). Additional psychometric tools used were the Clinical Global Impression-Severity of Illness scale (CGI-S) (Guy, Reference Guy1976), and the Global Assessment of Functioning, Split Version, Functions scale (GAF-F) (Karterud et al., Reference Karterud, Pedersen, Loevdahl and Friis1998).
Statistics
Categorical and continuous data were analysed in the SPSS software, version 24.0 (IBM SPSS Statistics, 2016). Cross-tabulation of categorical data was analysed by means of chi-square tests. ANOVA tests were used to analyse the differences between the group means in the sample. Post-hoc tests were utilized and adjusted with Bonferroni corrections for multiple testing. Analyses of associations between akathisia and depression, suicidality and agitation, respectively, were initially conducted by the means of Pearson and Spearman correlations. To adjust for potential confounding factors in the relationships between akathisia and depression, suicidality and agitation, linear regression analyses were undertaken with akathisia as the dependent variable, and modified CDSS sum score, the suicidality item of the CDSS, PANSS-EC and the Anxiety item (G2) of the PANSS as independent variables. Finally, depression, suicidality and agitation were entered as dependent variables, respectively, in separate linear regression models to explore the relationships among these and the other variables.
Ethics
The BPP was approved by the Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services. The first phase of the BPP was defined as a quality assurance project where only standard hospital routines were performed. For the quality assurance phase, the Regional Committee for Medical Research Ethics allowed eligible patients to be included before providing informed consent to the follow-up study. The present study reports data from the first phase of the BPP. The study was publicly funded and did not receive any financial or other support from the pharmaceutical industry. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975 (59th WMA General Assembly, Seoul, Republic of Korea, October 2008).
Results
A total of 109 patients were assessed at discharge/follow-up (approximately 4 weeks), of which 74 (68%) were males, and mean age with standard deviation (SD) was 34.0 (12.4) years (Table 1).
Table 1. Demographic and clinical characteristics at discharge (N = 109)
* Diagnosis: Schizophrenia and related disorders: Schizophrenia, schizoaffective disorder, acute polymorphic psychotic disorder with symptoms of schizophrenia, acute schizophrenia-like psychotic disorder, delusional disorder; Acute psychosis = Acute psychosis other than those categorized under Schizophrenia and related; Affective psychosis = Bipolar and unipolar depression; Other psychoses = Miscellaneous psychotic disorders.
† Positive And Negative Syndrome Scale (PANSS).
‡ Calgary Depression Scale for Schizophrenia (CDSS).
§ Clinical Global Impression-Severity of Illness scale (CGI-S).
# The Global Assessment of Functioning Split Version Functions scale (GAF-F).
A total of 100 patients (91.7 %) provided side effect data. Of these, 38% reported some level of akathisia, meaning a score of 1 or more on the UKU SERS Pat (item 2.6). The mean akathisia UKU score with standard deviation was 0.94 (0.91) as shown in Fig. 1. No difference was found between antipsychotic naïve patients and the previously medicated, or between genders in this regard.
Fig. 1. Distribution of akathisia based on UKU SERS Pat item 2.6.
A Pearson correlation analysis revealed a significant and positive correlation between akathisia and severity of depression using the modified CDSS-sum score (mCDSS) (Pearson R = 0.404, p < 0.001; Spearman rho = 0.357, p < 0.001), and between akathisia and the suicidality item of the CDSS (Pearson R = 0.388, p < 0.001; Spearman rho = 0.394, p < 0.001), but not between akathisia and PANSS-EC (Pearson R = 0.102, p = 0.311; Spearman rho = 0.177, p = 0.077).
In a linear regression model with akathisia as the dependent variable, and mCDSS, CDSS suicidality item, PANSS-EC and Anxiety (PANSS G2) as independent variables, no statistically significant associations were found. A positive association between akathisia and suicidality was found at trend level (Beta 0.224, p = 0.075). The linear regression was repeated in sub-analyses in men and women separately, finding that the association between akathisia and suicidality was strengthened in men (Beta 0.306, p = 0.048), but not in women. In sub-analyses in those previously unexposed to antipsychotics (antipsychotic naïve patients), a positive association between akathisia and PANSS-EC was found (Beta 0.288, p = 0.047). In those previously exposed to antipsychotics, a positive association was found between akathisia and the mCDSS sum score (Beta 0.375, p = 0.031).
Discussion
The main findings of the present study were that akathisia is still a prevalent side effect in a clinically relevant sample of patients treated with AAPs. We found that akathisia was associated with suicidality, agitation and depression, although with different associations in different sub-groups. A clinically important finding was that of an association between akathisia and agitation in the antipsychotic naïve group.
We assessed the first weeks corresponding to the acute phase of antipsychotic treatment as this is the critical period for the onset of acute akathisia (Juncal-Ruiz et al., Reference Juncal-Ruiz, Ramirez-Bonilla, Gomez-Arnau, Ortiz-Garcia de la Foz, Suarez-Pinilla, Martinez-Garcia, Neergaard, Tabares-Seisdedos and Crespo-Facorro2017). The time frame is consistent with results from The European First Episode Schizophrenia Trial (EUFEST) that found akathisia to be most prevalent after the first month of antipsychotic treatment and gradually decrease thereafter (Rybakowski et al., Reference Rybakowski, Vansteelandt, Remlinger-Molenda, Fleischhacker, Kahn and Peuskens2014). Recent reviews (Chow et al., Reference Chow, Kadouh, Bostwick and VandenBerg2020; Musco et al., Reference Musco, McAllister and Caudle2020) find akathisia rates up to 27%. In our study, the incident rate was somewhat higher, with about 40% of the patients reporting some level of akathisia; however, the majority of them presented mild symptoms.
Interpreting incident rates and prevalence estimates reported across research literature is challenging due to several methodological heterogeneities and the existence of various forms of antipsychotic-induced akathisia (Barnes & Braude, Reference Barnes and Braude1985; Poyurovsky & Weizman, Reference Poyurovsky and Weizman2020). Different rating scales used for assessing extrapyramidal symptoms do not discriminate clearly between the different types of movement disorders (Martino et al., Reference Martino, Karnik, Osland, Barnes and Pringsheim2018). Further complicating research interpretation is the lack of a universally agreed definition of the condition (Hansen, Reference Hansen2001), together with possible underreporting due to the subjective discomfort of akathisia that may be difficult for patients to describe (Hansen, Reference Hansen2001; Lohr et al., Reference Lohr, Eidt, Abdulrazzaq Alfaraj and Soliman2015). The intensity of akathisia may fluctuate over the course of a day; in our study, all patients were assessed at the same time of the day, around 11.00 am. Further, the incidence rate in our study is derived from subjective reports on scale-defined akathisia and not from spontaneous verbal reporting (Demyttenaere et al., Reference Demyttenaere, Detraux, Racagni and Vansteelandt2019), and accordingly the rate is not expected to be underestimated.
The antipsychotics in our study were used in therapeutic dosages as previously reported (Johnsen et al., Reference Johnsen, Kroken, Wentzel-Larsen and Jorgensen2010). We found no difference between the antipsychotic naïve patients, the earlier medicated ones, or gender with respect to the mean akathisia score. As our use of the term antipsychotic naïve patients can be used as a proxy for first-episode patients, one could thereby expect higher akathisia score in this group considering that previously untreated adolescents and FEP’s are particularly vulnerable to develop akathisia (Kane et al., Reference Kane, Fleischhacker, Hansen, Perlis, Pikalov and Assunção-Talbott2009; Poyurovsky & Weizman, Reference Poyurovsky and Weizman2020; Yoshimura et al., Reference Yoshimura, Sato, Sakamoto, Tsukahara, Yoshimura and So2019). With regards to the lack of difference between gender, it has been hypothesized that women report side effects more often than men because they tolerate them less well (Seeman, Reference Seeman2020), though this seems not to be applicable to our study.
We used the PANSS-EC (Lindenmayer et al., Reference Lindenmayer, Brown, Baker, Schuh, Shao, Tohen, Ahmed and Stauffer2004) to measure agitation. This commonly used rating scale has been validated with excellent results (Citrome & Volavka, Reference Citrome and Volavka2014; Montoya et al., Reference Montoya, Valladares, Lizán, San, Escobar and Paz2011), and our results in this regard are therefore expected to be valid. Previous research and case reports have suggested akathisia as a potential risk factor for violent behaviour and agitation (Cem Atbasoglu et al., Reference Cem Atbasoglu, Schultz and Andreasen2001; Salem et al., Reference Salem, Nagpal, Pigott and Teixeira2017). Our findings do, however, not support a general association between agitation and akathisia, but importantly we found a positive association in antipsychotic naïve patients. Antipsychotic naïve patients are more sensitive to antipsychotic side effects than chronically ill patients (Hasan et al., Reference Hasan, Falkai, Wobrock, Lieberman, Glenthoj, Gattaz, Thibaut and Möller2012). The subjective restlessness and dysphoria characterising akathisia is painful and mentally distressing. Pain is also a factor that can contribute to agitation in patients with psychosis (Marco & Vaughan, Reference Marco and Vaughan2005). Taken together, it is important to always include akathisia as a possible differential diagnosis when new motor or psychiatric symptoms resembling anxiety emerge during antipsychotic treatment (Musco et al., Reference Musco, McAllister and Caudle2020). Both in order to treat the condition effectively and also as a means to reduce agitation in those with early-phase psychosis, a group that has increased risk of violence (Nielssen et al., Reference Nielssen, Malhi, McGorry and Large2012).
We found significant associations between akathisia, suicidality and depression, respectively, although with different profiles in sub-groups. Over the years, researchers have tried to establish a firm relationship between akathisia and suicidality (Cem Atbasoglu et al., Reference Cem Atbasoglu, Schultz and Andreasen2001; Hansen, Reference Hansen2001; Hansen et al., Reference Hansen, Jones and Kingdon2004; Hansen & Kingdom, Reference Hansen and Kingdom2006; Padder et al., Reference Padder, Skodnek, Hashmi, Samad, Udyawar, Azhar and Jaghab2006; Reutfors et al., Reference Reutfors, Clapham, Bahmanyar, Brandt, Jonsson, Ekbom, Boden and Osby2016; Seemuller et al., Reference Seemuller, Schennach, Mayr, Musil, Jager, Maier, Klingenberg, Heuser, Klosterkotter, Gastpar, Schmitt, Schlosser, Schneider, Ohmann, Lewitzka, Gaebel, Moller and Riedel2012). However, the magnitude of suicidal risk is hard to establish due to the sporadic nature of the event and heterogeneities in and across various studies (Aguilar & Siris, Reference Aguilar and Siris2007). Albeit a unequivocal relationship between akathisia and suicidality is hard to establish, the possibility must not be excluded (Hansen, Reference Hansen2001). Our moderate association between akathisia and suicidality appears consistent with previous findings pointing towards a positive relationship between the two (Hansen, Reference Hansen2001; Reutfors et al., Reference Reutfors, Clapham, Bahmanyar, Brandt, Jonsson, Ekbom, Boden and Osby2016; Seemuller et al., Reference Seemuller, Schennach, Mayr, Musil, Jager, Maier, Klingenberg, Heuser, Klosterkotter, Gastpar, Schmitt, Schlosser, Schneider, Ohmann, Lewitzka, Gaebel, Moller and Riedel2012). Our sub-analysis revealed a strengthened association for men in this regard. To our knowledge, this association has not been established in previous studies. As suicide prediction may be more difficult in men, together with the notion that they have higher suicide risk (Brådvik, Reference Brådvik2018), vigilance may be called for when akathisia symptoms develops in men. Akathisia may have different impact on patients at different stages of illness and according to the duration of treatment (Hansen & Kingdom, Reference Hansen and Kingdom2006), as associations between akathisia and suicidality seem to be strongest in first episode and young patients compared to in treatment resistance (Seemuller et al., Reference Seemuller, Schennach, Mayr, Musil, Jager, Maier, Klingenberg, Heuser, Klosterkotter, Gastpar, Schmitt, Schlosser, Schneider, Ohmann, Lewitzka, Gaebel, Moller and Riedel2012). Akathisia may lead to medication non-adherence (Velligan et al., Reference Velligan, Sajatovic, Hatch, Kramata and Docherty2017) subsequent worsening of psychotic symptoms, increased suicidality and re-hospitalization (Musco et al., Reference Musco, Ruekert, Myers, Anderson, Welling and Cunningham2019). Consequently, it seems plausible to suggest that early emerging akathisia may be associated with a more complicating treatment course and possibly also a poorer prognosis.
Suicidal ideation has been known to fluctuate in time (Kleiman et al., Reference Kleiman, Turner, Fedor, Beale, Huffman and Nock2017), especially during the early stages of schizophrenia, where limited suicidal ideation may quickly intensify to a suicide attempt (Sher & Kahn, Reference Sher and Kahn2019). Depression is identified as a risk factor for suicidal behaviour during the course of schizophrenia (Tandon, Reference Tandon2005), extra attention may thus be required for patients with akathisia and comorbid depression. According to Poyurovsky (Reference Poyurovsky2010), an inter-correlation between akathisia, depressive symptoms and impulsiveness may account for suicidal and violent behaviour in patients with akathisia. Taken together, the relationship between akathisia and suicidality is highly relevant and may be mutually reinforced. The positive association we found between akathisia and depression among the previously antipsychotic exposed might reflect that awareness of long-term consequences of schizophrenia may induce feelings of hopelessness. Thus, it is of clinical importance to identify and treat both anxiety and depression at an early time point.
Strength and limitations
The major strength of this study is its naturalistic prospective design integrated in clinical practice with patients consecutively recruited from psychiatric emergency wards. The sample is representative of a diverse population suffering from psychosis (Kane et al., Reference Kane, Fleischhacker, Hansen, Perlis, Pikalov and Assunção-Talbott2009; Leucht et al., Reference Leucht, Cipriani, Spineli, Mavridis, Orey, Richter, Samara, Barbui, Engel, Geddes, Kissling, Stapf, Lassig, Salanti and Davis2013). Patients with a history of suboptimal response to antipsychotics were not excluded, nor patients with substance abuse.
There are limitations to this study that should be considered when interpreting the results. Patients with manic psychosis or other behavioral or mental problems resulting in inability to cooperate with assessments, including organic brain disorders (dementia), agitation, hostility or pronounced suspiciousness towards the assessor, inability to use oral antipsychotics or already medicated with clozapine upon admittance, history of head injury or mental retardation, or being candidates for electroconvulsive therapy, were excluded. These represent the most gravely ill patients with psychosis, and accordingly our results cannot be generalized to, for example, patients in need of depot formulations of the APs or those with treatment resistance towards first-line agents.
Primarily, our results are based on exploratory analyses of cross-sectional data. Analyses of causality are therefore not possible. However, our findings should be used for hypothesis generation and be put on trial in prospective, hypothesis-driven longitudinal studies sufficiently powered to capture aspects of causality as well as differential associations in different subpopulations with akathisia. From a methodological point of view, the assessment of akathisia was limited to subjective sensations reported by one single item of the UKU-SERS Pat. A thorough assessment with a more comprehensive inventory such as the Barnes Akathisia Rating Scale (Barnes, Reference Barnes1989) would have provided more detailed information about severity, frequency and impact, this was however, beyond the scope of this study. The suicidality assessments were based solely on one item in the CDSS scale. The inclusion of supplementary or more comprehensive inventory for measuring symptomatology of suicidality would have qualified this complex area and relation to akathisia and hence likely added more clinical value to the study. Finally, there is always the possibility of residual confounding from other factors not included in our analyses. Illicit drug use can potentially be an example of such a factor, but we do not expect this to have influential impact on our results as there were relatively few patients with illicit drug use in our sample. Understanding the relationship between akathisia and depression, suicidality and agitation can be helpful in order to identify early warning signs and prevent potentially fatal outcomes. Thus further investigations in large samples are warranted, preferably in studies with special focus on how individuals with psychosis experience antipsychotic-induced side effects and the interplay between side effects and quality of life.
Our results show that also in treatment periods with AAPs akathisia is a prevalent side effect significantly associated with depression, suicidality and agitation. One should still be aware of the probability of diagnostic overlap between akathisia and agitation. It seems reasonable to believe that a reduction of akathisia could alleviate dysphoric distress. Akathisia as a side-effect should, therefore, be highlighted, and always be assessed for when a patient is treated with APs. It is important to inform the patient thoroughly about the possibility of this particular side effect when starting AP treatment. Furthermore, due actions should be undertaken to combat this troublesome side effect when present. Screening protocols for several other antipsychotic-induced side effects already exists; therefore, one should routinely screen and monitor all patients assigned to antipsychotics for movement disorders with a validated tool. Appropriate prevention and early management of side effects like akathisia may enhance the net benefits of antipsychotics.
Acknowledgements
This work was supported by the Research Council of Norway, the Western Norway Regional Health Authority and Haukeland University Hospital. The Funding Source had no role in the study design; in the collection, analyses and interpretation of data; in the writing of the report or in the decision to submit the paper for publication.
Author contributions
JK and HNG drafted the manuscript. RAK participated in the data collection and helped draft the manuscript. EML participated in designing the study and helped draft the manuscript. HAJ participated in designing the study, participated in data collection and helped draft the manuscript. EJ collected the data, provided statistical analyses and helped draft the manuscript. All authors have read and approved the final manuscript.
Financial support
The Research Council of Norway initiated funding, followed by Haukeland University Hospital, Division of Psychiatry. The supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review or approval of the manuscript.
Conflict of interest
None of the authors declares any conflict of interest related to the present work
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