Does psychomotor retardation define a clinically relevant phenotype of unipolar depression?

Abstract

Background

The recognition and assessment of psychomotor retardation may have implications for better definition of the clinical phenotypes of depression. The aim of this study was to assess the clinical correlates of psychomotor retardation endorsed at any time during the patients lifetime (LPR).

Methods

The study sample included 291 patients with non-psychotic Major Depressive Disorder (MDD) participating in the clinical trial, “Depression: The Search for Treatment-relevant Phenotypes.” Psychomotor Retardation was measured using a factor derived from the Mood Spectrum Self-Report (MOODS-SR) assessment.

Using a pre-defined cut-off score on the lifetime psychomotor retardation (LPR) factor of the MOODS-SR, participants were classified into high and low scorers. Logistic regression analysis was used to evaluate the relationship between LPR and subthreshold bipolarity.

Results

Compared to low scorers, participants with high scores on LPR factor had greater severity of depression and more bipolarity indicators.

Conclusions

The MOODS-SR appears to be helpful to identify clinical phenotypes of unipolar depression and to highlight the usefulness of a lifetime approach to the assessment of psychopathology in the characterisation of patients with unipolar depression.

INTRODUCTION

There is growing evidence that the diagnosis of major depressive disorder, as defined in the DSM-IV, is heterogeneous in nature and includes subgroups that exhibit different responses to treatment (Akiskal et al., 2000; Angst et al., 2003; Zimmermann et al, 2009). Thus, contemporary clinical research is focusing on the need to identify specific subgroups among patients participating in clinical trials (Targum et al., 2008; Papakostas and Fava et al., 2009) or neuroimaging and genetic investigations (Keener & Phillips, 2007; Bearden & Freimer, 2006). For this reason, attention has been directed to the recognition of specific psychopathological dimensions or symptom clusters that may help to identify homogeneous and clinically useful groups of patients (Cassano et al, 2008; Gelenberg et al., 2008, Hasler et al, 2004).

Among a number of psychopathological dimensions, psychomotor retardation has proven to have both diagnostic and prognostic value in major depression (Sabin & Sackeim, 1997; Lecubrier, 2006). In DSM-IV-TR, the presence of "marked psychomotor retardation or agitation" is included among the criterion symptoms required for the diagnosis of a depressive episode and psychomotor disturbances are one of the main characteristics of the depressive subtype with melancholic features.

Psychomotor retardation usually characterises the depressive phase of bipolar depression, (so-called “shutdown depression”), and has been associated with “atypical” symptoms of depression, such as hypersomnia and hyperphagia (Goodwin & Jamison, 1990; Mitchell et al, 2001). Moreover, several authors have suggested that psychomotor retardation may represent a marker for bipolarity in patients with MDD (Parker et al., 2000; Akiskal. et al., 2000; Mitchell et al.,2001; Cassano et al.,2004; Akiskal et al.,2005; Benazzi & Akiskal, 2008). Thus, it appears that psychomotor retardation may be a primary component of a specific phenotype of unipolar depression with bipolar features, characterised by more severe symptoms and poorer response to treatment, especially when associated with early age at onset, higher tendency to recurrences, previous mixed depressive episodes, and a family loading for bipolarity (Akiskal et al.,2000; Cassano et al., 2004; Benazzi & Akiskal, 2008). This phenotype could be located along a continuum that embraces unipolar and bipolar disorders using a unitary approach, harkening back to a Kraepelinian view of manic-depressive illness (Kraepelin, 1921).

Assessment of psychomotor retardation has been typically conducted using interviewer-rated scales based on observable signs and symptoms (Widlocher, 1983; Parker and Hadzi-Pavlovic; 1996; Sobin et al., 1998); in a recent factor analysis of the depressive spectrum symptoms of the Mood Spectrum Self-Report Questionnaire (MOODS-SR), we identified a Lifetime Psychomotor Retardation (LPR) factor. As shown in Table 1, the MOODS-SR LPR factor includes 14 items from both the cognitive and motor domain and their impact on performance of daily activities (Cassano et al., 2008).

Table 1.

Frequency of endorsement of Items of the Lifetime Psychomotor Retardation factor.

Item	Item endorsement
58. difficulty starting to do anything	0.752
63. trouble getting out of bed in the morning	0.740
62. passive, sluggish	0.715
65. fatigued weak, or tired for the smallest task	0.687
101. using sleep as an escape	0.671
91. trouble thinking or concentrating	0.670
92. mentally dull or confused	0.633
90. difficulty making even minor decisions	0.615
89. your housework/performance deteriorated	0.608
61. time as passing very slowly, hanging heavy	0.599
59. physically "slowed down"	0.581
64. difficulty in taking care of yourself	0.576
60. speech or thinking seemed slowed down	0.513
132. difficulty working in the early morning	0.486

Like that of many other researchers and clinicians, our evaluation of patients with mood disorders gives considerable weight to the assessment of the lifetime symptoms and course of the disease. Indeed, the lifetime phenomenology very often inform our diagnosis and treatment decisions at least as much as those of the current episode.

The present paper aims to provide evidence that the lifetime assessment of psychomotor retardation in patients with non-psychotic unipolar depression, contributes to the characterization of a phenotype of unipolar depression with specific clinical features and supports the view that LPR is an indicator of a bipolar diathesis in patients with a lifetime history of unipolar depression.

METHODS

Participants

This study was carried out in the Depression and Manic-Depression Prevention Program at the Western Psychiatric Institute and Clinic of the University of Pittsburgh Medical Center and the outpatient psychiatric clinic of the Santa Chiara Hospital of the University of Pisa. Patients aged between 18 and 66 years (inclusive) meeting DSM-IV criteria for a non-psychotic major depressive episode, determined using the SCID interview, and with a Hamilton Rating Scale for Depression, (HRSD), score>=15 were eligible for a clinical trial focused on the identification of treatment-relevant phenotypes of major depression.

Exclusion criteria were: a primary diagnosis of schizophrenia, schizoaffective disorder, bipolar I or II disorder, anorexia or bulimia, meeting criteria for antisocial personality disorder or current alcohol or substance abuse. Individuals with severe, uncontrolled medical illness, those who had been unresponsive to an adequate trial of escitalopram or interpersonal psychotherapy in the current episode and women who were unwilling to practice an acceptable form of birth control were also excluded. Participants were randomly assigned to a treatment sequence that began with pharmacotherapy (SSRI–escitalopram) or interpersonal psychotherapy (IPT) and received the augmentation with the second treatment if they did not respond to the first treatment.

Study procedures were approved by the Institutional Review Board of the University of Pittsburgh and the Ethics Committee of the University of Azienda Ospedaliero-Universitaria of Pisa. All patients signed a written informed consent after receiving a complete description of the study and having an opportunity to ask questions. The study design and protocol are described in detail in Frank et al., 2008 and 2010.

Instruments

Study participants were administered the lifetime Mood Spectrum Self-Report (MOODS-SR) at study baseline. The MOODS-SR includes 161 items coded as present/absent, for one or more periods of at least 3 to 5 days in their lifetime. For some questions exploring temperamental features or the occurrence of specific events, duration is not specified because it would not be applicable. Items are organized into 3 manic/hypomanic and 3 depressive domains, each exploring mood, energy, and cognition, plus a domain that explores disturbances in rhythmicity (e.g., changes in mood, energy, and physical well-being according to the weather, the season, and the phase of menstrual cycle) and vegetative functions (including sleep, appetite and sexual function). The sum of the scores on the 3 manic/hypomanic domains constitutes the “manic component” (62 items) and that of the 3 depressive domains the “depressive component” (63 items). The rhythmicity and vegetative functions domain includes 29 items.

Separate factor analyses of the depressive and manic components of MOODS-SR identified 6 depressive factors (Cassano et al, 2008 (a)) and 9 manic-hypomanic factors (Cassano et al, 2008 (b)). “Depressive Mood,” “Psychomotor Retardation,” “Suicidality,” “Drug/illness-related Depression,” “Psychotic Features,” and “Neurovegetative Symptoms” constitute the depressive factors. The factors of mania/hypomania are: “Psychomotor Activation,” “Creativity,” “Mixed Instability,” “Sociability/Extraversion.” “Spirituality/Mysticism/Psychoticism,” “Mixed Irritability,” “Inflated Self-esteem,” “Euphoria,” and “Wastefulness/Recklessness”.

The last-month version of the MOODS-SR, that includes the same items as the lifetime version but refers to the month preceding the index assessment, was also administered at study baseline.

Clinical variables including duration of illness, age at onset of depression, number of depressive episodes, history of suicide attempts (coded as present or absent) were collected at baseline as part of the SCID interview. Severity of depression was rated using both a 17-item and a 25-item version of Hamilton Rating Scale for Depression (HRSD-17; Hamilton et al.,1960; Thase et al., 1983). Family history of psychiatric disorders was collected through a chart review by trained clinicians and coded as present or absent.

Statistical analyses

In order to determine the optimal psychomotor retardation threshold discriminating unipolar from bipolar patients we examined data from a separate sample of 249 patients with unipolar disorder (% F 83.9, mean age=38.0, SD=12.2) and 306 with bipolar disorder (% F 61.4, mean age=45.5, SD=14.8) recorded in the Italian and US spectrum project databases.

Using a ROC analysis, we set this threshold at ≥11 items endorsed; (sensitivity = 52.6%, specificity = 72.9%, area under ROC curve = 0.68, 95% Confidence Interval (CI): 0.63-0.72). Using this cut-off score on the LPR factor, we categorized our study participants into low and high scorers. Chi-square tests or Mann-Whitney tests were used to compare high and low scorers on clinical variables and on the mean scores on the self-report spectrum factors. Logistic regression analysis was carried out to analyse the relationship between LPR factor (coded as high/low) and various indicators of bipolarity, and manic/hypomanic component of the MOODS-SR factors, controlling for baseline severity of depression.

All statistical analyses were carried out with SPSS, version 15.0 (SPSS, Inc. Chicago 2007).

RESULTS

Of the 291 study participants, 286 (% F 71.7, mean age=39.6, SD=12.0) completed the MOODS-SR at baseline. The mean lifetime score on LPR factor was 8.5 (SD=4.1). Using the cut-off score of 11, subjects were classified as low (N=176, 61.5%) and high (N=110, 38.5%) LPR scorers.

LPR and indicators of bipolarity

Compared with low scorers, high LPR scorers had a longer duration of illness, an earlier age of onset, more depressive episodes and were significantly more likely to have a history of suicide attempts (Table 2). After adjusting for baseline severity of depression, gender and age, recurrent depression (OR=2.16 95% CI 1.08–4.31) and age of onset (OR=0.95, 95% CI 0.93–0.98) were significantly associated with being in the high LPR factor group in a logistic regression model (Hosmer & Lemeshow test: p=0.640). Patients with high LPR scores exhibited also higher scores on all lifetime mania-hypomania spectrum factors (except for the sociability/extraversion factor) (Figure 1). Three mania-hypomania spectrum factors were significantly and independently associated with LPR in logistic regression models after controlling for baseline severity of depression (Hosmer & Lemeshow test: p=0.996). These included “Mixed Irritability” (OR=1.25, 95% CI: 1.04–1.50), “Creativity” (OR=1.17, 95% CI: 1.05–1.30) and “Mixed Instability” (OR=1.42, 95% CI: 1.18–1.71). A negative association was found with “Sociability-Extraversion” (OR=0.84, 95% CI: 0.71–0.99). Assuming that LPR scores increase with age, we compared the proportion of high/low LPR scorers in the three age groups defined by the tertiles of distribution. We found that LPR scores were unrelated to age (χ²= 0.98, p=0.612).

Table 2.

Clinical correlates of the LPR factor

	LPR (N = 176) < 11	LPR≥11 (N = 110)	Mann-Whitney U test / Chi-square test	P
Age at onset of depression, mean (SD)	30.6 (12.9)	23.2 (11.8)	−4.66	<0.001
Duration of illness (years), mean (SD)	9.7 (11.5)	15.2 (13.2)	−4.26	<0.001
Number of episodes, median	2	3	−4.00	<0.001
History of suicide attempts, N (%)	17 (9.8)	22 (20.0)	5.95	0.015
Family history for psychiatric disorders, N (%)	78 (48.4)	32 (25.6)	15.5	<0.001

Figure 1.

LPR factor in mania-hypomania component

Mania/hypomania factors: PA=Psychomotor Activation, CR=Creativity, MIX1=Mixed Instability, SE=Sociability/Extraversion, SM=Spirituality/Mysticism/Psychoticism, MIX2=Mixed Irritability, HS=Inflated self-esteem, EU=Euphoria, WR=Wastefulness/Recklessness.

Finally, we examined the relationship between lifetime LPR scores and last-month LPR scores. On average, participants endorsed 7.5 (SD=4.2) LPR items in the month preceding the baseline assessment (range 0-14). The difference between the lifetime and the last-month score was 1.1 (SD=3.6), z (Wilcoxon test) = 5.68, p<0.001.

DISCUSSION

Our results, based on a spectrum approach to the assessment of psychopathology (Cassano et al., 2004), indicate that lifetime psychomotor retardation is associated with greater lifetime severity of depression and more indicators of bipolarity. In particular, patients with high levels of psychomotor retardation exhibited an earlier age at onset, longer duration of illness, higher frequency of episodes, more lifetime suicide attempts and a positive family history of psychiatric disorders. These patients were also more likely to endorse subthreshold bipolar features such as “Mixed Irritability”, “Mixed Instability” and “Creativity.” Moreover such associations appear to be stable even when adjusting for baseline severity of depression. Contrary to our hypothesis, psychomotor retardation was unrelated to age (younger, middle-aged, older). However, other reports indicate that psychomotor retardation is higher in elderly depressed patients compared with middle-aged patients (Brodaty, 1997; Sobin and Sackeim, 1997). Because our study includes adults (age 18-66 years) but not elderly patients, we failed to find an association between age and LPR scores.

Our study builds upon prior work showing that retardation is an indicator of clinical severity of depression, a validator’ of a bipolar diathesis in unipolar patients (Benazzi & Akiskal, 2008; Mitchell et al., 2008; Akiskal et al., 2005; Akiskal et al., 2000; Parker et al., 2000; Mitchell et al, 2001; Cassano et al 2004; Fink et al.,2007; Parker et al. 2007; Benazzi, 2002; Angst et al., 2008; Mitchell et al., 2001; Parker et al., 2000; Himmelhoch, 1998) and is a non-specific predictor of delayed response to treatment with either interpersonal psychotherapy or SSRI pharmacotherapy (Frank et al., 2010). Future studies could profitably be directed toward studying the comparative effect of serotonergic, noradrenergic and dopaminergic antidepressants in patients characterized along this dimension.

The present study has a number of limitations. The lifetime version of the MOODS-SR has the advantage of looking at MDD as a lifetime disorder, giving appropriate weight to the complete lifetime picture. However, each item is considered as endorsed if it has been present at any time during the subject s lifetime. Hence, the instrument does not permit one to evaluate whether the LPR factor items have ever been present as a cluster during the same time period. Moreover, the retrospective assessment of symptoms and behaviors carries the possibility of recall bias. However, concern about such bias is somewhat mitigated by the fact that the mean difference between the number of LPR items endorsed in the lifetime and in the last month is 1.1 (SD=3.6), suggesting that the majority of PR symptoms were also experienced during the current episode. The family history was collected through a chart review and not through a standardized interview. Therefore, we could not investigate in deeper detail the presence or absence of specific disorders in the family of the patient.

Concluding Remarks

The lifetime presence of psychomotor retardation correlates with a more pernicious clinical course and with the endorsement characteristics of mania/hypomania in patients with unipolar disorder.

A spectrum approach to the assessment of psychopathology may offer clinicians a tool to reliably identify subgroups of patients with unipolar disorder and may have important implications for research on the neurobiology, genetics, and treatment of unipolar depression.