Psychomotor symptoms in depression: A diagnostic, pathophysiological and therapeutic toolAbstractBackground: 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 HPAaxis 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.Keywords: Depression; Major Depressive Disorder; Psychomotor symptoms; Retardation; Agitation

Contents1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22. Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.1. Psychomotor symptoms over the centuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33.2. Manifestation and assessment of psychomotor symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.3. Observer-rated assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43.4. Experimental assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.5. Gross motor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.6. Fine motor activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.7. Speech . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.8. Other determinants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.8.1. Age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.8.2. Sex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.9. Diagnostic significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.9.1. Melancholia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.9.2. Dysthymia and bipolar depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.10. Medication studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73.11. Pathophysiological significance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.11.1. Neurotransmitter systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123.11.2. HPA-axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.11.3. Neurophysiology and imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133.12. One general syndrome?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134. Discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.1. Need for standardisation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.2. Psychomotor symptoms as a diagnostic marker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144.3. Impact of antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154.4. Neurobiological trends: fast forward or standstill?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154.5. Exploring functional outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Role of the Funding Source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Conflict of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

1. IntroductionPsychomotor disturbances have been described extensively 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 reviewof the literature mainly published in the second half of the twentieth century. Since then, advanced 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 inhibitors (SSRIs) on psychomotor functioning investigated andmany 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 explore the relevance of psychomotor symptoms for a better understanding of and a more efficient approach to Major Depressive Disorder (MDD). We, moreover, discuss the extent to which the new knowledge contributes to a better conceptualisation of the psychomotor construct and propose directions for future research.2. MethodologyOur 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 potentially relevant papers and all relevant cross-references examined in full. As the review focuses on psychomotor disturbances, papers primarily aimed at measuring cognitive and experimental neuropsychological processes were excluded, as were those about melancholic depression that did not specify psychomotor findings.

3. Results3.1. Psychomotor symptoms over the centuriesOver 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 psychomotor 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 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 symptomsDepressed patients manifest a wide range of psychomotor 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 assessmentsOne of the included studies used a clinical evaluation, 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 measuring severity of depression, but also contains one retardation and one agitation item. For the assessment of psychomotor performance, its reliability might be limited. 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 manifestations 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, although 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 methods 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 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 Hypothalamic- Pituitary-Adrenal (HPA) measures (Mitchell et al., 1996; see Table 4). Contrary to the SRRS that measures retardation only, the CORE system also encompasses 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 individualMARS 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 effects (e.g. Pier et al., 2004a,b) and associations to be made with neurobiological findings, enhancing the comprehension of important pathophysiological mechanisms in depression. Other distinct advantages the scales have over symptom-based measures and singleitem ratings are their high reliability and Independence from patient recall.

3.4. Experimental assessmentsNot all motor-system abnormalities can be discerned by means of observer-rated assessments or clinical observations. More sensitive, experimental performance measures allow the detection of psychomotor disturbances 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 reported by Kraepelin (1921; Berrios, 1988), an extended period of interest in measuring psychomotor disturbances 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).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 activityNineteen studies objectively evaluated disturbed gross motor activity using four different approaches: (1) 24-hour actometric measurements of limb or horizontal movements, (2) spatiotemporal gait-pattern analyses during over ground locomotion, (3) a frame-byframe 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 differences 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 identified only one preliminary actigraphic study (Parker et al., 2002) without there being sequel studies to validate and extend the findings.

3.6. Fine motor activityIn 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-sensitive pen (see Table 1) affords objective, real-time recordings, 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 performance (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), requiring a symbol to be replaced by its matching digit, and three copying tasks of increasing complexity requiring 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, visuospatial 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 simple (n=38) of medication-free patients. Conversely,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. SpeechDepressed patients present with a uniform, monotonous 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) demonstrated a correlation of speaking rate and pitch variation with HDRS scores, partially confirming previous reports (Sobin and Sackeim, 1997).

3.8. Other determinants3.8.1. AgeMost 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 association 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. SexAs 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 sexdependent differences (Hildebrandt et al., 2003a,b; Scheibe et al., 2003; Pier et al., 2004a). This challenges 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 determinant of the manifestation of psychomotor symptoms, which conclusion is refuted by our divergent findings.

3.9. Diagnostic significanceUncovering differences in the nature of psychomotor retardation in the different depressive subtypes might have considerable diagnostic value for clinicians. While previously psychomotor symptoms were exploited to isolate the clinical difference betweenpsychotic 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. MelancholiaMotor slowing is widely accepted as one of the main indicators of the melancholic subtype of depression (Taylor and Fink, 2006). Yet, does psychomotor performance effectively distinguish melancholic from nonmelancholic depression or are observed differences attributable to variations in symptom severity? Sobin and Sackeim only found one study linking global depression severity to motor-retarded but not motor-agitated depression. Some recent reports mention associations between depression severity and psychomotor functioning (Lemke et al., 1999a; Caligiuri and Ellwanger, 2000; Iverson, 2004), whereas others found no such correlations (Brebion et al., 1997; Lemke et al., 1999b; Hasler et al., 2004).

Comparing melancholic and non-melancholic samples, several researchers found that the melancholic patients, both medicated (Rogers et al., 2002) and unmedicated (van Londen et al., 1998; Pier et al., 2004a), differed from their non-melancholic peers in the degree 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. Psychomotor 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 empirically based hierarchical model in which disorder-specific 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 comprises two melancholic subtypes, one with and one without psychotic features, and a heterogeneous residue of non-melancholic depressive disorders. All threeexpressions of the disorder have a significant moodstate disturbance and observationally rated psychomotor disturbances determine the distinction between melancholic and non-melancholic depression, with psychomotor symptoms being highly unlikely in nonmelancholic 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 melancholic 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 hallucinations, 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 disturbance, even in the absence of formally eliciting delusions or hallucinations (Parker et al., 1991, 1996).

Summarizing, more and more evidence link psychomotor disturbances to the (psychotic and non psychotic) melancholic subtype, with the severity of the depression playing a role in melancholic depression in particular.

3.9.2. Dysthymia and bipolar depressionBy 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 melancholic subtype and, conversely, those with rigorously defined melancholic depression appear to be at considerable risk of having a bipolar course (Parker 2000; Parker et al., 2000). This is consistent with the previously 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 studiesVarious studies explored the psychomotor effects of antidepressants and the predictive capacity of psychomotor symptoms for clinical response. The most relevant studies are listed in Table 3.

In healthy volunteers, fluvoxamine and reboxetine did not have disruptive effects on psychomotor functioning, 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 shortterm (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 activity 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 longterm effects of different types of antidepressants (see Table 3). Beneficial long-term effects for several TCAs and newer antidepressants such as moclobemide, mirtazapine, 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 al., 2001; Stahl et al., 2002; Volkers et al., 2002; Hegerl et al., 2005). Concerning the SSRIs, most studies demonstrated significant psychomotor improvements (Gattaz 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 improvement 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 psychomotor symptoms for clinical antidepressant response.For patients with pre-treatment motor retardation or impaired 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 antidepressant response. This inconsistency may be explained by the fact that the studies we evaluated mainly examinedSSRIs 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 favourable 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 tan the non-agitated patients (Flament et al., 1999), in contrast with equal response rates to moclobemide, imipramine 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 information- 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 antidepressants 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 produce different short- and long-term psychomotor effects.Baseline psychomotor disturbances might predict antidepressant 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 electroconvulsive 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 remission when using antidepressants.

3.11. Pathophysiological significanceKnowledge about the neurobiological processes underlying 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 abnormalities in specific structures and pathways of the brain, which was explored further by subsequent pathophysiological studies, all itemised in Table 4.

3.11.1. Neurotransmitter systemsIt 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 subtypes to disturbances in neurotransmitter systems. Each subtype is underpinned by a disturbance in all three systems but their relative emphases vary. The psychomotor changes in the melancholic psychotic and nonpsychotic subtypes are mainly related to dopamine dysfunction, and the remaining melancholic features to impairments in noradrenergic and to a lesser extent serotonergic neurotransmission. Non-melancholic depression 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 the dopamine metabolite homovanillic acid were significantly reduced in patients with retarded depression (Winograd-Gurvich et al., 2006). Three functional imaging studies clearly demonstrated a striatal dopaminergicdisturbance during depression, being most prominent 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 psychomotor disturbances in melancholic (psychotic and nonpsychotic)depression may be due to diminished cerebral 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, melancholic depression is a disorder involving several neurotransmitter systems in complex interactions.

3.11.2. HPA-axisBesides 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 imagingBange and Bathien (1998) proposed the P300 eventrelated potential as an index of the contribution of the slowed central processing in retarded depressed patients, with the peak latency reflecting the duration of stimulusevaluation processes and the amplitude reflecting perceptual resources processing the stimulus. Relative to normal controls, the psychomotor slowing of both unipolar 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 abnormalities, 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 implicated in the cognitive and motor abnormalities accompanying 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 negative 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 reas (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 phenomenon, 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 proposed 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, Parkinsons 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 related disorders. Already since the early 20th century, studies pointed to a clinical similarity between bradykinesia in PD and motor retardation in melancholic depression (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 melancholic depressed patients only. These findings strongly 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 simple 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 patients, 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 disorders with impaired dopamine function will need to corroborate or refute this single syndrome hypothesis.

4. Discussion4.1. Need for standardisationIn 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 investigated 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 symptoms 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. Inconsistent correlations between psychomotor tasks andrating scales were reported, but, surprisingly, no study compared the different methods within one domain or between all three domains. Studies examining the various 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 construct 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 experimental tasks from each domain measuring both motor and cognitive aspects might help fine-tune the definition.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 markerWhile we found no new studies about the capacity of psychomotor symptoms to differentiate between the neurotic and psychotic depressive subtypes, psychomotor retardation was repeatedly demonstrated to be a strong marker for melancholic depression. Moreover, severe psychomotor changes were reported to be indicative of psychotic melancholia, even in the absence of delusions or hallucinations. Psychomotor disturbances also appear to discriminate between dysthymia and MDD, and unipolar and bipolar depression. These observations clearly award psychomotor symptoms a diagnostic role in the spectrum of depressive disorders.In the DSM-IV-TR, psychomotor retardation/agitation 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 melancholic subtype. This is underpinned by Taylor and Fink (2006) who proposed psychomotor disturbance to be one of the essential features of the single sndrome of melancholia. Moreover, these authors argue to consider melancholia as a separate category from other nonmelancholic depressive syndromes (Taylor and Fink, 2006).

4.3. Impact of antidepressantsBesides the widely used SSRIs, TCAs remain important in the first-line treatment ofMDD. 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 antidepressants 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 psychomotor 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). Moreover, ours and Sobin and Sackeim's findings are consistent with several clinical trials demonstrating a greater efficacy for dual-acting antidepressants or a combination of a serotonergic and a noradrenergic agent than for singleacting serotonergic agents in the treatment of (melancholic) depression (Stahl et al., 2002;Volkers et al., 2002). Psychomotor agitation predicted good response only to sertraline but not to other antidepressants.

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 predictive studies are based on the subjective psychomotor items from the HDRS; exploring these findings by means of the available experimental assessment methods is needed to confirm the present results. We further feel that the more recent computerised assessment techniques 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 factors 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 dopamine 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 specifically linkedmotor 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 EmissionComputed 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 PETand 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 cerebral dopamine functioning. Meyer et al. (2006) concluded that depressed subjects with motor retardation manifest a preferential response to antidepressants that induce sustained dopamine agonist effects such as dopamine reuptake inhibitors (i.e. bupropion and sertraline) 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 dopamine hypothesis to the daily psychiatric practice is yet to happen: with the role of dopamine having been confirmed and incorporated into a theoretical framework, research and development of dopaminergic antidepressants 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 biological 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 outcomePsychomotor symptoms may have considerable impact 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 probable given that Morrens et al. (2007) found clear associations between the two factors in patients diagnosed with schizophrenia. Yet, despite longer-term daily-life and work disability being one of the major consequences 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 Meulenbroek van der Meulen for her language corrections and editing suggestions in earlier versions.