Journal of Affective Disorders 109 (2008) 1 20

www.elsevier.com/locate/jad

Special review article

Psychomotor symptoms in depression: A diagnostic,
pathophysiological and therapeutic tool
Didier Schrijvers a,, Wouter Hulstijn a,b , Bernard G.C. Sabbe a,c
a
Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Universiteitsplein 1 B-2610 Antwerp, Belgium
b
Nijmegen Institute for Cognition and Information (NICI), University of Nijmegen, P.O. Box 9104, 6500 HE, Nijmegen, The Netherlands
c
Psychiatric Hospital Sint-Norbertus, Stationsstraat 22c, 2570 Duffel, Belgium

Received 22 June 2007; received in revised form 12 September 2007; accepted 25 October 2007
Available online 20 December 2007

Abstract

Background: Psychomotor disturbances have been described repeatedly over many centuries. More recently, Sobin and Sackeim
[Sobin, C., Sackeim, H.A., 1997. Psychomotor symptoms of depression. Am. J. Psychiatry. 154, 417.] discussed the relevance of
psychomotor symptoms in depression in an extensive review. Since their report, new pathophysiological, diagnostic and
therapeutic findings have been published. In the current review of the recent literature, we aim to argue the importance of
psychomotor symptoms in depression and propose directions for future research.
Method: A review of all the relevant reports on this topic, published between 1996 and 2006, was conducted.
Results: Several assessment methods demonstrate the diagnostic and pathophysiological significance of psychomotor symptoms.
Antidepressants show differential effects on psychomotor performance and findings concerning the symptoms' predictive capacity
for clinical response are contradictory. Numerous imaging studies as well as studies on the neurotransmitter systems and the HPA-
axis contribute to the elucidation of the neurobiological processes underlying impaired psychomotor functioning in depression.
Conclusions: Psychomotor disturbances are of great diagnostic significance for the depressive subtype of melancholia. To enhance
the conceptualisation of the construct psychomotor a standardised battery for their assessment is recommended. As to the
symptoms' predictive therapeutic power, to date research into functional outcome and studies applying objective experimental
assessment methods are lacking. Moreover, the reported pathophysiological importance of dopamine for retarded depression still
warrants translation to the daily practice.
2007 Elsevier B.V. All rights reserved.

Keywords: Depression; Major Depressive Disorder; Psychomotor symptoms; Retardation; Agitation

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Corresponding author. Tel.: +32 3 8202415; fax: +32 3 8202414.

E-mail address: didierschrijvers@hotmail.com (D. Schrijvers).

0165-0327/$ - see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2007.10.019
2 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120

3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1. Psychomotor symptoms over the centuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2. Manifestation and assessment of psychomotor symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.3. Observer-rated assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4. Experimental assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.5. Gross motor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.6. Fine motor activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.7. Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.8. Other determinants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.8.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.8.2. Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.9. Diagnostic significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.9.1. Melancholia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
3.9.2. Dysthymia and bipolar depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.10. Medication studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.11. Pathophysiological significance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.11.1. Neurotransmitter systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.11.2. HPA-axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.11.3. Neurophysiology and imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.12. One general syndrome?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
4. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1. Need for standardisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.2. Psychomotor symptoms as a diagnostic marker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.3. Impact of antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.4. Neurobiological trends: fast forward or standstill?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.5. Exploring functional outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Role of the Funding Source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

1. Introduction better understanding of and a more efficient approach to

Psychomotor disturbances have been described ex-
tensively over many centuries, from ancient greek over
medieval to modern times (Jackson, 1986; Parker and
Brotchie, 1996). More recently, Sobin and Sackeim
(1997) demonstrated the importance of psychomotor
symptoms in depression for clinical and research purposes
in a systematic review of the literature mainly published in
the second half of the twentieth century. Since then, ad-
vanced experimental methods investigating new domains
have been developed, the diagnostic role of psychomotor
symptoms in the different types of affective disorders
explored, the impact of selective serotonin reuptake in-
hibitors (SSRIs) on psychomotor functioning investigated
and many related neurobiological findings published. The
many interesting results and novel insights at the clinical,
prognostic, diagnostic and pathophysiological level,
however, have also raised new, important questions.
In the current review of the recent literature we ex-
plore the relevance of psychomotor symptoms for a
Major Depressive Disorder (MDD). We, moreover, dis-
cuss the extent to which the new knowledge contributes
to a better conceptualisation of the psychomotor con-
struct and propose directions for future research.
2. Methodology
Our review is based on a MEDLINE survey of the
relevant literature published between 1996 and 2006.
The search terms used (with number of hits) were:
psychomotor retardation (43), psychomotor agitation
(47), motor retardation (8), gait (5), actigraphy (11),
motor activity (31), fine motor (4), speech (38),
melancholia (202), and pathophysiology (50), all in
combination with Major Depressive Disorder and/or
psychomotor. All abstracts were screened and poten-
tially relevant papers and all relevant cross-references
examined in full. As the review focuses on psychomotor
disturbances, papers primarily aimed at measuring cog-
nitive and experimental neuropsychological processes
 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120 3

were excluded, as were those about melancholic depres-
sion that did not specify psychomotor findings.
3. Results
3.1. Psychomotor symptoms over the centuries
Over millennia, psychomotor changes have been
described extensively in a rich heritage of writings.
Whereas ancient greek literature already mentioned the
term melancholia to describe both a symptom state as
well as a style of temperament, the ascendance of psy-
chomotor disturbances as an observable and important
feature in melancholic depression occurred in the
seventeenth century. It subsequently lost its status as a
core feature in the late nineteenth and the beginning of
the twentieth century, when psychomotor disturbance
was more interpreted as a consequence of the mood

Table 1
Overview of the psychomotor assessment techniques employed and main research purposes of the studies reviewed
Type of assessment
1. Observer-rated assessments
Clinical evaluation 1 Diagnosis
Single-item observation
-Hamilton Depression Rating 17
Scale
-Diagnostic interview
Psychomotor rating scale
-Salptrire Retardation Rating 12
Scale
-CORE Assessment of
Psychomotor Change
-Motor Agitation and
Retardation scale
Number of Main research purposes
studies
Pathophysiology, predictive capacity,
daily-life activity
1 Study of young patients (preschool-age)
Validity, treatment effect, pathophysiology, Hickie et al., 1996a; Lemke et al, 1999b, 2000;
measurement, diagnosis
6 Validity, pathophysiology, predictive
capacity, diagnosis
2 Validity, treatment effect
Study reference
Benazzi, 2002
Bondareff et al., 2000; Delini-Stula et al., 1995;
Ferguson et al., 2002; Flament et al., 1999; Gattaz et
al., 1995; Guelfi et al., 2001; Kalayam and
Alexopoulos, 1999; Kiosses et al., 2000; Narita et al.,
2004; Navarro et al., 2001; Sechter et al., 1999, 2004;
Shah et al., 1997; Stahl et al., 2002; Taylor et al., 2006;
Tollefson and Sayler, 1996/1997; Wheatley et al., 1998
Luby et al., 2004
Martinot et al., 2001; Pier et al., 2004a,b; Sabbe et al.,
1999, 1996b; Sobin et al., 1998; van Hoof et al.,
1998; van Londen et al., 1997; Videbech et al., 2002
Hickie et al., 1996a,b; Mitchell, 1995; Rogers et al.,
2000, 2002; Sobin et al., 1998
Hoppner et al., 2003; Sobin et al., 1998

2. Gross motor activity

Wrist actometer
Belt-worn actometer
Movement analysis of gait
Movement-pattern analysis
(based on video-tape interview)
Wrist rotation approach
9 Study of young patients, measurement,
treatment effect, pathophysiology
2 Study in children, measurement
5 Measurement, treatment effect,
daily life activity
1 Diagnosis, pathophysiology
2 Measurement, predictive capacity
Armitage et al., 2004; Fairweather et al., 1996;
Lemke et al., 1999a, 1997; Parker et al., 2002;
Stanley et al., 1999; van Londen et al., 1998; Volkers
et al., 2002, 2003
Aronen et al., 1996; Iverson, 2004
Bader et al., 1999; Hausdorff et al., 2004; Hergueta et
al., 1996; Lecrubier, 2006; Lemke et al., 2000
Lemke et al., 1999c
Caligiuri and Ellwanger, 2000; Caligiuri et al., 2003

3. Fine motor activity: digitizer

Copying tasks (lines, simple and
complex figures)
Fitts' task
Symbol Digit Substitution Task
Sentence writing and drawing
superimposed concentric circles
5 Treatment effect, measurement, diagnosis,
5 Diagnosis, measurement, treatment
effect, pathophysiology
3 Diagnosis, pathophysiology
3 Treatment effect, measurement
Pier et al., 2004a,b,c; Sabbe et al., 1996a,b
Pier et al., 2004a,b, 2001; Sabbe et al., 1999, 1997
Pier et al., 2004a,b; van Hoof et al., 1998
Hegerl et al., 2005; Mergl et al., 2004; Tucha et al.,
2002

4. Speech analysis 3 Measurement, prognosis Alpert et al., 2001; Cannizzaro et al., 2004; Stassen et
al., 1998
4 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120

state. Later on, several psychiatrists challenged this
view by stating that retardation is a core behavioural
pattern and might even be the primary disturbance in
affective disorders. Towards the end of the twentieth
century, the presence of psychomotor changes was the
most recognized feature in almost all studies that
identify melancholia as a form of depression (Jackson,
1986; Parker and Brotchie, 1996; Taylor and Fink,
2006).
3.2. Manifestation and assessment of psychomotor
symptoms
Depressed patients manifest a wide range of psy-
chomotor symptoms that can be clinically observed and
assessed by various methods. Below, we will summarise
the assessment methods listed in Table 1 applied in
the recent literature.
3.3. Observer-rated assessments
One of the included studies used a clinical evalua-
tion, 18 single-item observations and 17 psychomotor
observation scales. As regards single-item ratings of
larger inventories, our search only yielded studies that
used the Hamilton Rating Scale for Depression (HDRS;
Hamilton, 1960). The scale is primarily aimed at mea-
suring severity of depression, but also contains one
retardation and one agitation item. For the assessment of
psychomotor performance, its reliability might be lim-
ited. One study (Benazzi, 2002) solely used the clinical
eye to assess psychomotor symptoms. Although the
objectivity of such unstructured clinical judgments is
dubious, Benazzis results were similar to those reported
in studies that did use observation scales (see Table 2).
The Salptrire Retardation Rating Scale (SRRS;
Widlcher and Ghozlan, 1989) gauges different mani-
festations of retardation such as slowed gait, gross and
facial movements, speech and thought. Dantchev and
Widlcher (1998) reported strong correlations between
SRRS scores and depression severity. However, al-
though Pier et al. (2004a,b) found strong correlations
between SRRS scores and retardation as measured by
experimental psychomotor tasks, others (Sabbe et al.,
1996a; van Hoof et al., 1998; Sabbe et al., 1999; Lemke
et al., 2000) found none. But note that the two meth-
ods differ substantially in their duration of observation:
SRRS ratings are based on prolonged observations
whereas experimental tasks just capture performance
during task execution. Important drawbacks of the

Table 2
Experimental studies published between 1996 and 2006 exploring the diagnostic significance of psychomotor symptoms in depressive subtypes
Study subject Samples (n) Methods Main findings
Melancholia
Benazzi, 2002 MDE (271 outpatients: Observable agitation Agitation and retardation: MEL (35.4%) N
48 MEL, 95 atypical) or retardation atypical group
Retardation: MEL (12.5%) N atypical group
Lemke et al., 1999c MEL MDE (12), HC (8) Analysis of video-taped Single, non-repetitive action units: MEL b HC
movement patterns Repetitive units: MEL N HC
Pier et al., 2004a MDE (38: 20 MEL, SRRS & digitiser Initiation time: MEL N HC, NMEL N HC.
18 NMEL), HC (38) Movement Time: MEL N HC, NMEL = HC
Rogers et al., 2002 MDE (17), HC (10) CORE & mental MEL and NMEL: both overall slower than HC; effect
rotation paradigm significantly greater for MEL; MEL patients showed
specific slope of mental rotation function, i.e. slowed
motor preparation relative to HC and NMEL.
van Londen et al., 1998 MDE (48: 26 MEL), HC (30) Actigraphy Activity during sleep: MEL N NMEL;
Activity during wakefulness: MEL0 N NMEL

Dysthymia
Pier et al., 2004b Dysthymia (20), SRRS & digitiser Initiation and movement time:
MDE (32), HC (32) Dysthymia = HC, MDE N HC

Bipolar depression
Swann et al., 1999 MDE (132: 85 uni-, Motor speed & visual Unipolar = Bipolar
47 bipolar), HC (37) tracking tests
van Londen et al., 1998 MDE (48: 9 bi-, 37 unipolar, Actigraphy Unipolar = Bipolar
2 psychotic), HC (30)
MDE: major depressive episode; (N)MEL: (non)melancholic; HC: healthy controls; SRRS: Salptrire Retardation Rating Scale.
 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
SRRS are its subjective (rater) component and the need
for large, heterogeneous patient samples.
The CORE Assessment of Psychomotor Change
(CORE; Parker and Hadzi-Pavlovic, 1996) assesses
cognitive processing deficits, agitation and retardation,
and is designed to differentiate between melancholic
and non-melancholic depression (Parker, 2000; Parker
et al., 2000; Rogers et al., 2000). Correlations between
CORE scores and reaction times have been reported for
several neuropsychological tasks as well as Hypotha-
lamic-Pituitary-Adrenal (HPA) measures (Mitchell
et al., 1996; see Table 4). Contrary to the SRRS that
measures retardation only, the CORE system also en-
compasses an agitation dimension.
Finally, Sobin et al. (1998) developed the Motor
Agitation and Retardation Scale (MARS), which rates 19
abnormal motor behaviours associated with depressive
agitation and retardation. Our search identified only one
study that applied the MARS (Hppner et al., 2003),
probably due to its focus on motor components only. The
individual MARS items have been found to correlate well
with the individual SRRS and CORE items.
Table 1 illustrates the great utility of psychomotor
rating scales in the various research domains. As they
are a standardised reflection of clinical observations, the
scales allow an adequate assessment of therapeutic ef-
fects (e.g. Pier et al., 2004a,b) and associations to be
made with neurobiological findings, enhancing the
comprehension of important pathophysiological mech-
anisms in depression. Other distinct advantages the
scales have over symptom-based measures and single-
item ratings are their high reliability and independence
from patient recall.
3.4. Experimental assessments
Not all motor-system abnormalities can be discerned
by means of observer-rated assessments or clinical ob-
servations. More sensitive, experimental performance
measures allow the detection of psychomotor distur-
bances that escape the clinical eye or may confirm
clinically observed disturbances (Shah et al., 1997;
Caligiuri and Ellwanger, 2000). Since experiments
assessing reaction times in depressives are already re-
ported by Kraepelin (1921; Berrios, 1988), an extended
period of interest in measuring psychomotor distur-
bances is evident: tests of speed of responding, visual
reaction time, perseveration, work decrement, memory
scanning, speech rate, motor speed and other constructs
as well as strategies for physiological measurements
have been mentioned in overviews and experimental
papers (Parker and Brotchie, 1996).
5
Next, we will discuss the recent experimental studies
according to their theme. Table 1 shows the methods
relevance for the various research paradigms.
3.5. Gross motor activity
Nineteen studies objectively evaluated disturbed
gross motor activity using four different approaches:
(1) 24-hour actometric measurements of limb or hori-
zontal movements, (2) spatiotemporal gait-pattern ana-
lyses during over ground locomotion, (3) a frame-by-
frame analysis of consecutive movements occurring
during videotaped interviews, and (4) recordings of
reaction times, peak velocity and velocity scaling during
wrist flexions (using a digitiser and hand-held rotation
sensor). All studies further substantiated Sobin and
Sackeim's earlier conclusions on the substantial differ-
ences in gross motor performance between depressed
and healthy subjects.
The difficulty of adequately evidencing agitation is
reflected by the lack of studies on this topic: we iden-
tified only one preliminary actigraphic study (Parker
et al., 2002) without there being sequel studies to vali-
date and extend the findings.
3.6. Fine motor activity
In contrast to impairments in gross motor activity,
disturbances in fine motor functions like writing or
drawing are less visible in depressed patients. Here, the
use of a graphics tablet (digitiser) and a pressure-sen-
sitive pen (see Table 1) affords objective, real-time re-
cordings, allowing the calculation of kinematic variables
such as initiation (IT) or reaction time (RT), mainly
reflecting the cognitive, and movement time (MT),
mainly reflecting the motor components of the perfor-
mance (Sabbe et al., 1996b; Pier et al., 2004a). The
studies applied various psychomotor tasks with variable
cognitive loads: Fitts' tasks, requiring subjects to draw a
line between two vertically placed circles varying in
size, the Symbol Digit Substitution Task (SDST), re-
quiring a symbol to be replaced by its matching digit,
and three copying tasks of increasing complexity re-
quiring straight lines, simple and complex figures to be
replicated.
Unequivocal findings of fine motor slowing were
reported for both the less demanding tests and the tasks
requiring more cognitive effort (e.g. coordination, visuo-
spatial storage, planning and sequencing; Sabbe et al.,
1996a; Sabbe et al., 1999; Pier et al., 2004b,c). Pier et al.
(2004a) later substantiated these results in a large sam-
ple (n = 38) of medication-free patients. Conversely,
6 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
although Mergl et al. (2004) found their depressed
sample to perform slower than the control group on a
writing task, when drawing circles the depressed patients
did not demonstrate a decreased velocity, nor did more
complex experimental conditions cause greater motor
differences. However, these divergent findings may be
attributable to large between-patient differences in
antidepressant medication and duration of illness.
3.7. Speech
Depressed patients present with a uniform, mono-
tonous speech; they tend to speak in a low voice, slowly,
and hesitatingly, as can be heard clinically and measured
by means of speech-analysis methods (Sobin and
Sackeim, 1997).
Alpert et al. (2001) confirmed earlier findings such as
decreased prosody (i.e. lack of emphasis and inflection),
and briefer utterances in an elderly depressed sample,
with the retarded subgroup showing briefer utterances,
longer pauses and shorter intervals talking than the
agitated subgroup. Cannizzaro et al. (2004) demon-
strated a correlation of speaking rate and pitch variation
with HDRS scores, partially confirming previous
reports (Sobin and Sackeim, 1997).
3.8. Other determinants
3.8.1. Age
Most of the literature on psychomotor symptoms in
depression concerned populations in the 1860 age
range, although various studies investigated younger or
elderly patients.
In geriatric depression psychomotor impairment is
one of the main characteristics of late-onset depression,
also known as vascular depression (Alexopoulos et al.,
1997) or depression-executive dysfunction syndrome
(Lockwood et al., 2002). Based on the pattern of fine
motor activity in their elderly depressed patients, Pier
et al. (2004c) suggested an additive effect of aging and
depression on psychomotor performance.
Remarkably, Sobin and Sackeim did not discuss
papers focused on younger age groups, whereas our
literature search revealed several on the subject. By
showing psychomotor slowing in a sample of young
children (aged 35 years) diagnosed with melancholic
depression, Luby et al. (2004) demonstrated that also at
a younger age the phenomenon should be seen as a core
depressive symptom. A significant negative correlation
of locomotor activity with a continuum of depressive
symptoms in 27 prepubertal patients indicated an asso-
ciation between the severity of depressive complaints
and the incidence of low-activity periods (Aronen et al.,
1996). Finally, Armitage et al. (2004) reported lower
activity levels in adolescents with MDD.
3.8.2. Sex
As to sex-related differences, some authors reported
a more pronounced retardation in depressed women
and more agitation in men (Kornstein et al., 2000;
Khan et al., 2002) while others could not find any sex-
dependent differences (Hildebrandt et al., 2003a,b;
Scheibe et al., 2003; Pier et al., 2004a). This chal-
lenges the higher retardation frequencies in men and
the higher agitation rates in women Sobin and Sackeim
reported. Based on their evaluations, they concluded
that besides age, sex could also be considered a de-
terminant of the manifestation of psychomotor symp-
toms, which conclusion is refuted by our divergent
findings.
3.9. Diagnostic significance
Uncovering differences in the nature of psychomo-
tor retardation in the different depressive subtypes
might have considerable diagnostic value for clini-
cians. While previously psychomotor symptoms were
exploited to isolate the clinical difference between
psychotic and neurotic patients (Sobin and Sackeim,
1997), more recent studies, summarised in Table 2,
mainly explored the discriminative power of slowing
phenomena for melancholia, dysthymia and bipolar
depression.
3.9.1. Melancholia
Motor slowing is widely accepted as one of the main
indicators of the melancholic subtype of depression
(Taylor and Fink, 2006). Yet, does psychomotor per-
formance effectively distinguish melancholic from non-
melancholic depression or are observed differences at-
tributable to variations in symptom severity? Sobin and
Sackeim only found one study linking global depression
severity to motor-retarded but not motor-agitated de-
pression. Some recent reports mention associations be-
tween depression severity and psychomotor functioning
(Lemke et al., 1999a; Caligiuri and Ellwanger, 2000;
Iverson, 2004), whereas others found no such correla-
tions (Brebion et al., 1997; Lemke et al., 1999b; Hasler
et al., 2004).
Comparing melancholic and non-melancholic sam-
ples, several researchers found that the melancholic
patients, both medicated (Rogers et al., 2002) and un-
medicated (van Londen et al., 1998; Pier et al., 2004a),
differed from their non-melancholic peers in the degree
 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
and nature of their psychomotor disturbances (see
Table 2).
If psychomotor slowing is indeed a key marker of
melancholic depression, it should be found in nearly all
melancholic patients, independent of the setting. If it is a
sign of symptom severity, however, it should be less
common in less severe outpatient depressions. Although
they assessed psychomotor symptoms through clinical
judgment only, Benazzi (2002; Table 2) found their
moderately melancholic outpatients to exhibit slightly
more psychomotor changes than the high frequencies
reported for severely depressed inpatient samples. Psy-
chomotor changes may thus be taken to reflect severity
of melancholic depression rather than the syndrome's
core feature.
Parker (2000) is a strong advocate of a dichotomous
view separating melancholic from non-melancholic
MDD patients. His group (2000) proposed an empiri-
cally based hierarchical model in which disorder-spe-
cific clinical manifestations are the paradigm for
distinguishing different classes of depression, with an
impressive specificity of melancholia for CORE-rated
psychomotor symptoms versus a lack of specificity for
purely clinically assessed symptoms. The model com-
prises two melancholic subtypes, one with and one
without psychotic features, and a heterogeneous residue
of non-melancholic depressive disorders. All three
expressions of the disorder have a significant mood-
state disturbance and observationally rated psychomotor
disturbances determine the distinction between melan-
cholic and non-melancholic depression, with psycho-
motor symptoms being highly unlikely in non-
melancholic and highly probable in melancholic
depression. Thus, observable psychomotor symptoms
may be regarded as the surface marker of a specific
underlying neuropathological process, allowing the
identification of a neurobiologically discrete melan-
cholic subtype (Parker, 2000; Parker et al., 2000; Malhi
et al., 2005). With regard to the melancholic subtype
with psychotic features, it should be mentioned that, in
addition to the presence of delusions and/or hallucina-
tions, the most consistently reported additional feature is
the presence or greater severity of psychomotor change
(agitation and/or retardation). It is suggested that
clinicians should be aware of a diagnosis of psychotic
depression when there is severe psychomotor distur-
bance, even in the absence of formally eliciting
delusions or hallucinations (Parker et al., 1991, 1996).
Summarizing, more and more evidence link psycho-
motor disturbances to the (psychotic and non psychotic)
melancholic subtype, with the severity of the depression
playing a role in melancholic depression in particular.
7
3.9.2. Dysthymia and bipolar depression
By showing that fine motor slowing was present in
MDD but absent in dysthymia in two medication-free
samples, Pier et al. (2004b; see Table 2) demonstrated
psychomotor symptoms to have discriminating power
between the two syndromes.
Bipolar patients are very likely to have the melan-
cholic subtype and, conversely, those with rigorously
defined melancholic depression appear to be at con-
siderable risk of having a bipolar course (Parker 2000;
Parker et al., 2000). This is consistent with the pre-
viously reported higher probability of bipolar depressed
patients manifesting retardation as compared to unipolar
patients who are more likely to manifest agitation
(see Sobin and Sackeim, 1997). However, note that
some reports could not confirm these assumptions (van
Londen et al., 1998; Swann et al., 1999; Table 2).
3.10. Medication studies
Various studies explored the psychomotor effects of
antidepressants and the predictive capacity of psycho-
motor symptoms for clinical response. The most rele-
vant studies are listed in Table 3.
In healthy volunteers, fluvoxamine and reboxetine
did not have disruptive effects on psychomotor func-
tioning, but administration of dothiepin or amitryptiline
did substantially impair psychomotor performance
(Fairweather et al., 1996; Kerr et al., 1996; Siepmann
et al., 2001).
With regard to patient studies, a detrimental short-
term (1012 days) performance effect was demonstrated
in patients on tricyclic antidepressants (TCAs), whereas
patients on SSRIs performed similarly to the healthy,
medication-free controls (Stanley et al., 1999; Tucha
et al., 2002). Long-term treatment with antidepressants
(ranging from 3 to 12 weeks) resulted in total or partial
improvement of psychomotor functioning, mostly due
to clinical recovery, as assessed with rating scales and
various methods measuring fine and gross motor ac-
tivity as well as speech performance (Sabbe et al.,
1996b, 1997; Bader et al., 1999; Alpert et al., 2001;
Ferguson et al., 2002; Lecrubier, 2006). Any persisting
psychomotor impairments in remitted patients might
be attributable to residual depressive symptomatology
(Sabbe et al., 1997). Several studies compared the long-
term effects of different types of antidepressants (see
Table 3). Beneficial long-term effects for several TCAs
and newer antidepressants such as moclobemide, mir-
tazapine, venlafaxine and reboxetine have been reported
(Gattaz et al., 1995; Ravindran et al., 1995; Tollefson
and Sayler, 1996/1997; Wheatley et al., 1998; Guelfi et
 8
Table 3
Experimental studies investigating psychomotor effects of antidepressants and the predictive capacity of psychomotor symptoms for antidepressant response
Study Samples (n) Assessment method Type of treatment (duration) Main findings
Healthy volunteers
Fairweather et al., 1996 HC (12) Tasks of RT, tracking, Test: drug-free; Retest: 1,2,3,4,6 h post-single Dothiepin: impaired performance and reduced
CFFT & Actigraphy dose of fluvoxamine, dothiepin or placebo daytime activity.
Mean daytime activity with fluvoxamine = with placebo
Kerr et al., 1996 HC (10) Tasks of RT, tracking, CFFT Test: drug-free; Retest: 1,2.25,3.5,6,9 h Reboxetine: little or no effect on performance compared with placebo.
post-single dose of reboxetine Amitryptiline: impaired performance on all tests, compared
(0.5, 1 or 4 mg), amitryptiline or placebo with placebo and/or reboxetine.

D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120

Siepmann et al., 2001 HC (12) Tasks of RT, CFFT, 2-hand Test: drug-free; Retest (day 14): Reboxetine at therapeutic doses: no psychomotor impairment.
coordination, tapping reboxetine or placebo

Short-term effects
Stanley et al., 1999 MDE (14) Actigraphy Test: drug-free; Retest (day 10): fluoxetine Daytime activity: dothiepin b fluoxetine
vs dothiepin
Tucha et al., 2002 MDE (36), HC (18) Digitiser Group1 (n = 18): TCA (day 12) MT: TCA N SSRI & HC;
Group2 (n = 18): SSRI (day 10) Handwriting: severe dysfluency in TCA;
Velocity & acceleration: TCA b SSRI & HC

Long-term effects
Alpert et al., 2001 elderly MDE (22), Speech analysis Test: drug-free; Retest (week 12): Improvement reflected in fluency but not in prosody measures:
HC (19) nortriptyline (n = 10) or sertraline (n = 12) (a) retarded patients: briefer pauses, (b) agitated patients:
shorter utterances.
Difference between medication groups not examined
Bader et al., 1999 MDE (20), HC (20) Gait analysis Test: maintenance medication Partial improvement, persisting difference with HC
Retest (week 3): ADs not specified
Ferguson et al., 2002 MDD (703); data Retardation item HDRS Test: drug-free; Retest (week 48): Reboxetine: psychomotor improvement.
from 4 trials reboxetine (n = 350) or placebo (n = 353)
Gattaz et al., 1995 MDD (53) Agitation & retardation Test: drug-free; Retest (week 1,2,3,4): Moclobemide & fluoxetine: psychomotor improvement
item HDRS moclobemide (n = 27) or fluoxetine (n = 26) Week 1: improvement with moclobemide N with fluoxetine;
Week 4: improvement with moclobemide = with fluoxetine
Gorenstein et al., 2006 MDD (56), HC (31) Cancellation task, symbol Test (with mean duration of treatment): Inserting Pins & RT test: slightly better performance for HC
copying test, tapping, imipramine (n = 15; 2.4 years), clomipramine than imipramine patients
inserting pins, RT task (n = 9; 2.8 years), fluoxetine (n = 14; Performance on tapping: increased dose/weight for clomipramine
1.8 years), sertraline (n = 18; 1.5 years) & fluoxetine gives decreased difference with HC
Guelfi et al., 2001 MEL (157) Retardation item HDRS Test: drug-free; Retest (week 1,2, 4,6,8): Mirtazapine & venlafaxine: psychomotor improvement
mirtazapine (n = 78) or venlafaxine (n = 79) Improvement with mirtazapine = with venlafaxine.
Hegerl et al., 2005 MDE (28) Digitiser Test: drug-free; Retest (week 4): citalopram Overall increase in velocity of rapid hand movements with
(n = 16) vs. reboxetine (n = 12) reboxetine N citalopram, especially under more difficult task conditions
Hppner et al., 2003 MDE (30) MARS d2 test rTMS add-on treatment: sham (n = 10), Motor improvement only after real stimulation: on day 5
1 Hz (n = 10), 20 Hz (n = 10) for 20 Hz and on day 10 for 1 Hz.
Test: day 0; Retest (day 5, final AD response: patients with less severe psychomotor impairments N
treatment day, weeks 2,4,8 post-treatment) patients with more severe impairments
Lecrubier, 2006 MDE (26), HC (26) Gait analysis Test: drug-free; Retest Early (week 3) improvement of propulsion velocity,
(weeks 3, 4, 12): venlafaxine late (3 months) improvement of stride length
Ravindran et al., 1995 MDD (58) Digit symbol substitution, Test: drug-free; Retest (week 8): placebo, Desipramine & sertraline: trend towards psychomotor improvement
Trail making & RT test desipramine, sertraline Improvements most obvious with desipramine
Sabbe et al., 1999, MDE (21), HC (21) SRRS & Digitiser Test: fluoxetine (week 1) Cognitively loaded tasks: total cognitive (RT) improvement in
1996b, 1997 MDE; no motor (MT) improvement.
Retest: fluoxetine (week 6) Pure motor tasks: partial motor improvement (MT), no increase
in velocity, persisting difference with HC
Sechter et al., 1999 MDD (238) Agitation item HDRS Test: drug-free; Retest (week 2,4, 8,12,18,24): Sertraline & fluoxetine: psychomotor improvement;
sertraline (n = 118) or fluoxetine (n = 120) Improvement with sertraline N with fluoxetine.
Stahl et al., 2002 MDD (2072); Agitation & retardation Test: drug-free; Retest (week 1,2, 3,4,6,8): Venlafaxine & SSRIs: psychomotor improvement
data from 8 trials item HDRS venlafaxine (n = 865), SSRI (n = 757; fluoxetine, Improvement with venlafaxine N with SSRIs.
paroxetine, fluvoxamine) or placebo (n = 450)
Tollefson et al., MDD (3153); Agitation item HDRS Test: drug-free; Retest: (a) fluoxetine (n = 1244) Improvement in agitation: fluoxetine(58%) N placebo(49%;p b 0.001)
1996/1997 data from 31 trials vs placebo (n = 585); (b) fluoxetine (n = 661) Fluoxetine & TCAs: diminished agitation; improvement
vs TCAs (n = 663) with fluoxetine (66%) = with TCAs (61%)
Volkers et al., 2002 MDE (52) Actigraphy Test: drug-free; Retest (week 4): imipramine Imipramine: increase in daytime motor activity and in fragmentation
(n = 25) vs. fluvoxamine (n = 27) of motor activity during sleep.

D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120

Fluvoxamine: no alterations in motor-activity pattern
Wheatley et al., 1998 MDE (133) Retardation item HDRS Test: drug-free; Retest (week 6): mirtazapine Mirtazapine & fluoxetine: psychomotor improvement
(n = 66) or fluoxetine (n = 67) Improvement with mirtazapine = with fluoxetine.

Predictive capacity
Bondareff et al., 2000 MDE (144), Agitation & retardation Test: drug-free; 12-week treatment: sertraline Agitation: response rate sertraline (74%) N nortriptyline (64%; p = 0.08)
N60 years item HDRS (n = 74) or nortriptyline (n = 70) Retardation: equal response rates (p = 0.18)
Caligiuri et al., 2003 MDE (28: Wrist rotation Test: drug-free; 8-week treatment: sertraline Baseline neuromotor impairment: RESP b NRESP; proportion
27 uni-, 1 bipolar) Retardation item HDRS (n = 9), phenelzine (n = 12), bupropion (n = 7) of improvement correlated with baseline impairment;
Retardation item HDRS: RESP = NRESP.
Delini-Stula et al., 1995 MDD (2416); Agitation item HDRS Test: drug-free; 4-week treatment: moclobemide Response rate: all ADs N placebo
data from 40 trials & HDRS factor score (n = 1215), imipramine(n = 619), sedative Response rate moclobemide = imipramine = sedative AD
ADs (n = 242) or placebo (n = 340) Response rate agitated subgroup = non agitated subgroup
Dunkin et al., 2000 MDE (14) Neuropsychological battery Test: drug-free; 8-week fluoxetine treatment Pre-treatment executive functioning: RESP N NRESP
Pre-treatment information processing: RESP = NRESP
Flament et al., 1999 MDE (248) Agitation & Retardation Test: drug-free; Retest (weeks 1, 2, 4, 6): Retarded patients: overall lower response rate (sertraline = fluoxetine);
item HDRS sertraline (n = 124) vs. fluoxetine (n = 124) Agitated patients: response rates sertraline (62%) N fluoxetine (39%)
MEL subgroup: response rate sertraline (59%) N fluoxetine (44%)
Retardation item HDRS: RESP = NRESP.
Hickie et al., 1996a,b DS not specified (81) CORE SRRS Test: baseline; 6 ECT treatments High CORE & SRRS scores predict ECT response
Kalayam and elderly MDE (49), Retardation item HDRS Test: drug-free; 6-week treatment: Retarded patients: poor or delayed AD response
Alexopoulos, 1999 HC(22) nortriptyline & nontricyclic ADs
Navarro et al., 2001 MDE (58), Retardation item HDRS Test: drug-free; 12-week treatment: Severe retardation: response rate nortriptyline (82%) N citalopram (11%)
N60 years nortriptyline (n = 29) or citalopram (n = 29) Mild retardation: equal response rates (95 & 100%)
Sandor et al., 1998 MDD (36; 24 MEL) DSM-III-R MEL criteria Test: drug-free; 6-week treatment: fluoxetine Response rate: MEL = NMEL
(n = 19) or doxepin (n = 18) MEL: response rate fluoxetine = doxepin
Sechter et al., 2004 MDD (302) Retardation item HDRS Test: drug-free; 6-week treatment: Baseline retardation predicted good response to milnacipran, but not
milnacipran (n = 149) or paroxetine (n = 153) to paroxetine
Stassen et al., 1998 DS not specified (43) Speech analysis 6 repeated assessments over first 2 weeks Early improvement is predictive of long-term RESP; parallel
of AD (not further specified) treatment development over time for HDRS scores and combination of
acoustic variables in 74.4% of cases
Taylor et al., 2006 MDE (37) Retardation item HDRS Test: drug-free; 12-week fluoxetine treatment COWAT FAS performance: NRESP b RESP;
& COWAT FAS HDRS retardation item score: NRESP N RESP
AD: antidepressant; COWAT FAS: Controlled Oral Word Association Test FAS; CFFT: critical flicker fusion threshold; DS: depressive syndrome; ECT: electro convulsion therapy; HDRS: Hamilton Depression Rating Scale;
HC: healthy controls; MARS: Motor Agitation and Retardation Scale; (N)MEL: (non)melancholic; MDE: Major Depressive Episode; MT: movement time; (N)RESP: (non)responders; RT: reaction time; rTMS: repetitive
transcranial magnetic stimulation; SRRS; Salptrire Retardation Rating Scale; SSRI: selective serotonine reuptake inhibitor; TCA: tricyclic antidepressant.

9

Table 4
Experimental studies exploring the pathophysiological significance of psychomotor symptoms in depression
Study
Neurotransmitter systems
Austin et al., 2000
Martinot et al., 2001
Meyer et al., 2006
Shah et al., 1997
Samples (n)
MEL MDE (7), HC (5)
MDE (12: 6 retarded,
6 impulsive), HC (10)
MDE (21), HC (21)
MDE (15), HC (15)
Methods
CORE & timed motor task
& neuro-psychological tests
PET & SRRS
PET & Finger tapping task
IBZM-SPET & neuro-psychological
tests & handgrip task
10
D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
Main findings
Single administration of the dopamine agonist apomorphine (placebo-controlled;
2,5 mg; test: pre-injection, retest: 30 min post-injection): no improvement of
cognitive or motor function in MEL MDE and HC.
Fluorodopa uptake in the left caudate: retarded patients b patients with high
impulsivity or HC.
MDE: correlation between putamen D2 binding potential and motor speed;
MDE with motor retardation: most significant elevation of caudate
and putamen D2 binding potential.
MDE patients: higher IBZM binding in the right striatum
This IBZM binding: correlation with measures sensitive to reduced speed
of motor performance, but not with the HDRS retardation item.

HPA-axis
De Winter et al., 2003
Mitchell, 1995
van Londen et al., 1998
van Londen et al., 1997
MDE (66) Factors from CPRS & AVP levels: high in MEL MDE (non significant) & anxious-retarded-MEL MDE
HPA measures AVP-cortisol correlation: weak in MEL MDE, strong in anxious-retarded
MDE & anxious-retarded-MEL MDE.
MDE (100) CORE & HPA measures MEL MDE with psychomotor disturbances: clear association between the
dimensional CORE system and concentrations of postdexamethasone cortisol
& dexamethasone.
MDE (48), HC (30) Actigraphy & HPA measures MDE & HC: inverse relationship between plasma AVP concentrations and
motor activity during wakefulness.
MDE (52), HC (48) SRRS & HPA measures Plasma AVP concentrations: severe retarded MDE N mild/no retarded MDE.

Neurophysiology and imaging studies

Bange and Bathien, 1998 MDE (23: 12 uni-, P300 with simple visual Uni- and bipolar MDE: longer RTs, reduced accuracy on oddball task;
11 bipolar), HC (20) & visual oddball task Remitted uni- and bipolar MDE: reduced P3 latencies.
Bipolar: delayed peak latency for oddball task, no change in amplitude;
Bench et al., 1993
Hickie et al., 1995b
Hickie et al., 1999
Mayberg et al., 1994
Naismith et al., 2002
Narita et al, 2004
Videbech et al., 2002
MDE (40), HC (23)
MDE (39: 32 uni-, 7 bipolar)
MDE (25)
MDD (13), HC (11)
MDE (47), HC (20)
MDE (35)
MDE (42), HC (47)
PET & retardation factor SADS
MRI & RT task, TMT, SDMT,
PALT, FAS word fluency
SPECT & choice RT task
SPECT & unified PD rating scale
MRI & CORE & TMT
SPECT & item HDRS
PET & SRRS
Negative correlation of psychomotor retardation with BF in the left
dorsolateral prefrontal cortex and left angular gyrus.
Association between white matter hyperintensities and impaired
psychomotor speed (RT, decision time, TMT, SDMT).
Severely retarded MDE: least increase in neostriatal BF after a choice RT task.
Negative correlation of retardation degree with frontal and cingulate BF.
Association between right caudate nucleus volume and slower
psychomotor speed (TMT). No association with CORE scores.
PR correlated with prefrontal and anterior cingulate BF.
Negative correlation between retardation degree and BF to dorsolateral and
supraorbital prefrontal cortices.

D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120

Single syndrome hypothesis
Caligiuri & Ellwanger, 2000 MDE (36: 31 uni-, Wrist rotation MDE: velocity scaling measure impairment and longer RTs;
5 bipolar), HC (22) 40% (4 bi-, 10 unipolar): Parkinsonian-like motor programming deficits.
Fleminger, 1992 MDE & PD Movement tasks with Equivalent slowing for MDE and PD, but different pattern of impairment.
simultaneous movements
Pier et al., 2001 MDE (21) & HC (20), PD Digitiser Total movement times: MDE = PD = elderly MDE.
(23) & HC (24), elder Differences between MDE, PD, elderly MDE in (a) initiation time,
MDE (12) & HC (18) (b) relative time to achieve peak velocity and (c) pen pressure.
Rogers et al., 2000 23 MDE (23), HC (24) CORE & serial choice reaction MEL: Parkinsonian pattern of impairment, i.e. a particular difficulty to
time task initiate movements in the absence of external cues;
NMEL: no motor impairment.
Sachdev and Aniss, 1994 MEL (10) & PD (10) Simple and complex MEL and PD: disturbed execution of simple and complex ballistic
& HC (10) ballistic movements movements (disturbances for MEL and PD were similar).
NMEL: no motor impairment.
van Hoof et al., 1998 MDE (20), HC (20), SRRS & digitizer MDE: overall slowing (prolonged matching & writing times) relative to HC
schizophrenia (20) Schizophrenia: prolonged matching times only.
AVP: Arginine-Vasopressin; BF: blood flow; CPRS: Comprehensive Psychopathological Rating Scale; HC: Healthy Controls; HDRS: Hamilton Depression Rating Scale; HPA: Hypothalamic-
Pituitary-Adrenal; IBZM-SPET: 123I-3-iodo-methoxybenzamide-single photon emission tomography; MDE: Major Depressive Episode; (N)MEL: (non)melancholia; MRI: Magnetic Resonance
Imaging; PALT: Paired Associate Learning Subtest; PD: Parkinsons Disease; PET: positron emission tomography; RT: reaction time; SADS: Schedule for Schizophrenia and Affective Disorders;
SPECT: single photon emission computed tomography; SDMT: Symbol Digit Modalities Test; SRRS: Salptrire Retardation Rating Scale; TMT: Trail Making Test.

11
12 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
al., 2001; Stahl et al., 2002; Volkers et al., 2002; Hegerl
et al., 2005). Concerning the SSRIs, most studies dem-
onstrated significant psychomotor improvements (Gat-
taz et al., 1995; Ravindran et al., 1995; Tollefson and
Sayler, 1996/1997; Wheatley et al., 1998; Stahl et al.,
2002) except for the studies of Volkers et al. (2002) and
Hegerl et al. (2005). Additionally, sertraline has been
demonstrated to produce a larger psychomotor improve-
ment compared with fluoxetine (Sechter et al., 1999). A
prolonged antidepressant therapy of at least 6 months
resulted in minimal, clinically irrelevant differences in
psychomotor performance of imipramine treated
patients relative to healthy controls (Gorenstein et al.,
2006).
Studies also explored the predictive power of psy-
chomotor symptoms for clinical antidepressant response.
For patients with pre-treatment motor retardation or im-
paired psychomotor functioning a poor response has
repeatedly been reported (Flament et al., 1999; Kalayam
and Alexopoulos, 1999; Dunkin et al., 2000; Caligiuri
et al., 2003; Hppner et al., 2003; Taylor et al., 2006;
Table 3). This is at odds with Sobin and Sackeim who
reported motor retardation to predict superior antide-
pressant response. This inconsistency may be explained
by the fact that the studies we evaluated mainly ex-
amined SSRIs and the studies Sobin and Sackeim
reviewed predominantly TCAs, which is underpinned by
the findings in late-life depression of Navarro and
coworkers (2001). Note that a recent study also reported
baseline retardation to be a predictive factor of favour-
able response to the dual-acting agent milnacipran
(Sechter et al., 2004). Concerning agitation, agitated
patients treated with sertraline (but not fluoxetine)
achieved a substantially greater clinical remission than
the non-agitated patients (Flament et al., 1999), in con-
trast with equal response rates to moclobemide, imip-
ramine and several sedative antidepressants for both
subgroups (Delini-Stula et al., 1995). With regard to the
melancholic subtype, some authors found SSRIs to be
less effective than TCAs (Perry, 1996) whereas others
demonstrated equal efficacy (Sandor et al., 1998;
Hirschfeld, 1999). As to the predictive power of infor-
mation-processing speed, one study reported negative
(Dunkin et al., 2000) and another positive results (Taylor
et al., 2006). The prognostic capacity of psychomotor
symptoms comparing clinical response to different anti-
depressants has also been explored: high baseline CORE
scores and baseline agitation were associated with a
higher response rate for SSRIs (fluoxetine and sertraline
respectively) relative to nortriptyline (Bondareff et al.,
2000; Joyce et al., 2002) and, in addition, response
rates on sertraline were shown to be greater than rates
on fluoxetine in agitated and melancholic subgroups
(Flament et al., 1999).
Summing up, different types of antidepressants pro-
duce different short- and long-term psychomotor effects.
Baseline psychomotor disturbances might predict anti-
depressant response depending on the type of disturbance
(agitation or retardation) and the type of antidepressant.
Sobin and Sackeim concluded that the prognostic
value of psychomotor symptoms regarding electrocon-
vulsive therapy (ECT) was uncertain. Surprisingly, only
one study in this field was published in the last decade,
finding high SRRS and CORE scores to predict good
ECT response (Hickie et al., 1996a,b).
Finally, Stassen et al. (1998) found speech analysis to
be very useful in determining the onset of clinical re-
mission when using antidepressants.
3.11. Pathophysiological significance
Knowledge about the neurobiological processes un-
derlying impaired psychomotor functioning could help
identify the brain regions implicated in psychomotor
retardation. This could contribute to our understanding
of the brain mechanisms involved in MDD. Sobin and
Sackeim already suggested that motor symptoms in
major depression might indicate concomitant abnorm-
alities in specific structures and pathways of the brain,
which was explored further by subsequent pathophy-
siological studies, all itemised in Table 4.
3.11.1. Neurotransmitter systems
It has been hypothesised that melancholic depression
and its concomitant psychomotor features are associated
with a hypodopaminergic state. Based on evidence from
pharmacological and neurobiological studies, Parker et
als hierarchical depression model (Parker, 2000; Parker
et al., 2000) tries to link the different depressive sub-
types to disturbances in neurotransmitter systems. Each
subtype is underpinned by a disturbance in all three
systems but their relative emphases vary. The psycho-
motor changes in the melancholic psychotic and non-
psychotic subtypes are mainly related to dopamine dys-
function, and the remaining melancholic features to
impairments in noradrenergic and to a lesser extent
serotonergic neurotransmission. Non-melancholic de-
pression is supposed to be largely serotonergically
driven (Malhi et al., 2005).
Most experimental results support the model. Changes
in the plasma levels of dopamine precursors correlated
with HDRS scores, cognitive disturbance and retardation
factors (Mann and Kapur, 1995). Additionally, relative to
healthy individuals the cerebrospinal fluid levels of
 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
the dopamine metabolite homovanillic acid were sig-
nificantly reduced in patients with retarded depression
(Winograd-Gurvich et al., 2006). Three functional
imaging studies clearly demonstrated a striatal dopami-
nergic disturbance during depression, being most promi-
nent when patients displayed motor retardation (Shah
et al., 1997; Martinot et al., 2001; Meyer et al., 2006; see
Table 4), corroborating earlier findings of therapeutic
effects of dopaminergic drugs in depression associated
with psychomotor symptoms (Mann and Kapur, 1995).
Mentioned studies all strongly suggest that psycho-
motor disturbances in melancholic (psychotic and non-
psychotic) depression may be due to diminished cere-
bral dopamine functioning (Malhi et al., 2005). Yet,
Austin et al. (2000) failed to find cognitive or motor
improvements in their patients with strictly defined
melancholia following administration of a dopamine
agonist. They hence proposed that dopamine-receptor
stimulation alone may not be sufficient to improve the
deficits because, rather than associating psychomotor
retardation solely with a hypodopaminergic state, mel-
ancholic depression is a disorder involving several neu-
rotransmitter systems in complex interactions.
3.11.2. HPA-axis
Besides the well-documented HPA-axis deregulation
(de Winter et al., 2003), Mitchell et al. (1996) suggested
a strong relationship between psychomotor symptoms
and HPA system overactivity in depression, indicating
an intriguing association between cortisol production
rates and dexamethasone metabolism on the one and the
degree of central biological disturbance in melancholia
on the other hand.
More recent studies reported increased plasma levels
of arginine vasopressin (AVP) to play a role in the
clinical picture of psychomotor behaviour in MDD (van
Londen et al., 1997, 1998; de Winter et al., 2003). de
Winter et al. (2003) also proposed anxious-retarded
depression as a useful refinement of the melancholic
subcategory with regard to deregulation of the HPA axis
and plasma AVP release.
Together, the results provide strong evidence for an
involvement of the HPA system in clinical psychomotor
symptoms, adding an extra dimension to the already
extensive role of the HPA system in depression.
3.11.3. Neurophysiology and imaging
Bange and Bathien (1998) proposed the P300 event-
related potential as an index of the contribution of the
slowed central processing in retarded depressed patients,
with the peak latency reflecting the duration of stimulus-
evaluation processes and the amplitude reflecting per-
13
ceptual resources processing the stimulus. Relative to
normal controls, the psychomotor slowing of both uni-
polar and bipolar depressed patients featured a motor
component, but only in bipolar patients did it show an
additional cognitive impairment (P3 latency).
Hickie et al. (1995a,b) argued that structural abnor-
malities, like the association between white matter
hyperintensities and impaired psychomotor speed they
found in severely depressed patients, might be more
evident in patients with clinically manifest psychomotor
changes. Naismith et al. (2002) contended reduced
caudate and putamen nuclei volumes to also be im-
plicated in the cognitive and motor abnormalities ac-
companying melancholia.
Functional abnormalities associated with MDD have
been repeatedly documented, and particularly symptom
clusters in depressive subgroups proved to correlate
with specific regional functional abnormalities (Dolan
et al., 1994). Six new functional imaging studies (and
two published before 1996; see Table 4) focused on
depressive retardation. Most consistently was the nega-
tive correlation of depressive psychomotor retardation
with perfusion in the dorsolateral prefrontal cortex
(DLPFC) and angular gyrus (Bench et al., 1993;
Mayberg et al., 1994; Videbech et al., 2002; Narita
et al., 2004), and with perfusion in other regions such as
the anterior cingulate (Mayberg et al., 1994; Narita
et al., 2004) and bilateral supraorbital prefrontal areas
(Videbech et al., 2002). Rogers et al. (1998) suggested
that the DLPFC is not of primary importance in the
regulation of mood per se but that it is in retardation.
However, since decreased DLPFC activity was also
found in schizophrenic patients displaying psychomotor
poverty, rather than being a disease-specific phenom-
enon, it might be more symptom-specific (Dolan et al.,
1994). Based on their imaging data, Hickie et al. (1999)
proposed abnormalities within the neostriatum to
underpin the key psychomotor features of severe
depressive disorders.
3.12. One general syndrome?
Psychomotor changes in psychiatric and neurological
pathologies with dopaminergic deregulations are pro-
posed to originate from one general syndrome, reflecting
a similar pathophysiology. Faulty basal gangliar output
might underlie psychomotor abnormalities in disorders
such as schizophrenia, melancholic depression, Parkin-
sons Disease (PD), and Huntington's Disease (Rogers
et al., 1998), which is underpinned by the elevated
incidence of depression in basal ganglia disorders and by
the clinical parallels between melancholia and dopamine
14 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
related disorders. Already since the early 20th century,
studies pointed to a clinical similarity between bradyki-
nesia in PD and motor retardation in melancholic de-
pression (Rogers, 1992). Exploring the hypothesis more
recently, Caligiuri and Ellwanger (2000) demonstrated
Parkinsonian impairment patterns in a subset of their
depressed patients and Rogers et al. (2000) in their mel-
ancholic depressed patients only. These findings strong-
ly support the concept that psychomotor disturbance in
melancholic depression and bradykinesia in PD share a
common basal ganglia neuropathology. Besides local
basal gangliar disturbances, melancholic patients also
displayed impairments in the frontostriatal pathways,
in contrast to the non-melancholic depressed patients
exihibiting purely frontal dysfunction (Rogers et al.,
1998).
However, van Hoof et al. (1998) and Pier et al.
(2001) respectively reported different patterns of SDST
performance in depressed and schizophrenic patients,
and subtle kinematic differences in adult MDD, PD and
elderly depressed patients. When comparing the altered
gait features they observed in their depressed sample
with the findings of similar studies in PD, Hausdorff
et al. (2004) noted much greater reductions in gait speed
and swing time for PD than for depression. Also before
1996, studies comparing melancholic to PD subjects
were not clear-cut: while Rogers et al. (1986) reported
equivalent prolongation of both motor and cognitive
components of the SDST for melancholic and PD pa-
tients, Hart and Kwentus (1987) demonstrated a slowing
of motor response in both patient groups but only a
slowing of information processing in the PD subjects. A
similar lack of consensus could be noticed for studies
looking at more complex tasks of simultaneous motor
function in PD and melancholic subjects (Fleminger,
1992; Sachdev and Aniss, 1994).
Hence, additional neurobiological studies of dis-
orders with impaired dopamine function will need to
corroborate or refute this single syndrome hypothesis.
4. Discussion
4.1. Need for standardisation
In the current paper, we distinguished three major
psychomotor domains: speech, and gross and fine motor
activity. Our distinction was based on Sobin and
Sackeim's (1997) original four domains and was adapted
to current shifts in research: movements of the head,
torso and limbs, for instance, were not further investi-
gated while the area of fine motor activity was the focus
of many new studies.
When looking at the methodologies employed, we
may ask what exactly the term psychomotor represents
and how the manifestations can best be tested. Does
psychomotor disturbance automatically implicate
impaired performance in all three domains? Possibly,
not all patients will show the same psychomotor symp-
toms in the same combination or to the same degree.
While one patient may demonstrate high SRRS scores
and exhibit manifest fine motor slowing, in another the
slowing may reveal itself more in gait or speech. In-
consistent correlations between psychomotor tasks and
rating scales were reported, but, surprisingly, no study
compared the different methods within one domain or
between all three domains. Studies examining the var-
ious psychomotor domains with different assessment
tools in one and the same patient could help establish
relationships between the different experimental and
rating methods and determine whether all domains are
affected to the same degree. Currently, it is difficult to
distil a coherent story from all the isolated experimental
reports with our knowledge about the contribution of
different component processes remaining limited.
We evidently need a clear-cut definition of the con-
struct psychomotor, which today still reflects too broad
an area of psychomotor signs. We propose the adjective to
describe all those activities in which movement or action,
i.e. planning, programming and execution, is the principal
component rather than thinking or feeling. The term thus
not only encompasses the output of muscle contractions,
but also the wider involvement of perceptual processes
and cognitive-control mechanisms, underlining that
motor control involves more than an adjustment of
timing and initiation of muscle contractions.
The use of a combination of psychomotor assessment
tools comprising psychomotor rating scales and experi-
mental tasks from each domain measuring both motor
and cognitive aspects might help fine-tune the defi-
nition. One could even argue for the deployment of a
standardised test battery of well-specified tools to allow
more reliable and effective comparisons of studies. The
test combination would also compensate for the various
disadvantages inherent to the respective tools.
4.2. Psychomotor symptoms as a diagnostic marker
While we found no new studies about the capacity of
psychomotor symptoms to differentiate between the
neurotic and psychotic depressive subtypes, psychomo-
tor retardation was repeatedly demonstrated to be a
strong marker for melancholic depression. Moreover,
severe psychomotor changes were reported to be indica-
tive of psychotic melancholia, even in the absence of
 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
delusions or hallucinations. Psychomotor disturbances
also appear to discriminate between dysthymia and
MDD, and unipolar and bipolar depression. These obser-
vations clearly award psychomotor symptoms a diag-
nostic role in the spectrum of depressive disorders.
In the DSM-IV-TR, psychomotor retardation/agita-
tion is listed as one of the nine core symptoms of MDE
(Major Depressive Episode) and one of the main
characteristics of the melancholic depressive subtype.
The recent findings on melancholia and the strong
association between bipolar depression and melancholia/
retardation, however, might justify an elimination of the
psychomotor item from the MDE core symptom list,
leaving it exclusively as a key symptom of the melan-
cholic subtype. This is underpinned by Taylor and Fink
(2006) who proposed psychomotor disturbance to be one
of the essential features of the single syndrome
of melancholia. Moreover, these authors argue to con-
sider melancholia as a separate category from other non-
melancholic depressive syndromes (Taylor and Fink,
2006).
4.3. Impact of antidepressants
Besides the widely used SSRIs, TCAs remain im-
portant in the first-line treatment of MDD. The use of other
newer antidepressants such as venlafaxine, mirtazapine,
reboxetine and moclobemide in the pharmacotherapy
of MDD has also increased last decade. Our review
revealed differential effects of all these types of anti-
depressants on psychomotor performance. On the short
term, TCAs appear to impair psychomotor functioning in
healthy as well as in depressed subjects. However, most
antidepressants produced beneficial long-term psycho-
motor effects with variances in level of improvement
between the different types of drugs, mostly in favour of
the dual-acting agents. As to their predictive capacity, the
studies we reviewed showed severe retardation to predict
poor SSRI response which contradicted Sobin and
Sackeim' who reported the opposite for (mainly) TCAs.
These seemingly contradictory results are, however, in
harmony with the functional hierarchical depression
model, linking depressive subtypes to disturbances in
the neurotransmitter systems (Malhi et al., 2005). More-
over, ours and Sobin and Sackeim's findings are con-
sistent with several clinical trials demonstrating a greater
efficacy for dual-acting antidepressants or a combination
of a serotonergic and a noradrenergic agent than for single-
acting serotonergic agents in the treatment of (melan-
cholic) depression (Stahl et al., 2002; Volkers et al., 2002).
Psychomotor agitation predicted good response only to
sertraline but not to other antidepressants.
15
Overall, the collected studies clearly indicate that the
predictive capacity of psychomotor symptoms depends
on the type of disturbance (retardation or agitation) as
well as the type of antidepressant. Note that most pre-
dictive studies are based on the subjective psychomotor
items from the HDRS; exploring these findings by
means of the available experimental assessment meth-
ods is needed to confirm the present results. We further
feel that the more recent computerised assessment tech-
niques merit more application in effect studies of TCAs
and newer antidepressants. Their effect on psychomotor
functioning is likely to corroborate and refine the current
knowledge. Finally, it should be mentioned that age
and gender also might account for some differences in
clinical efficacy and predictive capacity since both fac-
tors have been demonstrated to be critical variables in
understanding differential antidepressant responses to
TCAs and SSRIs in melancholic depression (Joyce
et al., 2003).
4.4. Neurobiological trends: fast forward or standstill?
Sobin and Sackeim already mentioned the shift in
psychomotor-based depression research towards dopa-
mine with important roles for the basal ganglia and
circuits connecting basal ganglia to the prefrontal and
anterior cingulate cortex. However, up to 1996, only
Mayberg et al. (1994) and Bench et al. (1993) had spe-
cifically linked motor disturbance to patterns of functional
deficits. New imaging studies, focusing on the functional
disturbances in retarded depressed subjects, confirmed
earlier findings on dopamine in this population.
All studies involved Positron Emission Tomography
(PET) or Single Photon Emission Computed Tomography
(SPECT); functional Magnetic Resonance Imaging
(fMRI) was not used. And although the neurochemical
PET and SPECT studies revealed important findings
relating to D2 receptor binding and regional activations,
confirmation of the latter with fMRI would be welcomed.
As the cerebral blood-flow-based brain activation maps
generated by PET and fMRI proved to have a high degree
of similarity (Feng et al., 2004), corresponding fMRI data
would strengthen earlier results. Remarkably, all the
functional studies we reviewed comprised resting-state
scans only. As fMRI allows straightforward comparisons
of baseline and activation states, with an event-related
design relating brain activity to performance differences,
fMRI protocols for scans during the activation of the
regions known to be involved in retarded depression will
undoubtedly enhance existing knowledge.
Pharmacological and metabolite studies also link
psychomotor disturbance in depression to decreased
16 D. Schrijvers et al. / Journal of Affective Disorders 109 (2008) 120
cerebral dopamine functioning. Meyer et al. (2006)
concluded that depressed subjects with motor retarda-
tion manifest a preferential response to antidepressants
that induce sustained dopamine agonist effects such as
dopamine reuptake inhibitors (i.e. bupropion and sertra-
line) and monoamine oxidase A and A/B inhibitors.
Hence, besides the previously mentioned dual-acting
antidepressants, existing dopamine-increasing agents
should be applied in the treatment of retarded depression
and the development of antidepressants with higher
dopamine reuptake blockage encouraged.
Still, although promising, a translation of this dopa-
mine hypothesis to the daily psychiatric practice is yet to
happen: with the role of dopamine having been con-
firmed and incorporated into a theoretical framework,
research and development of dopaminergic antidepres-
sants remains scarce and the agents were not awarded a
prominent role in recent treatment protocols.
Finally, last years research has been conducted to
elucidate the genetic basis of MDD by proposing several
endophenotypes. Being one of the key components of
MDD, psychomotor disturbance has also been explored
as a potential endophenotype candidate. However, of the
6 necessary criteria, only the criteria concerning bio-
logical and clinical plausibility and specificity were
fulfilled. Information on the 4 remaining criteria, i.e.
state-independence, heritability, familial association,
and cosegregation of specific psychomotor disturbances
is lacking, which makes it very unlikely to include
psychomotor disturbance as an endophenotype for
MDD (Hasler et al., 2004).
4.5. Exploring functional outcome
Psychomotor symptoms may have considerable im-
pact on activities of daily living. Studies in elderly
populations revealed clear correlations between (psycho)
motor retardation on the one hand and a greater disability
(Alexopoulos et al., 1996; Kiosses et al., 2000) and
increased risk of falls (Hausdorff et al., 2004) on the other.
This clinically relevant association evidently merits
closer scrutiny, both in elderly and in adult patients.
A relationship between psychomotor slowing and
functional outcome in depression is also highly proba-
ble given that Morrens et al. (2007) found clear as-
sociations between the two factors in patients diagnosed
with schizophrenia. Yet, despite longer-term daily-life
and work disability being one of the major conse-
quences in MDD, surprisingly few studies have sought
to determine what accounts for this disability. The
one study that did showed a predictive association for
motor functioning with 6-month functional outcome
(Jaeger et al., 2006). Here again, new study designs are
warranted to help fill this patent gap in depression
research.
Role of the Funding Source
This paper was supported by a grant from FWO-Vlaanderen (Fund
for Scientific Research-Flanders).
Conflict of Interest
There are no conflicts of interest to be reported for any of the
authors.
Acknowledgements
The authors would like to thank Hanneke Meulen-
broekvan der Meulen for her language corrections and
editing suggestions in earlier versions.
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