Brief report
Recurrence of major depressive disorder is predicted by inhibited startle magnitude while recovered

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Abstract

Background

Major depressive disorder, for some, follows a chronic relapsing course. However, no reliable marker has been established that allows the identification of this sub-group of patients. Preliminary findings suggest that baseline startle magnitude may be such a marker. This study evaluated whether differences in baseline startle magnitude during remission could prospectively predict depressive symptomatology and recurrence.

Methods

A group of previously depressed individuals (n = 25), who were in full remission at the time of testing, had their startle reflex measured via surface EMG electrodes on the left orbicularis oculi muscle. These people were then followed-up 2 years later and their depressive symptomatology during the intervening period was assessed using the psychiatric ratings scale of the Longitudinal Interval Follow-up Evaluation (LIFE; [Keller, M.B., Lavori, P.W., Friedman, B., Nielsen, E., Endicott, J., McDonald-Scott, P., et al. (1987). The Longitudinal Interval Follow-up Evaluation. A comprehensive method for assessing outcome in prospective longitudinal studies. Arch. Gen. Psychiatry, 44(6), 540–548]) and incidents of recurrence assessed using the Structured Clinical Interview for DSM-IV (SCID-I/P; [First, M.B., Spitzer, R.L., Gibbon, M., & Williams, J.B.W. (2001). Structured clinical interview for axis 1 DSM-IV disorders. New York: New York State Psychiatric Institute]).

Results

It was found that a relatively attenuated startle response at initial assessment was strongly predictive of both depressive symptomatology and those who would experience relapse.

Limitations

This study has a relatively small sample size that limits the degree to which a thorough co-variant analysis can be conducted and also makes the analysis of gender-based difference impracticable. Additionally, as no healthy control group is included, we report a relative rather than absolute attenuation of startle to be indicative of symptom severity and recurrence proclivity.

Conclusions

These preliminary findings suggest that an attenuated startle response may have utility as an endophenotypic marker of risk for recurrence of Major Depression and residual sub-syndromal symptomatology. Such a marker may facilitate the early identification and treatment of those most at risk of recurrent Major Depression.

Introduction

For approximately 50% of those who suffer from depression their illness will follow a chronic, relapsing course associated with considerable disability and impairment (Crown et al., 2002). Furthermore, repeated episodes are associated with neurobiological and psychological changes that progressively increase the person's vulnerability to further episodes, with the probability of external proximal triggers diminishing as the number of previous episodes increases (Post, 1992). Despite advances in the treatment of depression, research shows that the long-term outcome for those who experience multiple episodes has altered little over the last 20 years (Kennedy et al., 2003). Therefore, a pressing clinical issue is early identification of those most at risk for this type of chronic relapsing course.

The magnitude of the startle reflex may be an endophenotypic marker for vulnerability to recurrent depression. The startle reflex, which is widely used in the investigation of the physiology of affect and attention, consists of a cascade of physical reactions to an intense stimulus with sudden onset; for example a loud noise. One of the earliest and most stable components is the eye-blink response. This is a burst of electromyographic (EMG) activity in the orbicularis oculi muscle associated with the presentation of the startle stimulus (Andreassi, 2000). Variation in the affective and attentional modulation of the eye-blink startle reflex is associated with a number of psychopathologies (Grillon and Baas, 2003). However, relatively little research to date has specifically examined the association of the magnitude of the unmodulated baseline startle reflex and MDD.

Baseline startle is, however, reported to be highly heritable (Anokhin et al., 2007, Anokhin et al., 2003, Carlson et al., 1997), suggesting that baseline startle, may be a candidate as an endophenotypic marker. Anokhin et al. (2003) reported, in a study that utilized a twin paradigm, that while pre-pulse inhibition of startle (that is, the degree to which one is able to gate or filter out environmental stimuli) is approximately 50% heritable, baseline startle is approximately 70% heritable. Additionally, in a more recent paper also using a twin design, these investigators report that while affective modulation of the startle response does not appear to be heritable, the individual differences in the overall (baseline) magnitude of startle show substantial heritability (Anokhin et al., 2007). These twin studies do not explore what the candidate genes may be for the transference of this heritability. However, a recent paper reports that within a clinically healthy sample, the overall startle response is sensitive to allelic variation in the serotonin transporter gene, while fear potentiation of startle is not (Brocke et al., 2006). Baseline startle may therefore be a more promising endophenotypic marker than modulation of startle to emotional stimuli.

Allen et al. (1999) reported that those with more severe depression had significantly lower baseline startle magnitude, a finding that has recently been replicated in a study of depressed outpatients which found that those with the lowest levels of positive affect (anhedonia) displayed an inhibited baseline startle amplitude (Allen et al., submitted for publication). Additionally, Kaviani et al. (2004) reported that while only startle reactivity to pleasant stimuli is reduced at low levels of depression and anhedonia, all reactivity is reduced at higher levels. Furthermore, and consistent with the findings of Allen and colleagues, it was also found that those with the highest levels of depression showed a lower startle amplitude. In all of the studies thus far, this reduced startle reactivity is reported in participants who are currently depressed, raising the question of whether the reduced startle amplitude is related to current symptomatology, such as psychomotor retardation, or represents a more enduring biological marker for a sub-group of people with MDD who are more prone to severe depression.

On the basis of these previous findings demonstrating an association between depression and attenuated startle, as well as the literature suggesting attenuated startle is highly heritable and therefore may be an endophenotypic marker of vulnerability to depression, we conducted an analysis of data originally collected for a longitudinal study concerning affective modulation of startle and vulnerability to recurrence of MDD (Di Parsia et al. submitted for publication). Because of its emphasis on the cognitive and affective processes that determine startle modulation, this previous paper did not examine the impact of individual differences in overall startle magnitude on outcomes. As recent findings have demonstrated that there are distinct mechanisms involved in determining affective startle modulation versus baseline startle magnitude, especially with respect to genetic mechanisms (e.g., Anokhin et al., 2007, Anokhin et al., 2003, Brocke et al., 2006), a separate investigation of the correlates of baseline magnitude is called for. Therefore, here we report the relationship between baseline startle magnitude measured during remission from depression and symptomatic and diagnostic outcomes over a two-year follow-up period. We evaluated the hypothesis that inhibited baseline startle reflex magnitude is not merely reflective of symptomatology associated with severe MDD, but when measured during full clinical remission can prospectively predict recurrence of case level depression and depressive symptoms.

Section snippets

Method at time one

Of the 33 participants who were initially assessed while in remission from depression, 25 were followed-up (19 female, 6 male; age range 20 to 63 years) 2 years later. As depression is reported as up to three times more likely in females than males (Urstan, 2000) this gender ratio is not unrepresentative of population prevalence. Participants took part in follow-up diagnostic interviews approximately 24 months after they took part in the initial psychophysiological study. Drug and alcohol

Results

Participants who failed to startle reliably on 50% of trials were excluded from those analyses addressing startle reflex (n = 4). There was no evidence of multi-colinearity between any of the variables, with all VIF statistics < 10 and Durbin–Watson statistics approximately 2. Case wise diagnostics were used for multivariate outliers and no cases were identified.

During the two-year follow-up period, three males and four females experienced case level relapse. Although most of the participants did

Discussion

This study suggests that baseline startle magnitude may have utility as a marker of risk for recurrence of depression. Previous studies have reported attenuated baseline startle reactivity in severely depressed individuals (Allen et al., 1999, Kaviani et al., 2004), but this study found it to be also present during remission in those at greatest risk for recurrence. As all participants were relatively symptom free at the time of initial testing this result suggests that the attenuated startle

Role of funding source

This research was partially supported by Australian Research Council grant A10020926. The funding body had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

No conflict declared.

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