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Patrick LEMOINE
MD, PhD, ScD
Clinique Lyon-Lumière
Meyzieu – FRANCE

The principal synchronizer in human beings is light. Like almost all beings that inhabit the Earth, the predominant periodicity in humans is circadian. It is light that realigns rhythms that, in turn, are controlled by oscillators— notably the suprachiasmatic nuclei. It appears that the general reduction in sleeping time of nearly 2 hours nightly, observed since the introduction of electric light sources, has had notable consequences on the body weight and blood sugar levels of poor sleepers and insomniacs. It may also favor depression and aggressiveness. In the event of light deficiency, other synchronizers such as work, mealtimes, or group activities can compensate. To measure rhythms in a research context, the core body temperature can be recorded in continuous mode. The blunting or flattening of circadian body temperature rhythms constitutes the biologicalmarker that remains themost specific physiological trait in depression. In clinical practice, it ismore practical to use sleep diaries and an actimeter to measure rhythms, before turning to polygraphic sleep recordings. All these measuring instruments enable an objective view of relatively specific criteria for depression. Mood that is worse in the morning and better in the evening is one of the principal clinical markers for major depression, although it is difficult to determine whether this is the cause or consequence of physiological anomalies.

What are social zeitgebers and social rhythms?

What are the consequences if they are disturbed?

Originally, human beings were mammals that were both diurnal and arboreal, which means that their strongest sense was that of sight, their principal synchronizer or zeitgeber was light, and like almost all beings inhabiting Earth, their predominant rhythm was circadian, notably their vigilance/sleep rhythm.¹ Since the invention of electricity, humans have probably lost an average of 2 hours of sleep per night. To be more precise, it is generally considered that 1 lost hour of sleep can be attributed to artificial lighting, and an additional hour to television, the Internet, or other electronic stimuli.

It is, however, difficult to confirm such theories objectively and quantitatively, because clearly no sleep recordings existed before electricity was invented. To gain an idea of the real sleeping time of pre-electricity humans, it would be necessary to record the everyday habits of humans in the rare, inaccessible regions of Africa, New Guinea, and the Amazon basin, where a few ethnic groups still live without artificial light according to a purely day/night rhythm. This would provide an objective view of the average time we would sleep under so-called “natural” conditions. It would not, however, inform us about natural conditions in temperate regions of the world.²

Nevertheless, in a recent andmore precisely-conducted study performed in the general population of North America (USA), subjects tested were reported to have probably lost an average of 21.5 minutes of nightly sleep per decade since 1960.³ If this phenomenon persists, we will reach a total of 107.5 minutes’ less nightly sleep in 2010 than in 1960, or indeed nearly 2 hours less. This is a considerable amount, and no one has a precise idea as to its effects on health, but it would be astonishing if there were none. Indeed, there is nothing to suggest that this downward trend is starting to slow, and who knows what figures might ultimately be reached, because we cannot determine the incompressible, “hard core” duration of sleep.

It is generally considered that the ideal amount of nightly sleep in humans averages around 7 to 8 hours, but with major individual variations. The sleep debt is associated with an increased consumption of alcohol, tobacco, and caffeine. Body mass index is correlated with sleep time, which suggests that chronic sleep deprivation at the continental level in North America may be linked to the obesity epidemic that is invading this region of the world.³

Some authors⁴ consider that the sleep debt is likely to be associated with a risk of diabetes. Although this suggestion remains controversial, it is generally true that insulin resistance is aggravated as sleeping time diminishes. A reduction in sleeping time may also be correlated with a rise in blood pressure.² Chronic insomniacs have been shown to have lower levels of education and less favorable career paths than those who sleep well. Finally, it is also known that chronic insomnia favors depression or is even a precursor of this condition, to the point where it is thought by some that 20-yearold insomniacs will become 40-year-old depressives.⁵

However, it should not be forgotten that by definition, epidemiological studies demonstrate associations of phenomena, but never any causal relationships. In other words, one can say that although more obesity is found in insomniacs, this does not necessarily mean that the former is responsible for the latter. Indeed, it is possible to imagine the inverse situation, whereby those who are obese sleep less well because of their weight (experiencing different types of pain, difficulty in breathing, sweating, etc); one can also imagine that if a person sleeps badly, they may go to the refrigerator and eat what they find there. In this latter case, insomnia is the indirect cause of obesity.

A certain number of other arguments highlight the clear link between emotional control and sleeping time. It suffices to spend a night without sleep to understand the degree to which a simple reduction in sleeping time can cause moodiness, aggressiveness, episodes of crying, explosions of rage, and other emotional reactions. All these symptoms are directly linked to the most archaic parts of our brains, collectively called the limbic zone. Under normal circumstances, these areas are linked to the prefrontal lobe, which is the “adult” and reasonable area responsible for our intelligence. Indeed, many authors think that human beings are above all a “prefrontal animal.”

It was in order to allow the development of the prefrontal lobe that our ancestors experienced a gradual diminution of the supraorbital ridge and disappearance of the receding forehead characteristic of most large apes. This part of our brain, capable of controlling instinctive and affective movements, is probably the anatomical seat of what differentiates humans from other animals. Indeed, it has been shown that experimental conditions of sleep deprivation will “disconnect” the prefrontal lobe from the limbic zone. This disconnection deprives the conscious and reasonable part of our brain of any control over emotions, hence an increase in emotiveness and ultimately in violence and aggressiveness. It is therefore possible to hypothesize fromthesemechanisms that chronic sleep deprivation favors depression, which would help to explain the increased incidence of this condition at a general epidemiological level.⁶

However, synchronizers other than light do exist in man, but they are difficult to clarify because of the preponderant importance of light. It is in the totally blind, who by definition are deprived of sight and any light stimulation, that these synchronizers can best be demonstrated. In this population, a higher prevalence of insomnia and depression has been noted. When deprived of sight, humans as social animals call upon donors of social rhythms in order to synchronize themselves with their environment, principally by means of hearing: working or family hours indicated by the alarm clock or time clock, television programs, meals, and group activities at fixed times, or in other words, anything that “requires” an individual to adopt regular rhythms.

It is the time of getting up in the morning that forms the basis for different social rhythms, and the “chronotherapist” should use this when proposing a resynchronization program to a depressive patient.²

How can one measure rhythm disruption in depression?

In terms of fundamental research, themost important chronobiological parameter is the circadian rhythm of body temperature. Depression is probably the best example of a disease that results from circadian malfunction. The now historical data acquired by Beersma⁷ demonstrated an “extreme blunting or even flattening of circadian body temperature rhythms in depressives.” Body temperature rhythms drive all other circadian rhythms (blood pressure, heart rate, hormones, receptor sensitivity, mitosis, meiosis, etc). They are governed by the suprachiasmatic nuclei (oscillators) and are correlated with what has become known as “form,” ie, a combination of levels of vigilance, physical and intellectual performance, and mood.

If we accept that major depression is associated with abnormal functioning of the central oscillators, it becomes easy to understand why it is accompanied by excessive vigilance during the night, because there is no change (or only a slight reduction) in nocturnal temperature, and daytime somnolence. This is particularly flagrant in the event of major depression with “melancholy” (Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; DSM IV), where time-related disturbances are of particular importance. Nevertheless, for technical reasons, it remains difficult to record variations in body temperature in everyday clinical practice.

In the context of clinical practice rather than research, a detailed clinical interview regarding lifestyle, and particularly a sleep diary, will enable the best assessment of rhythm disturbances in depression.¹ This simple self-assessment tool for clinical use provides a clear picture of circadian, weekly (social), and monthly rhythms (the latter of particular value in women). The opportunity for a depressed patient to visualize, and thus become aware of, regular variations in rhythm and mood can thus constitute an important therapeutic tool. A “mental pain” item can also be added to the sleep diary that the subject can complete twice a day, once in the morning when getting up and once at around 6 PM, so as to provide an objective assessment of mood fluctuations over the day. The situation most frequently cited is that of the “melancholic feature” of major depression in DSM IV, where a worsening of pain is regularly found in the morning, and an improvement (or lightening) of mood is observed in the evening. This symptom can be considered as a marker of the severity of what was previously referred to as the endogeneity of depression.

In subjects who work, it is common to observe a worsening of depressive mood at the beginning of the week, when social rhythms have been lost during the weekend and have not yet been retrained by professional constraints (Monday mornings). Finally, in women, a gradual and general worsening of mood between ovulation and the start of menstruation, correlated with a blunting of circadian body temperature rhythms, helps us to understand why cases of attempted and successful suicides are significantly more numerous during the week preceding menstruation. Premenstrual syndrome can then be considered as equivalent to depression, as progesterone is a hormone that is both thermogenic (nocturnal), sedative, and depressogenic.²

In clinical practice, it is also possible to use an actimeter, an inexpensive instrument like a wristwatch that can continuously record rhythms of movement and inactivity for periods of up to a month. This easy-to-use device can objectively demonstrate vigilance/sleep rhythms and reveal the degree of slowing of depressed subjects during the day.

Finally, polygraphic sleep recordings can be envisaged in some specific cases of insomnia or depressive hypersomnia.8 However, this remains a complicated procedure when not performed in a research context. The anomalies observed are almost constant, although not very specific when taken in isolation. They are focused on three main areas:

_ Continuity of sleep: this is the first disorder to have been noted, with a prolongation of sleep latency, and an increase in the number and duration of nighttime awakenings and waking early in the morning, all of which cause a fragmentation phenomenon that reduces the efficacy of sleep.

_ Diminished delta sleep: this trait has been found by all authors, even if it does not concern all types of depression. Spectral analysis shows that this loss of delta sleep is of major importance during the initial period of sleeping, but that it also persists throughout the night; there is an abnormal distribution of delta sleep, because it is less well represented during the first sleep episode than during the second episode.

_ Paradoxical sleep (PS): classically, there is a reduction in the latency of onset of the first period of paradoxical sleep (<90 minutes), and an increase in the duration of this first episode, often accompanied by increases in the density of rapid eye movements and the percentage of PS compared with total sleep.

The specificity of the reduction in PS latency for depressive sleep can reach 70%, and if several of the aforementioned parameters are combined, it is possible to clearly distinguish depressive from healthy sleep, and the sleep of elderly individuals with depression and pseudo-dementia from that of those with Alzheimer’s disease. The association of latency of the first PS episode and prolongation of the first PS episode is a clear sign of depression, although this parameter is not unanimously recognized; some authors consider it as a simple reflection of the number of daytime naps, as depressed individuals adopt clinophiliac behavior like those who take naps under normal physiological conditions.

Morningness and eveningness: are they predictors of depression?

In a recent, as yet unpublished study, we tried to correlate “morningness” and “eveningness” types of individual with various psychiatric disorders managed by clinical psychiatrists. Two thousand subjects were assessed. No correlations were found with any psychiatric disorder.

However, the aforementioned clinical rhythms in depressed individuals may give a temporary illusion of “eveningness,” as patients are generally in better form in the evening than in the morning. In addition, clinical experience quite frequently shows that in depressed individuals, behavior that mimics “evening” subjects with late arising in the morning (more than 30 minutes after spontaneous awakening) causes a morose mood and a certain number of depressive symptoms. It is then possible to consider that for a “morning” subject with a chronorigid nature, extending morning sleep time or traveling eastward by plane, ie, creating almost experimental conditions of phase delay, represents an increased risk of depressive decompensation.

It is based on this type of clinical observation that some authors have proposed phase advance for therapeutic purposes; in practice, they propose that individuals get up much earlier in the morning and definitively ban any morning lie-ins. Getting up quite early, always at the same time, followed by healthy rhythm measures such as physical exercise, a hot shower, exposure to a brilliant white light with an intensity of 10 000 lux for 30 minutes, and a relatively high-protein breakfast, can enhance living conditions for depressives, and (although it remains speculative) bring about a reduction in the risk of relapse after remission.²

Diurnal mood rhythms in depression: do they result from weakened circadian function? Are there core or associated symptoms more specifically treated by social rhythm therapy?

This issue could be compared to that of the chicken and the egg: which comes first? Is it an anomaly of circadian temperature rhythms that provokes depression, or does the particular behavior of depressed individuals alter their circadian rhythms? At present, it is impossible to answer this question with certainty.⁹ Nevertheless, the polysomnographic anomalies observed, notably at the level of PS and delta sleep, appear to persist during remission, which might suggest that they are more a trait of depressives than an effect (state) of depression. It is then possible to hypothesize that a reduction in circadian rhythms, notably those of body temperature, are crucial to the problem of depression, at least in major, severe, and endogenous (unipolar and bipolar) depression.

What type of alleviation of symptoms can social rhythm therapy provide?

Whether we consider antidepressants, thymoregulators, electroconvulsive therapy, light therapy, or cognitive and behavioral therapies,¹⁰ there is a common, final pathway in the event of a positive response, which is an increase in the amplitude of circadian body temperature rhythms. Partial or total sleep deprivation also produces the same result.

Therapy involving adjustment of rhythms must be considered as supplementary to the therapies referred to above. It is thus necessary to reinforce the circadian rhythms through behavioral measures: getting up earlier in the morning (always at the same time), physical exercise immediately on rising, a long hot shower, a relatively high-protein breakfast, and exposure to brilliant white light at 10 000 lux. In the evening, no intensive physical exercise or excessively stimulating or stressful activities, an evening meal containing slow-release carbohydrates, a warm bath, and low lighting to encourage the release of endogenous melatonin.

When these recommendations regarding healthy rhythms are respected, a rapid improvement can be observed in general wellbeing and a reduction in residual symptoms: morning tiredness, insomnia, morning gloominess. Although there is a dearth of studies in this area, it is possible that rigorous compliance with this chronotherapy may to some extent reduce the risk of recurrence. _

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Julien MENDLEWICZ, MD, PhD
Professor, Free University
of Brussels – BELGIUM

Time has always been in the focus of attention of psychiatrists, with authors like Minkowski and Strauss interpreting psychopathological changes in time perception as the “slowing down or inhibition of lived time in depression.” ^1,2 This perceived slowing down of time is very characteristic of depression and is accompanied by hopelessness in regard to the future, while clinging to the past. In contrast, manic patients experience time as being sped up and focus primarily on the present, and tend to neglect the past and future, as described recently by Ghaemi.³

When diagnosing mental disorders, clinicians elicit information about symptoms, identify one or several syndromes, and based on these, finally come to a diagnosis. Although this approach appears very cross-sectional, as if one were “freezing” the patient’s condition in time, the dynamic dimension of time is essential in the process. This dimension is taken into account, for example, by the Diagnostic and Statistical Manual of Mental Disorders (DSM)–IV requirement of at least 2 weeks’ symptom duration for a diagnosis of depression, or by the observation of seasonal changes in symptom severity.

As this issue of Medicographia makes abundantly clear, the concept of time plays multiple and ubiquitous roles in depression.

Time and depression both are complex concepts. In physics, time, along with space, length, mass, etc, belongs to the rarified group of fundamental quantities, for which the only definition can be a circular one: ie, time can only be defined by time, length by length, etc. Time does not derive from anything else than time, but leads to a host of quantities that derive from time, such as velocity, acceleration, frequency, etc, so that time can be used to define velocity, but the reciprocal isn’t true.

If we now look at time in depression, we find that in some cases, time can be used to define depression, in others not.

It is increasingly clear that the normal function of time is « lost » in depression, hence the cover title of this issue of Medicographia: « In search of lost time: À la recherche du temps perdu » taken from Marcel Proust’s monumental work. The most obvious alteration concerns the subjective perception of time, which in most patients suffering from depression is perceived as passing more slowly. But this perception is very difficult to differentiate from the normal subjective perception of time, which varies widely depending on the social context, attention and vigilance, and mood.

Therefore, this subjective manifestation reported by depressed patients of time passing more slowly although it derives from depression (as velocity derives from time) cannot be used to define depression (just as velocity cannot be used to define time).

But other time-related symptoms of depression have totally different implications. Depression leads to disturbances in physiological rhythms, which result in disturbances in circadian sleep-wake cycles, hormonal secretion patterns, and fluctuations in mood, all of which can be objectively measured. In this case, these disturbances, which are associated with depression, can, contrary to our first example (perceived slow passing of time), be used to define depression.

These disturbances can also be used to define a novel therapeutic approach, which by resetting the internal biological clock restores circadian rhythms, thereby leading to clinically demonstrable efficacy on depression symptoms. This is what agomelatine—released in 2009 in Europe for the treatment of depression—does, through its action on the melatonergic MT₁ and MT₂ receptors, and the 5-HT_2C receptors.

Beyond these « transversal » time-related symptoms, there are the « longitudinal » time-related symptoms, since depression evolves over a long period of time, with a profound impact on a person’s life, and is often associated with long-term psychosocial consequences. Taking this idea one step further, if we symbolize the whole of a person’s life by a line, there are sections along this timeline at which a person is more prone to the risk of developing depression than others, some common to all, like higher age, others depending on each individual’s lifetime events: psychological trauma, a succession of traumas, shortly before or after giving birth, following the onset of menopause, or in the wake of somatic diseases such as diabetes or cancer.

Time also plays a role before depression has been formally identified as such. In spite of the availability of adequate health care systems in many parts of the world, the time between the occurrence of the first depressive symptoms and diagnosis is often considerable. Time also is an issue after diagnosis, when the patient is under treatment, because the time-toonset of improvement in symptoms is dependent on a latency period that is usually of 4 to 6 weeks before improvement is reported, and this in spite of the fact that pharmacological and psychosocial treatments are constantly improving, and display increasing efficacy and safety. Nowadays, fast onset of action has become a key performance indicator for antidepressants—both in terms of patient expectations, as well as being a goal of research to develop new agents with more rapid onset of action. This also has obvious major health economics implications: the STAR*D trial (Sequenced Treatment Alternatives to Relieve Depression) showed that early symptomatic relief is a positive predictor of remission. Improving the efficacy of treatment will consequently alleviate the burden of depression over time, both for the individual and for society.

In addition to the “two-dimensional relationship” between time and depression, as described above, some authors, like de Leval,⁴ have attempted to develop a “three-dimensional approach” involving time, depression, and quality of life. In his model, de Leval describes the dislocated temporal horizon of the depressed patient, who experiences time as passing more slowly, the present as being dissociated from the past, and who no longer recognizes the potential of the future, but views it with hopelessness. For depressed patients, the past increasingly becomes a “golden age” when life was better than now. These patients would like to go back to their past in a quest that becomes their only future. De Leval postulates a “phenomenological depression” related to the perception of a gap between a healthy past and the present illbeing. “The greater the gap between past and present, the greater the phenomenological-depression.” In de Leval’s theory, quality of life is perceived as the gap between actual experience and future aspirations and is defined as being “the appropriateness of future aspirations to the present” or “the making present of the future.”⁵

The impact of depression on quality of life becomes even clearer when one tries to quantify quality of life. Years Lost to Disability (YLD) is a measure of the equivalent years of healthy life lost through time spent in states of less than full health, and thus statistically quantifies decreased quality of life through the amount of time lost.When all the years of life with reduced capability are added up for all sufferers of an individual condition and weighted according to the condition’s particular “disability weight,” a total of YLD is obtained for the condition.

In this issue of Medicographia, several renowned authors elucidate these concepts and aspects of time as a relevant entity in depression, approaching them from several angles:
◆ The temporal characteristics of depression from the epidemiological perspective are the topic of the contribution by H. U. Wittchen and S. Uhmann, who describe aspects and risk factors of depression pathogenesis.
◆ G. M. Goodwin discusses time in the course of depression, aspects of the prediction of further episodes, and the timing and duration of treatment.
◆ P. Gorwood looks at subjective time and the perception of time by depressed patients, and the therapeutic implications.
◆ H. J. Möller, F. H. Seemüller, and M. Riedel reflect on objective aspects of time and their importance in depression, and the predicament of antidepressants with a slow onset of action when it is known that early improvement is a predictor of response and remission.
◆ G. Hajak and M. Landgrebe enlarge on the linear concept of time by exploring circadian rhythms and their role in depression, which extends beyond diurnal mood variation in depressed patients.
◆ The bridge from time to clocks will be spanned by D. Tardito, G. Racagni, and M. Popoli, who present the pharmacology of the internal clock and the regulation of circadian rhythms at the intercellular and intracellular levels.
◆ C. Muñoz describes the efficacy of Valdoxan, the first melatonergic antidepressant, at each and every time phase of the management of depression, based on the resynchronization of circadian rhythms.
◆ In the Controversial Question, a panel of experts discuss time in relation to the speed of onset of antidepressant efficacy.
◆ P. Lemoine addresses the issue of social rhythms in depression in an interview, by showing how to measure them, how their resynchronization can provide alleviation of symptoms, and how this can be achieved.
◆ S. H. Kennedy, P. Giacobbe, and S. Rizvi describe the criteria for measuring early onset of efficacy in the treatment of depression.
◆ Finally, B. Saletu, P. Anderer, and G. M. Saletu-Zyhlarz show how advanced imaging technology allows us to visualize and thus better understand the effects of antidepressants in the brain. _

References

1. Minkowski E. Lived Time: Phenomenological and Psychopathological Studies. Metzel N, trans. Evanston, IL: Northwestern University Press; 1970.
2. Straus EW. Phenomenological Psychology: Selected Papers. Eng E, trans. New York, NY: Basic Books; 1966.
3. Ghaemi SN. Feeling and time: the phenomenology of mood disorders, depressive realism, and existential psychotherapy. Schizophr Bull. 2007;33:122-130.
4. de Leval N. Quality of life and depression: symmetry concepts. Qual Life Res. 1999;8:283-291.
5. Moore M, Höfer S, McGee A, Ring L. Can the concepts of depression and quality of life be integrated using a time perspective? Health Qual Life Outcomes. 2005;3:1. doi:10.1186/1477-7525-3-1.
Keywords: time; concept; depression; onset; circadian rhythm; body clock

Le temps a toujours fait l’objet d’une attention particulière de la part des psychiatres, avec des auteurs comme Minkowski et Strauss interprétant les changements psychopathologiques de la perception du temps comme le « ralentissement ou l’inhibition du temps vécu dans la dépression »^1,2. Ce ralentissement perçu du temps est très caractéristique de la dépression, et s’accompagne d’une vision sans espoir de l’avenir, parallèlement à un cramponnement au passé. À l’opposé, les patients maniaques ressentent une accélération du temps, se concentrent principalement sur le présent, et ont tendance à négliger le passé et l’avenir, comme l’a récemment décrit Ghaemi ³.

Dans l’exploration de troubles mentaux, les cliniciens obtiennent des informations au sujet des symptômes, identifient un ou plusieurs syndromes, et sur la base de ces observations finissent par poser un diagnostic. Toutefois, cette approche semble très transversale, comme si l’état du patient était « gelé » dans le temps, alors que la dimension chronologique dynamique est essentielle dans le processus. Cette dimension est prise en compte, par exemple, par le Manuel Diagnostique et Statistique des Troubles Mentaux (Diagnostic and Statistical Manual of Mental Disorders [DSM]–IV), qui exige une durée d’au moins deux semaines pour un diagnostic de dépression, ou par la constatation de changements saisonniers dans la sévérité des symptômes.

Comme ce numéro de Medicographia le montre de façon particulièrement claire, le concept de temps joue des rôles multiples et omniprésents dans la dépression.

Le temps et la dépression sont tous deux des concepts complexes. En physique, le temps, avec l’espace, les dimensions, la masse, etc., appartiennent au groupe très « sélect » des quantités fondamentales, pour lesquelles la seule définition ne peut être que circulaire : c’est-à-dire, que le temps ne peut être défini que par le temps, une dimension par une dimension, etc. Le temps ne provient de rien d’autre que du temps, mais conduit à une grande variété de quantités qui en dérivent, par exemple, la vitesse, l’accélération, la fréquence, etc. Ainsi, le temps peut être utilisé pour définir la vitesse, mais la réciproque n’est pas vraie.

Si nous examinons la notion de temps dans la dépression, nous constatons que le temps peut être utilisé pour définir la dépression dans certains cas, mais pas dans tous. Il devient de plus en plus clair que la fonction normale du temps est « perdue » dans la dépression, d’où le titre de couverture de ce numéro de Medicographia : « À la recherche du temps perdu », emprunté au chef-d’oeuvre de Marcel Proust. L’altération la plus évidente concerne la perception subjective du temps, qui, chez la plupart des patients souffrant de dépression, est ressenti comme s’écoulant plus lentement. Toutefois, il s’agit d’une perception qu’il très est difficile de différencier de la perception subjective normale du temps, et qui varie largement en fonction du contexte social, de l’attention et de la vigilance, et de l’humeur. Par conséquent, la manifestation subjective d’un écoulement plus lent du temps observée chez les patients dépressifs si elle dérive de la dépression (comme la vitesse dérive du temps) ne peut pas être utilisée pour définir la dépression (comme la vitesse ne peut pas être utilisée pour définir le temps).

Néanmoins, d’autres symptômes de la dépression liés au temps ont des conséquences totalement différentes. La dépression conduit à des troubles des rythmes physiologiques, qui provoquent des perturbations des cycles circadiens de sommeil et de veille et des profils de sécrétion hormonale ainsi que des fluctuations de l’humeur, autant de manifestations pouvant être objectivement mesurées. Dans ce cas, ces altérations, qui sont associées à la dépression, peuvent, contrairement à notre premier exemple (perception d’un écoulement ralenti du temps), être utilisées pour définir la dépression.

Ces troubles peuvent également être utilisés pour définir une nouvelle approche thérapeutique, qui, en ajustant l’horloge biologique interne, restaure les rythmes circadiens, apportant par conséquent une efficacité cliniquement démontrable sur les symptômes de la dépression. C’est précisément le mode d’action de l’agomélatine—commercialisée en 2009 en Europe pour le traitement de la dépression — qui s’exerce sur les récepteurs mélatoninergiques MT₁, MT₂, et les récepteurs 5-HT_2C.

Au-delà de ces symptômes « transversaux » liés au temps, il existe des symptômes « longitudinaux » liés au temps, dans la mesure où la dépression évolue sur une période prolongée, qui exercent un impact profond sur la vie de la personne, s’accompagnant souvent de conséquences psychologiques à long terme. En poussant cette idée un peu plus loin, si nous symbolisons le déroulement de la vie d’une personne par une droite, il existe certaines sections de cette ligne chronologique au cours desquelles une personne sera plus sujette au développement d’une dépression que d’autres, certaines communes à l’ensemble de la population, par exemple le vieillissement, d’autres dépendant des événements de la vie de chacun : traumatisme psychologique, succession de traumatismes, ou périodes précédant ou suivant immédiatement un accouchement, suivant le déclenchement de la ménopause ou en corrélation avec des maladies somatiques, comme le diabète ou le cancer.

Le temps joue également un rôle avant que la dépression ait été formellement identifiée en tant que telle. Malgré l’existence de systèmes de santé adéquats dans de nombreuses régions du monde, le délai entre la survenue des premiers symptômes dépressifs et le diagnostic est souvent considérable. Le temps est également un problème après le diagnostic, lorsque le patient est sous traitement, dans la mesure où le délai d’amélioration des symptômes dépend d’une période de latence qui est généralement de 4 à 6 semaines avant qu’une amélioration ne soit observée, et ceci en dépit du fait que les traitements pharmacologiques et psychologiques s’améliorent constamment et fassent preuve d’une efficacité et d’une tolérance toujours plus importantes. Aujourd’hui, un délai d’action rapide est devenu un indicateur de performance essentiel pour les antidépresseurs — à la fois comme critère répondant aux attentes des patients, mais également comme objectif de recherche pour développer de nouveaux agents possédant un délai d’action plus rapide.

Cet aspect a des conséquences médico-économiques majeures évidentes : l’étude STAR*D (Sequenced Treatment Alternatives to Relieve Depression, Alternatives Thérapeutiques Séquencées pour Soulager la Dépression) a montré qu’un soulagement symptomatique précoce constituait un facteur de prédiction positif d’une rémission. L’amélioration de l’efficacité du traitement soulagera par conséquent le fardeau de la dépression avec le temps, à la fois pour le patient, mais également pour la société.

Outre la « relation bidimensionnelle » entre le temps et la dépression, décrite ci-dessus, certains auteurs, comme de Leval ⁴, ont tenté de développer une « approche tridimensionnelle » faisant intervenir le temps, la dépression et la qualité de vie. Dans son modèle, de Leval décrit l’horizon temporel disloqué du patient déprimé, qui ressent un écoulement ralenti du temps, le présent étant dissocié du passé, et qui ne reconnaît plus les promesses du futur, mais le considère comme sans espoir. Les patients déprimés ressentent de plus en plus le passé comme un « âge d’or » au cours duquel la vie était meilleure qu’aujourd’hui. Ces patients souhaiteraient revenir dans leur passé et se livrent à une quête qui devient leur unique futur.

De Leval postule une « dépression phénoménologique » liée à la perception d’un décalage entre un passé heureux et un présent douloureux. « Plus le fossé entre le passé et le présent est important, plus la dépression phénoménologique est profonde ». Dans la théorie de de Leval, la qualité de vie est perçue comme le décalage qui sépare l’expérience actuelle des aspirations futures, et elle est définie comme « l’adéquation entre les aspirations futures et le présent » ou « la réalisation du futur dans le présent »⁵.

L’impact de la dépression sur la qualité de vie devient encore plus clair lorsque l’on essaie de quantifier la qualité de vie. Les « années perdues pour cause d’incapacité » (AVI) constituent une mesure de l’équivalent en années de vie saine perdues pendant la période au cours de laquelle la santé était diminuée, et permettent de quantifier de manière statistique la diminution de la qualité de vie par la quantité de temps perdue. La somme de toutes les années de vie caractérisées par une diminution des capacités pour toutes les personnes souffrant d’une affection particulière, pondérées selon la « pondération d’incapacité » particulière de la pathologie, permet de définir un total d’AVI pour cette maladie.

Dans ce numéro de Medicographia, plusieurs auteurs renommés explorent ces concepts et ces aspects liés au temps en tant qu’entité significative dans la dépression, et les abordent sous différents angles :
◆ Les caractéristiques temporelles de la dépression selon une perspective épidémiologique constituent le sujet de la contribution de H. U.Wittchen et S. Uhmann, qui décrivent les aspects et les facteurs de risque de la pathogenèse de la dépression.
◆ G. M. Goodwin aborde le sujet du temps au cours du déroulement de la dépression, les aspects concernant la prédiction de futurs épisodes, ainsi que le moment et la durée du traitement.
◆ P. Gorwood examine le temps subjectif et la perception du temps chez les patients déprimés, ainsi que leurs conséquences thérapeutiques.
◆ H. J. Möller, F. H. Seemüller et M. Riedel réfléchissent sur les aspects objectifs du temps et leur importance dans la dépression, mais également sur le problème posé par les antidépresseurs dont le délai d’action est lent, alors qu’il est établi qu’une amélioration précoce constitue un facteur de prédiction de réponse et de rémission.
◆ G. Hajak et M. Landgrebe développent le concept linéaire du temps en explorant les rythmes circadiens et leur rôle dans la dépression, qui va au-delà de la variation d’humeur diurne observée chez les patients déprimés.
◆ Le pont entre le temps et les horloges sera jeté par D. Tardito, G. Racagni et M. Popoli, qui présentent la pharmacologie de l’horloge interne et la régulation des rythmes circadiens au niveau intercellulaire et intracellulaire.
◆ C. Muñoz décrit l’efficacité de Valdoxan, le premier antidépresseur mélatoninergique, à chacune des phases de la prise en charge de la dépression et sur leur ensemble, en se basant sur la resynchronisation des rythmes circadiens.
◆ Dans la section « Question à Controverse », un groupe d’experts discutent du temps sous l’angle de la rapidité du délai d’apparition de l’efficacité des antidépresseurs.
◆ P. Lemoine aborde le problème des rythmes sociaux dans la dépression au cours d’une interview, en montrant comment les mesurer, comment leur resynchronisation peut apporter un soulagement des symptômes, et comment cet objectif peut être atteint.
◆ S. H. Kennedy, P. Giacobbe et S. Rizvi décrivent les critères de mesure d’un délai d’apparition rapide de l’efficacité dans le traitement de la dépression.
◆ Enfin, B. Saletu, P. Anderer et G. M. Saletu-Zyhlarz montrent comment les progrès de l’imagerie médicale nous permettent de visualiser, et par conséquent demieux comprendre, les effets des antidépresseurs sur le cerveau. _

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Hans-Ulrich WITTCHEN, PhD
Stefan UHMANN, Dipl Psych
Institute of Clinical Psychology
and Psychotherapy
Dresden, GERMANY

A number of the characteristics of depression are known to vary over time. A full and comprehensive epidemiological characterization of the temporal characteristics of depression is, however, lacking. In this paper, we discuss the methodological challenges and provide a selective review of recent epidemiological evidence covering the following issues: (i) prevalence of major depression by age and gender; (ii) patterns of incidence by age of onset and birth cohort; and (iii) number and duration of major depressive episodes. We also discuss vulnerability and risk factors influencing the temporal characteristics of depression, and comment on cohort trend findings that suggest that there has been an increase in the rate of depression over time. One can conclude that despite the relatively stable pathoplastic structure of depression, there is epidemiological evidence of considerable variability in the onset, episode frequency, and duration of depression over the lifespan. An early onset in youth is associated with a greater frequency of depressive episodes of mostly shorter duration compared with depression with an older age of onset. Depression in old age is associated with considerably greater persistence, as indicated by high proportions of long episodes (>51 weeks) and chronicity. We also confirm the existence of substantial birth cohort effects, and a shift of first onset of depression to a younger age. Overall, this suggests that the rates of major depressive disorders are increasing.

Several salient characteristics of depression vary over time. This is reflected, for example, in the typically episodic nature of major depression and the relevance of biological rhythms in its etiology (manifest, for example, as sleep pattern disturbance), but also in our heavy reliance on the characteristic duration and persistence of depressive symptoms in the differential diagnosis and when separating clinical depression from normal mood variations. The importance of temporal issues is also evident when considering the incidence patterns of depression over the lifespan of males and females, and the associated variation in terms of number and length of episodes and risk factors. Despite numerous epidemiological studies, our current understanding about the timing of depression remains fragmented and incomplete.

Figure 1. Point (1-month), 12-month, and lifetime estimates for
major depressive disorder in community surveys of the European
Union. Based on data from reference 14.

Several critical issues can be held responsible for this deficit: (i) few studies have ever attempted a comprehensive epidemiological characterization of depression across the lifespan, including number and duration of episodes; (ii) temporal aspects are mostly studied in isolation, and interactions with developmental risk factors are rarely addressed; (iii) methodological factors, such as reliance on retrospective cross-sectional studies, sampling, age group composition and power, differences in diagnostic assessment tools used, and other factors (somatic factors, secular trends, etc) make the aggregation of findings difficult; (iv) the determination of age of onset and number and duration of episodes depends on retrospective accounts from patients, which are subject to recall bias, current mood state, other comorbid conditions, as well as birth cohort effects^1-6; (v) the interpretation of depression findings is further complicated by the possibility that secular trends might exist^7-10: that is, younger birth cohorts might have a substantially higher risk of experiencing depressive episodes and suffering from depression at an earlier age than older birth cohorts. This could be relevant, because an early onset of depressive disorders has been shown to be a risk factor for more frequent and longer episodes¹¹; and (vi) there is no general agreed strategy on how to define the onset and offset of episodes.¹² From a broader dimensional view, critical questions arise, such as: should onset be defined as the point in time at which all diagnostic criteria for a particular depressive disorder are met, or should subthreshold expressions that might precede or follow the episode—when dealing with duration—also be taken into account? And if yes, how much symptomatology would be regarded as sufficient? Because of the substantially greater difficulties with such broader concepts, this article will concentrate mainly on major depression and major depressive episodes (MDE), for which firmer evidence is available.

Against these mostly methodological caveats, we will provide a selective review of recent epidemiological evidence covering the following issues: (i) lifetime and current estimates for major depression by age group and gender; (ii) patterns of incidence by age of onset and birth cohort; and (iii) characteristics of duration and course. Furthermore, we will discuss vulnerability and risk factors influencing the temporal characteristics, and comment on cohort trend findings.

Lifetime and current estimates of major depression

_ How frequently does depression occur over the lifespan?
An abundance of epidemiological research^13-15 over the past decades throughout the world10,16 has provided evidence that depressive disorders and major depression are much more frequent than was thought in the early 1980s and before. Believed to be relatively rare disorders with cross-sectional rates of 1%-2% and lifetime rates of 4%-5% in the pre-Diagnostic and Statistical Manual of Mental Disorders (DSM)-III studies, increasing and substantial evidence from most studies in the 1990s suggested that major depression and MDE are in fact much more frequent, especially when considering rates of 12-month and lifetime depression. Figure 1 clarifies the different time period references for these rates, ranging from point prevalence (1 month) to lifetime risk.¹⁴

In a previous review,¹⁰ Wittchen et al reported a median point prevalence of major depressive disorder from studies up to the early 1990s of 3.1 (1.5-4.9), a median rate of 6.5% (2.6%- 9.8%) for 6-month and 1-year prevalence, and 16.1% (4.4%- 18%) for lifetime rates in the community. These data also suggest that we can estimate that up to a high age, the “true” rate of major depression is likely to be above 21%. The differences between fairly low point and high lifetime rates also underline that major depression is an episodic disorder. It is noteworthy that these estimates are conservative, because subthreshold (prodromal or residual) and successfully-treated depressive patients are not considered! This review also explained the higher estimates in more recent studies, which use increasingly more sophisticated depression assessment methodologies that probe more intensively for the presence particularly of past episodes and the existence of cohort effects. Cohort effects suggest that depression rates have been increasing over the last decades due to increasingly higher rates in more recent birth cohorts compared with older cohorts.

Figure 2. Lifetime (A) and 12-month (B) prevalence estimates for major depressive episode by age group and gender, according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition/Composite International Diagnostic Interview. Based on data from reference 5.

_ Depression rates and age of onset
Concentrating on MDE in adults (18-65+ years of age), the most recent US National Comorbidity Survey-Replication (NCS-R)⁵ found—by and large consistent with the most recent studies in the European Union¹⁴—that the lifetime prevalence of MDE is 22.9% in females and 15.1% in males (Figure 2A).

Rates are highest in the age group 35-49 (females 26.7%, males 18.6%), and are dramatically lower among subjects aged 65+ (females 13.0%, males 5.3%). Interestingly, the youngest age group reveals onlymarginally lower lifetime rates compared with the older groups. 12-month prevalence rates (Figure 2B) are about half the rates for lifetime, revealing similar patterns for age and gender. These findings are counterintuitive at first sight: first, there are high rates even among the youngest age group and there is only a small difference with regard to the age group 35-49, typically assumed to be the high-risk phase and the age group mostly frequently seen in inpatient and outpatient settings. Second, the considerably lower lifetime rates in the elderly appear to be inconsistent with the perception that rates of depression in the elderly should be higher, and not lower, because of their considerably longer time period at risk formajor depressive disorder, and because of other factors (see later).

_ High prevalence and incidence risk in childhood and adolescence?
Carefully conducted prospective longitudinal studies^17-21 all come to the same conclusion: major depressive disorder and MDE, although rare in children (age <10 years) of both sexes, are already quite prevalent in adolescence, a time period during which the gender difference becomes apparent. Figure 3 displays this gender differentiation using data from birth to the mid 30s from the prospective-multiwave Early Developmental Stages of Psychopathology (EDSP) study. The curves reveal a higher estimated cumulative incidence (35.6%) for first onset in females at age 33 years than for males (23.1%). Most cases with MDE emerged between the ages of 12 and 25 years, with a significant gender difference apparent at around age 14 years. Both males and females showed continued new onsets of MDE after the age of 25 years, suggesting continued, though attenuated, incidence rates over the lifespan. The consistent evidence of high depression rates in adolescence and young adulthood, along with similar or even stronger evidence for substantial impairment, disability, and treatment rates associated with young age depression,^5,21,22 leaves little doubt that the high community estimates in the young describe clinically meaningful depression.

Figure 3. Age of onset hazard ratios for major
depressive episode (MDE) in males and females.

Figure 4.
Resilience
model for
depression
over the
human
lifespan.

_ Low rates in the elderly?
The substantially lower rates for the elderly are puzzling and have prompted the search for reasons for this finding. Initially, research suggested that the diagnostic instruments were not valid and were inappropriate for older adults,² with authors suggesting a series of modifications in order to account for different response styles in the elderly. However, these adaptations did not result in substantial increases in subsequent estimations. Kessler et al5 also excluded the possibility that recall failure accounts for the difference, by showing that the estimate ratio for subjects aged 65+ is lower for both 30-day and 12-month estimates (31%-32%) than for lifetime prevalence. This gradient suggests that recall error is not responsible for the lower prevalence among the elderly. Recall error, as suggested by Simon and vonKorff,23 would produce an opposite pattern. Related observations are that: the ratio of 12- month prevalence to lifetime prevalence is consistently lower among respondents aged 65+ (22%-28%) than in younger respondents (37%-57%), depression in the elderly is more frequently “clinically mild” (21.8% vs 8.2% in 18-34 year olds, 6.8% in 35-49 year olds, and 10.3% in 50-64 year olds), and is associated with a significantly lower degree of severe role impairment and a lower number of days out of social role because of depression. Consistent with some previous research,^24,25 these findings suggest that community rates of major depressive disorder and MDE in the elderly, as defined by DSM-IV criteria, are indeed considerably lower than in the younger age cohorts.

Several explanations have been suggested for this finding, such as: (i) the existence of cohort effects; (ii) a different phenomenological presentation of depression in the elderly requiring possibly a modified set of criteria; (iii) disproportionably high (as compared with younger age groups) exclusion rates of severely ill older subjects suffering from somatic and neurological and neurodegenerative diseases; and (iv) increased resilience of older people that protects them against severe depression (Figure 4).

_ Phenomenology
Depression in old age differs both in subtle and obvious ways from depression earlier in the lifespan. Presentation, etiology, risk, and protective factors all reflect aspects of the older adult’s position in the lifespan. Further, there is some consensus that late-onset depression in old age has distinctly different risk factors (eg, increased rates of vascular, including cerebrovascular, disorders)²⁷ and presentation (eg, decreased rates of cognitive-affective symptoms of depression and increased sleep disturbance)²⁸ than earlier-onset depression. In this context, a number of old age depression variants have been suggested: for example, “vascular depression executive dysfunction syndrome,”²⁹ “depression without sadness” or “depletion syndrome,”^30,31 Parkinson’s Disease Depression,³² or Alzheimer’s Disease Depression.³³ Yet none of these concepts has received wider acceptance. Furthermore, there is little evidence from psychometric explorations that the structure of depression in the elderly is overall significantly different from that seen in younger age groups.³⁴

_ Exclusion of severely comorbid patients
Undoubtedly, rates of major depression among older subjects are substantially higher in particular high-risk subsets of the population, such as those requiring intensive medical attention, including inpatient and residential treatment. For example, epidemiological studies in Parkinson’s disease patients report amean prevalence of at least 17%³⁵ and up to 25.2%.³⁶ Similarly elevated rates have been reported for Alzheimer’s dementia patients,37 patients with stroke and coronary heart disease,38,39 and residents of long-term care facilities (14%- 42%).^34,40,41 Thus, one might speculate that the lower rates in the elderly could be due to the exclusion of such high-risk populations in epidemiological “door to door” surveys. However, given the prevalence of these conditions, it is unlikely that this factor alone can account for the difference. Furthermore, the recent World Mental Health Survey found no indication that the increased burden of pain and somatic diseases in the elderly is associated with corresponding increases in depression status.¹⁶ The majority of older people in this analysis had chronic physical or pain conditions without comorbid mental disorders and depression in particular. Yet it remains unclear as to how these findings match the well-established finding that pain and chronic somatic conditions can be risk factors for depression, and the significant relationship between increased rates of depression and somatic syndromes—in particular, increasing rates as a function of number of multimorbid somatic diseases.^42,43

_ Increased resilience
Since most older adults experience disability, pain, and bereavement and have agerelated changes in immune, neurological, and other biological systems, there has been some research into resilience factors that might explain why the elderly less frequently report experiencing depression. As summarized by Fiske et al²⁶ and Hendrie et al,⁴⁴ three groups of explanations have been suggested as representing depression buffers (Figure 4): (i) the perceived importance of resources like socioeconomic status, remaining cognitive function, and health; (ii) life experiences that have taught older adults psychological strategies and ways to use social support and manage the stress; and (iii) the role of meaningful engagement, whether in social activities, volunteer work, or religion.

To conclude, none of the current explanations fully accounts for the observed low depression rates in older adults. The preponderance of current evidence indicates that at least major depressive disorder is less common in old age, while clinically significant subthreshold depression, which can also be consequential and is treatable,⁴⁵ might be quite common.

Number of episodes and duration

With very few exceptions,^5,46-49 most studiesmerely report rates of MDE by age group, but do not specify frequency and duration. Thus, even the proportion of single versus recurrent episodes, or chronic versus episodic depression, remains frequently unreported.

Figure 5. Birth (current age) cohort effect for estimates of major depressive episode
in the general population. Based on data from reference 50.

Kessler et al⁵ report a mean age of onset of 26.2 years for a first episode of MDE, with the lowest age of onset for 18-34 year olds (mean 17.8 years) and substantially higher ages for subsequent age groups (35-49 age group, 25.5 years; 50-64 age group, 33.1 years; 65+ age group, 43.0 years). Among cases with recurrent depression, the mean number of MDE was 18.6 overall, with the lowest number among the young (18-44 years, 15.4 episodes) and the highest for the elderly (30.2 episodes). Spijker et al48 reported a median duration of MDE of 3 months in the community. A total of 50% of the participants recovered within 3 months, 63% within 6 months, and 76% within 12 months, and nearly 20% were not recovered at 24 months. Determinants of persistence of the episode were severity of depression and comorbid dysthymia; recurrent depression typically had a shorter episode duration. This is by and large in agreement with a more fine-graded analysis50 based on a total of 736 DSM-IIIR MDE cases from the general population. Considerable birth cohort effects regarding the total cumulative MDE risk and age of onset were found (Figure 5), suggesting that the number of episodes and their duration might be different by birth cohort. Overall in this analysis, 53% reported only one episode, while 17.4% had 2-3 episodes, and 29.6% had 4 or more episodes (Figure 6A, see page 120).

The proportion of cases with one single episode of MDE declined fairly consistently from 67.9% in those with less than 10 years at risk, to 46.2% among cases with 40-50 years at risk. Conversely, the proportion of those with 2-3 episodes increased from 9.5% to 19%, and for those with 4+ episodes from 22.7% to 34.7%. This finding is in agreement with a similar analysis recently reported for patient populations by Coryell et al.⁵¹ What is remarkable though, is that the oldest group with the longest period at risk for depression also revealed a higher proportion of single episodes, suggesting a substantial number of new-onset cases in old age.

In terms of episode duration, overall, 39.6%had short episodes (2-5 weeks) and 17% had an intermediate length of 6-20 weeks (Figure 6B). The majority of cases of MDE reported an episode duration of more than 21 weeks, and chronic depres- sion (more than 51+ weeks) is strikingly frequent (32%). The proportion of long episodes (21+ weeks) increased steadily by time at risk, being lowest in those with exposure time of less than 10 years (33.5%) and highest among the elderly (exposure time 50+ years; 66.7%). Rates of episodes lasting 51+ weeks increased accordingly from 27% (<10 years) to 59% (50+ years).

Figure 6. Number of depressive episodes (A) and episode duration in weeks (B) among community cases with lifetime major depressive episode (MDE) by years at risk.

These findings suggest that in contrast to recent interpretations of clinical samples,⁵¹ there is a pathoplastic effect of age or birth cohort on the temporal expression of depression over the lifespan, with more frequent episodes of shorter duration in the young, and the elderly being characterized mainly by long episodes and chronic depression.

Factors influencing the timing of depression

_ Sociodemographic factors
Gender is the best-supported risk marker for depression.^43,52,53 The approximately twofold higher risk of women suffering from depressive disorders than men is consistent over cultures and most age groups (see Figure 2).^5,49,54,55 The 2:1 ratio develops not before puberty and cannot be observed among children before the age of 10 years.56 Attempts to explain this gender difference by psychosocial, sociodemographic,⁵⁷ or biological factors have, however, been inconclusive.⁵⁸ Recent attempts to shed light on this gender difference focus on the interaction of genetic and biological factors on the one side, and environmental and psychosocial factors on the other (see below).^53,54

Consistently, studies have found associations between higher lifetime and 12-month prevalence and one or more markers of less privileged social position, such as being unemployed or disabled, living in—or near—poverty, and having a low income. Homemakers were found to have elevated rates of 12- month, but not consistently lifetime, MDE. Being unmarried was also consistently found to be related to depressive disorders,^13,55 the risk for those having lost their partner through divorce, separation, or death of the partner sometimes being found to be even higher.¹³ The effects of marital breakdown or death of the partner appear to be stronger for men; ie, the increase in risk for a depressive disorder is more pronounced among men. This sometimes results in comparable rates of depressive disorders above 20% among men and women who are divorced, separated, or widowed.⁵⁷ No consistent associations are generally reported for different geographical areas when other confounding factors are taken into account.⁵⁹

_ Family genetic factors
There is consistent evidence from family studies that parental depression substantially increases the risk of the offspring also developing depressive episodes.^60-63 Such studies have also included examinations of the familial aggregation of recurrence risk^60,64-66 and duration of key symptoms.^61,67 Meta-analyses of family, twin, and adoption studies reveal that the risk of recurrence of major depression is the measure with strongest empirical support for familial aggregation, while evidence for duration is less convincing.⁶³ However, it should be noted that there is little diagnostic specificity. That is, familial anxiety, substance use disorder, or other mental disorders have often been found to be as important as depression or other mood disorders in predicting depression.¹³

A particularly informative community study in this respect was carried out by Lieb et al,⁶⁸ who prospectively studied the longitudinal risk of depressive episodes in 3021 offspring over the first three decades of life by parental mental disorder status, assessed by independent diagnostic interviews. Offspring of depressed mothers (odds ratio, 2.9) and depressed fathers (odds ratio, 3.0) were at substantially increased risk of also developing depression up to age 28. The effects were more pronounced when both parents had suffered a lifetime episode of depression and were also elevated in comorbid anxiety disorders. Particularly noteworthy was the finding that parental depression shifts the age of onset of depression in childhood significantly forward. Furthermore, affected offspring had an increased risk of recurrent episodes (among those with nonaffected parents the mean number of recurrent episodes was 2.7, among those with affected parents it was 5.2; odds ratio, 1.8), and persistent depression (9 weeks versus 30 weeks; odds ratio, 4.5).⁶⁹

_ Childhood and developmental adversities, life events and disasters
Retrospective assessment in cross-sectional studies has shown that childhood adversities, including traumatic events, are significant predictors of an increased prevalence of depression and earlier age of onset. Intercorrelations between different types of childhood adversities make it difficult to pinpoint any particularly important type of adversity.¹³ More recent prospective longitudinal studies have also highlighted the particular caution that is warranted if using only retrospective designs.⁷⁰ By comparison with childhood adversities, more specificity has been found in the effects of stressful life events and their relationship to depression.⁴³ Stressors involving loss are more strongly related to depression, while stressors involving threat and danger are more strongly associated with anxiety, and stressors involving both a combination of danger and loss are related to comorbid presentations and higher levels of persistence.^52,71,72 There are also important associations with lack of social support⁷³ as well as familial and genetic elements.⁶³ The effects of life events in women seem to be slightlymore pronounced than inmen across all ages,^74,75 suggesting one potential reason for the gender difference in prevalence. The relationship between life events and first onset⁷⁶ and remission^77,78 appears to be stronger than for successive recurrent episodes, which seem to be less dependent on external triggers.⁷⁹ These findings, however, might be dependent on the type of life event or stress assessed; chronic stress seems to be more relevant for the first episode, and acute stress and an interaction of chronic and acute stress⁸⁰ might foster recurrent episodes.⁸¹ The complex interplay with neurobiological factors in this respect has been recently highlighted by Caspi et al,⁸² Moffit et al,⁸³ and Zimmermann,⁸⁴ revealing that adverse events are particularly pathogenic in individuals with genetic or familial genetic susceptibility.

Adverse events and chronic life difficulties have also been suggested as an explanation for sociodemographic associations between depression and socially disadvantaged groups, who might have fewer resources to cope with stressful situations. Recently, Kessler et al presented an impressive example of the effect of life events on the risk for mental disorders, and the temporal pattern,⁸⁵ in a representative sample of prehurricane residents involved in Hurricane Katrina. Contrary to results from other disaster studies in which psychiatric morbidity has typically declined with time, substantial increases in post traumatic stress disorder (14.9% to 20.9%) as well as depressive disorders (10.9% to 14%) over a 2-year observation time were found. Unresolved hurricanerelated stresses accounted for large proportions of the intertemporal increases in depression (89.2%).

_ Effects of cormorbid conditions
_ Mental disorders
The effect of all anxiety disorders^86,87 on the onset and course of depression has been well established through cross-sectional^{88- 94} and prospective longitudinal investigations,^86,95-97 as well as through clinical studies.^98,99 Studies in adolescents and young adults are particularly informative, because this is the high-risk incidence phase for anxiety disorders. Such studies^95,100 have demonstrated the substantially and consistently increased risk of subsequent depression, as well as a moremalignant course and character of secondary depression.

With some variation according to type of anxiety disorder, up to 50% of all subjects (Figure 7A, page 122) with a primary anxiety disorder have been shown to develop depression, constituting a threefold increased risk of depression. Furthermore, a considerable shift forward in the age of onset of the first episode of depression has been found (see Figure 7B), so that depression occurs earlier. These findings suggest etiologic links between these two types of disorders. Similar, though less consistent, data have also been found for other mental disorders (eg, somatoform disorders,¹⁰¹ substance use disorders¹⁰²).

_ Somatic comorbidity
Community studies¹⁰³ show a close relationship between major depression and physical illness. Evidence for the possibly bidirectional influence of somatic and mental disorders has been provided for such diverse conditions as acute coronary syndromes and depression,¹⁰⁴ as well as “disorders of the female reproductive cycle”^105-109 for example. Among adults, particularly strong associations were found between chronic disorders and increased risk for MDE, particularly if the disorders involved pain and suffering or major long-lasting restrictions or disability ormultimorbidity.⁴² Chronic diseases and poor general health were particularly predictive of new depressive episodes over a period of 1 year.¹¹⁰ It should be noted though that the relationship is apparently quite complex, since there is no consistent linear relationship between the degree of somatic morbidity and the risk of depression, nor a consistent relationship with aging,⁵ suggesting that there are also interactions with environmental and biological factors at play.¹¹¹ Because of the complexity of multimorbid presentations, there is still insufficient knowledge and data to identify causal relationships and risk factors.¹¹²

Figure 7.
A. The risk from
primary pure
anxiety disorders
for development
of a secondary
depressive
episode over a
period of 10
years, by type of
anxiety disorder.
B. The risk of a
major depressive
episode (MDE)
according to age
of onset of MDE,
in those with and
without a primary
anxiety disorder.
GAD,

Age cohort effects: are depression rates increasing?

Given the topic “the timing of depression,” it is almost inevitable that finally one should address the controversial question of whether depression rates are increasing. Examination of the epidemiological evidence leaves little doubt: almost invariably across studies, using a range of different methods, higher overall rates of depression have been documented over time as well as successively younger birth cohorts. Particularly increasing rates in the young have been found, which are associated with a shift forward to younger ages in each successively younger age group. Furthermore, despite proportionally lower rates for the elderly, there is also evidence from recent studies that rates of depression in the elderly are higher compared with those of the 1980s. Thus, why question this trend? At the core of this continued controversy is the question of whether this constitutes a “true” increase, that is, have people in communities around the world “really” become more frequently depressed than 2-3 decades ago? This is almost a philosophical question, because we deal with a theoretical construct measured with imperfect assessment instruments, in studies that are necessarily imperfect as well. Because our understanding of depression, the defining criteria, and our assessment instruments have changed, as has probably the awareness and perception of depression in society, it seems impossible to give a definite answer. Admittedly the meaning of the increasing rates and the cohort effects remain not well understood, and there are other valid concerns that range from methodological concerns regarding the reliability and validity of diagnostic criteria and assessment tools used in the studies, to design and statistical issues inherent in time trend analyses, to speculations about the artifactual nature of such findings, for example with regard to the role of recall failure, response biases, and willingness to report depressive symptoms. However, most of these issues have directly or indirectly been addressed,^5,25,113 revealing that none of these factors alone or in combination is able to explain the increase and the cohort effects.

Furthermore, the demonstration of increasing rates is consistent with a broad range of external indicators, such as increased rates of depression in mental health care and primary care institutions, substantially higher rates of children and adolescents receiving treatment, increased rates of suicide attempts, and substantially increasing disability burden due to depression.¹⁴ Assuming that such cohort effects and increases exist, there are tremendous implications for the future. For example, the higher rates and the shift to an earlier age of onset in younger birth cohorts can be expected to be associated with an increasing risk for recurrent episodes and increasingly longer and chronic episodes over the lifespan. In addition, given the continued increase in life expectancy in most countries, one can anticipate a continued high—and even increasing—global societal burden, and a substantial challenge for the mental health field. _

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Keywords: depression; age of onset; disease course; risk factor; development; prevalence; rate

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Guy M. GOODWIN, FMedSci
Department of Psychiatry
University of Oxford
Warneford Hospital
Oxford, UK

Time is an important defining feature in the diagnosis of major depression, its prognosis, and its tendency to recur over a lifetime. Major depression is conventionally defined as a collection of depressive symptoms present together for at least 2 weeks. The longer symptoms have been present and unremitting, the more confident one becomes of any diagnosis of major depression, and the greater the impact the depression is likely to have on personal, psychological, and social function. Depression lasting many months is more difficult to treat. The phases of treatment were established by consensus definition about 20 years ago. Response is defined as a 50% reduction in symptoms from baseline, followed by a continuing reduction in symptoms to a point defined as remission (usually a fixed point on a rating scale like the Hamilton Rating Scale for Depression). From remission, it is conventional to describe the treatment phase as “continuation” for the next 8 weeks, and “maintenance” after that point. The neurobiology that underpins the subsequent risk of recurrence is only now emerging. Acute treatment is now covered by many clinical guidelines, the most challenging problem being the next step after failure of an initial antidepressant. Continuation is that phase following remission when treatment should always be continued and further reduction of symptoms hopefully seen. Maintenance is continuation of treatment beyond full recovery to a phase in which the treatment is conceptualized as preventing new episodes of illness in the longer term. Its duration may be indefinite, but most guidelines recommend at least 6 months.

It can be argued that major depression is important because of the time it steals from people’s lives and the disability or burden of disease that it therefore imparts. The appearance, disappearance, and recurrence of depression occupy a central position in defining the disorder. Accordingly, the domain of time is central in the diagnosis of major depression, its prognosis, and its tendency to recur often over a lifetime.

The very long time constants that seem to be involved in the condition are still poorly understood, but they clearly have implications for our understanding of the neurobiology and finally for the treatment strategies that we currently adopt in trying to overcome individual episodes of depression. These aspects of time and depression will be the focus of this article.

Diagnosis

Major depression is conventionally defined as a collection of depressive symptoms, which, according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR), must have been present together for at least 2 weeks.¹ The choice of a 2-week cut-off is obviously arbitrary, and if a constellation of depressive symptoms is present for only 2 weeks, such an episode is likely to be of limited clinical significance. Indeed, broadly speaking, the longer symptoms have been present and unremitting, the more confident one becomes of any diagnosis ofmajor depression, the greater the impact it is likely to have on personal, psychological, and social function, and the more important treatment success becomes. It also turns out that the length of time during which an individual has been depressed is a predictor of subsequent outcome. Thus, in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the duration of illness was an independent predictor of failure to respond to treatment in a large population (over 3000) of index cases of major depression, all treated systematically with citalopram.² The STAR*D finding echoes those from other studies showing that the duration of illness may well have an impact that is both statistically and clinically significant. However, the duration of illness that makes this impact is months rather than weeks. Hence the DSM-IV-TR definition of major depression is a relatively liberal one. It is durations of illness of up to 2 years that seem to have the most major impact in lowering subsequent rates of response to acute treatment.

The natural history of a depressive episode in the general population is recovery: symptoms remit, the subjective burden of depression disappears, and objective wellbeing eventually returns. The definition of the phases of this response rests on principles that were established by consensus about 20 years ago.³ The conventional terms and the time course that they describe are shown in Figure 1. The acute phase of depression is seen as requiring some form of acute treatment. For reasons of space, the episode is shown schematically as having a very recent onset, although in practice this is a little unlikely, as will be clear from the preceding discussion. Treatment will hopefully facilitate early response, which is often defined as a 50% reduction in symptoms (the point where the solid line in Figure 1 crosses the broken axis). Response rates allow comparisons between different early acute treatments. Response is followed by a continuing reduction of symptoms to a point defined as remission (usually a level of symptoms defined by a fixed point on a rating scale like the Hamilton Rating Scale for Depression [HAM-D]). However, remission takes time, and many acute placebo-controlled studies are kept short to enhance patient retention.

Figure 1. Definitions used in unipolar depression.

Response rates have significant limitations if one wishes to extrapolate research findings to expected clinical benefits. It has been argued more recently that remission is the key objective, and should thus be the primary outcome in shortterm treatment studies.⁴

“Time course” is a term used in defining other terms relating to the phases of treatment and the nature of any return of symptoms. From the point when a patient reaches remission, it is conventional to describe the treatment phase as “continuation” for the next 8 weeks, and “maintenance” after that point. Continuation is the phase following remission when treatment should always be continued and further reduction in symptoms should hopefully be seen. Maintenance is continuation of treatment beyond full recovery to a phase in which the treatment is conceptualized as preventing new episodes of illness in the longer term. Its duration may be indefinite, but most guidelines recommend at least 6 months.

Symptoms returning within the acute and continuation phases are described as relapse (of the original index episode), and those occurring after recovery (in the maintenance phase) are defined as a recurrence (and notionally as the appearance of a new episode). These ideas imply that there is some- thing unitary about a depressive episode, and that once it has gone away, the patient moves into a different state of risk and perhaps a different state of neurobiology. Thus, in effect, the treatment of a single episode can be thought of as taking place within a finite period of time. Whether this is actually true is not yet known, and indeed it is doubtful as to whether we yet have the measures that would necessarily allow us to know whether it is true. However, it is a potent hypothesis and a useful one. While it is now enshrined in our terminology, as shown, we should regard it as provisional, seek better understanding of what actually determines patterns of symptom response and remission, and be prepared to change our terminology if it does not correspond to the facts.

Prognosis and recurrence

Repeated episodes of illness are frequently similar clinically, but they show potentially different temporal patterns. Longterm study of severe episodes of depression requiring admission to hospital has shown that patients with unipolar depression tend to have characteristic rates of relapse, with rather different probabilities of recurrence after repeated episodes such that the probability of further illness is increased with each successive episode (see Figure 2). In unipolar disorder, the times to re-admission to hospital tend to be longer than for bipolar patients in the same clinical population.⁵ Although beyond the scope of this article, the differences (and similarities) between bipolar and unipolar depression are of great current interest.⁶

Figure 2. Time to recurrence of major depressive disorder as a function of number
of previous depressive episodes.

The process whereby an individual first episode is triggered and subsequent episodes develop remains of great interest. Most first episodes tend to be preceded by a set of identifiable risk factors. Those that confer vulnerability relate to family history of depression, personality (anxious worrying/high neuroticism), female gender, and/or early abuse and neglect. These factors seem to be translated into depressive episodes by themoderating effect of adversity, either in the formof acute life events or chronic difficulties in the face of which patients may develop episodes of clinical depression.⁷ The excess of depressive episodes usually reported in women was associated in a study by Kendler et al with depressive episodes in the context of low stress, but this finding requires confirmation. Most available twin data comes from women, although a parallel series of studies is also emerging for men.⁸ There are minor differences and, in particular, the genetic overlap between neuroticism and major depression in men may be greater than in women.⁹ However, there is broad convergence in the apparent causes of major depression between both sexes.

The pattern in women is best established for first episodes of depression, for which life events that apparently “trigger” the episode are a relatively common observation. They become less obvious for recurrence in individual patients, suggesting that in some sense, patients become primed to depression and therefore more likely to develop an endogenous pattern of illness as time goes by.¹⁰ Expressed another way, with recurrent episodes of major depression, the role of environmental stressors progressively diminishes. Proving that this occurs and determining its naturalistic properties requires control of a variety of confounding factors and has been best addressed in female twins. With increasing numbers of previous episodes (up to approximately 10 episodes), the association between life events and new depressive episodes fell approximately linearly. More than 10 previous episodes had little additional impact.¹⁰

The nature of this process—sometimes described as kindling—is poorly understood. It has been suggested that differences between individuals with high and low genetic loading may be that to be highly loaded means to start with a greater degree of priming for the onset of a first depressive episode. Whether a priming or kindling effect is a useful heuristic idea will depend upon developments in our understanding through neurobiological studies. In young people with a family history of depression but no personal history of a depressive episode, there is evidence of increased cortisol secretion and impaired modulation of the anterior cingulate cortex in response to emotionally valenced stimuli.^11,12 There is also evidence that rather similar emotional biases can be detected in those with high neuroticism (and no family history) when studied at an early age before any personal history of mood disorder.^13,14 However, interestingly, changes in cortisol secretion appear to be confined to subjects with a family history of depression at that age.

Figure 3.
Summary of
the UK National
Institute For
Health and Clinical
Excellence
Stepped Care
model for depression
treatment.

There is also evidence that patients who have had an episode of depression and who have fully recovered show abnormalities in their underlying neurobiology. The most impressive demonstration, which links mood regulation directly to serotonin metabolism, is the precipitation in a matter of hours of a depressive syndrome as a result of tryptophan depletion.¹⁵ Such patients with a previous history of depression can also be challenged with a less severe depletion of tryptophan.¹⁶ Under these circumstances, there is no recurrence of any depressive symptoms, but there are differential effects on cognitive function compared with age-matched controls, with differential effects in the patient group for the amplitude of startle responses, episodic memory, and recognition of happy facial expressions. These changes suggest a dysregulation in emotional processing and memory function following acute reduction in serotonin function. These changes could represent the pathways in mood dysregulation per se. They were not, in this case, sufficient to cause a mood change.

While implicating serotonin directly, these findings do not of course exclude a contribution from other neurotransmitter systems in mediating different components of the depressive syndrome that remain incompletely understood. Reduced neural processing of positive primary consummatory cues (eg, chocolate) is also attenuated in recovered depressed patients and may implicate dopamine.¹⁷ Abnormalities of the circadian system may be yet more complex.

Major depression is a recurrent disorder, and over a period of many years may have a major impact on the lives of individuals simply by virtue of the impact of chronic or recurrent symptoms, which are socially and personally incapacitating. However, in addition, it is now understood that depression has an impact on simple memory performance, which is also potentially cumulative with episode recurrence and may contribute to a professional disability and difficulties in employment. Cognition as an end point in the treatment of depression is a new concept, but one that seems set to assume increasing importance. The time spent depressed during multiple previous depressive episodes in the clinical history seems to be an important predictor of minor, but nevertheless significant, cognitive impairment following recovery from individual episodes.¹⁸

Treatment guidelines for single depressive episodes

As already indicated, chronicity of the depressive episode predicts reduced responsiveness. It suggests that long delays in treatment are highly undesirable. On the other hand, short delays may make rather little difference, and for that reason, the UK National Institute for Health and Clinical Excellence (NICE) guidelines have recommended that for patients with minor levels of symptoms and relatively short histories, a time of watchful waiting may allow recovery without the need for active intervention.¹⁹ How effective this approach may be has not been addressed in effectiveness studies, but is simply derived from a consideration of first principles. It may be appropriate in health care systems with relatively easy access to primary care services, but it requires clinical vigilance and not neglect.

Long-term watchful waiting is clearly not likely to be a helpful strategy, and escalation through a system of stepped care to further treatments, either with effective psychotherapy or antidepressants, is the recommendation of almost all guidelines. The recommendations from NICE are summarized in Figure 3. The particular choice of antidepressant is not dictated overwhelmingly by weight of evidence favoring one treatment over another, although on average, some antidepressants are probably more effective/well tolerated than others. Head-to-head studies can be aggregated to allow meta-analysis, and a recent study suggested that published data favors, for example, sertraline compared with reboxetine.²⁰ However, many other factors other than clinical evidence influence the first choice, from simple economics to patient preference.

_ Next step treatments after failure of an initial drug treatment
Treatment failure is not uncommon in a major depressive episode. Time is again an important determining factor in clinical decision-making. How long one should wait before failure is declared has not been established, and is perhaps always a complex clinical decision. Careful analysis of early time points in clinical trials has shown that improvement comes relatively early, and so, in principle, early decisions about treatment benefits (at 2 weeks, perhaps) may be possible.²¹ However, as with other aspects of clinical judgment in mood disorders, the greater the time that elapses, the greater the confidence in the clinical decision, and many guidelines have advocated waiting 4 or even 6 weeks before making a change. STAR*D was originally designed to guide the next treatment step after the failure of a selective serotonin reuptake inhibitor (SSRI; citalopram). Unfortunately, the randomization steps were largely subverted by planned patient preference options. There is a lack of direct evidence on the comparative efficacy of a range of next steps after initial treatment of a single episode has failed.

The treatment options are as follows (broadly taken from the British Association for Psychopharmacology [BAP] Guidelines 2008, which should be consulted for more detailed justification).²² Since there is a relative dearth of compelling evidence for one strategy over another, guidelines may produce rather different recommendations if attempts are made to concoct an algorithm to anticipate particular successive preferences. STAR*D provides an interesting example of just such an overall strategy, and it has been argued that overall response rates in the study support its use²³: in the absence of anything better, this may be worth further study.

_ Increasing the dose of the medication after initial treatment nonresponse
There may be a dose response with agomelatine, escitalopram, TCAs, or venlafaxine that merits a dose increase from the recommended starting dose, but there is little experimental support in the case of other SSRIs. This strategy is obviously most attractive when there are minimal or no side effects at the prescribed dose, and/or there has been some improvement.

_ Switching to a different antidepressant
Switching to another antidepressant is probably the commonest approach, including switches within the same class. There is some evidence for enhanced efficacy with venlafaxine after switching from an SSRI. The potential for pharmacokinetic or pharmacodynamic interactions requires care in some circumstances. For example, a switch from monoamine oxidase inhibitors to serotonin reuptake inhibitors may provoke the serotonin syndrome. Where possible, recommended protocols should be followed to minimize risks.

Switching is worth consideration when there is poor tolerability as a result of significant side effects or no improvement on careful clinical assessment. The switch options include antidepressants of a similar class (sometimes recommended as the simplest first option), followed by a different antidepressant class after a second failure within a class. Venlafaxine is specifically supported after more than one SSRI failure.

_ Augmentation of the ineffective antidepressant
There is evidence for the efficacy of augmentation of antidepressants with lithium, olanzapine, risperidone, quetiapine, and aripiprazole. Aripiprazole appears to be the most promising of these.24 Tri-iodothyronine also has adherents, as does mirtazapine, tryptophan, methylphenidate, lamotrigine, modafinil, antiglucocorticoids, and estrogen (in perimenopausal women), although more specialized combinations probably require expert supervision. Augmentation may be logically preferred when there has been a partial/insufficient response on the current antidepressant, but with good tolerability, or when switching antidepressants has been unsuccessful.

_ Psychological treatment options
Addition of cognitive behavioral therapy to ongoing antidepressant treatment may be effective, but requires significant therapist expertise. Adding other psychological or behavioral treatments that have established acute treatment efficacymay also be merited.

_ Physical treatment options
Electroconvulsive therapy should be considered in more severely symptomatic patients in whom two or more treatments have failed. Electrode placement affects both efficacy and adverse effects on memory (which are probably positively correlated). Unilateral treatment is often preferred as first-line treatment.

Vagal nerve stimulation is an option for patients with chronic treatment-resistant depression, as is deep brain stimulation and even ablative neurosurgery. A full discussion of who could be considered eligible having proved refractory to pharmacological and psychological treatment, is beyond the scope of this article.

_ The long term
In addressing treatment, the objective is to enable the patient to achieve remission and a full recovery within at most 3-4 months, and to continue treatment for at least 6 months. Given the strong evidence of relapse prevention in studies that, for regulatory purposes, have been designed to confirm efficacy over longer periods of time, longer term treatment should clearly be considered in patients believed to be at increased risk of recurrence of depression.²⁵

There have been rather few true maintenance studies in which patients have been allowed to recover, then been withdrawn fromantidepressants, and then re-randomized tomaintenance treatment de novo. The only large example with sertraline26 again showed a positive benefit reflecting the findings seen in relapse prevention studies.

More conventional relapse prevention studies involve open treatment with a single antidepressant to remission of the acute episode, followed by double-blind continuation or withdrawal (to placebo). Such designs are usually said to enrich the sample for responders to the acute treatment, and so may favor finding a positive effect when treatment is withdraw. A true maintenance study excludes this effect.

Conclusion

Elapsed time plays a key role in defining the diagnosis and course of single and recurrent episodes of major depression, treatment responses, decisions to change interventions when treatments fail, and outcomes. There is a certain symmetry in this when looked at from the patient perspective, since recurrent and chronic depression steal significant fractions of the lifetime of individual patients. In reflecting back on time spent depressed, patients rarely regard it as time well spent. This implies that a challenge for the future is to reliably shorten all the time periods that are currently too often long and uncontrolled in depression. This means time to diagnosis, time to effective treatment, and most critically time spent depressed. _

References

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
3. Frank E, Prien RF, Jarrett RB, et al. Conceptualization and rationale for consensus definitions of terms in major depressive disorder—remission, recovery, relapse, and recurrence. Arch Gen Psychiatry. 1991;48:851-855.
4. Rush AJ, Kraemer HC, Sackeim HA, et al. Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology. 2006;31:1841-1853.
5. Kessing LV, Andersen PK, Mortensen PB, Bolwig TG. Recurrence in affective disorder. I. Case register study. Br J Psychiatry. 1998;172:23-28.
6. Goodwin GM, Anderson I, Arango C, et al. ECNP Consensus Meeting. Bipolar depression. Nice, March 2007. Eur Neuropsychopharmacol. 2008;18:535-549.
7. Kendler KS, Kuhn J, Prescott CA. The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression. Am J Psychiatry. 2004;161:631-636.
8. Kendler KS, Gardner CO, Prescott CA. Toward a comprehensive developmental model for major depression in men. Am J Psychiatry. 2006;163:115-124.
9. Fanous AH, Neale MC, Aggen SH, Kendler KS. A longitudinal study of personality and major depression in a population-based sample of male twins. Psychol Med. 2007;37:1163-1172.
10. Kendler KS, Thornton LM, Gardner CO. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Am J Psychiatry. 2000;157:1243-1251.
11. Mannie ZN, Harmer CJ, Cowen PJ. Increased waking salivary cortisol levels in young people at familial risk of depression. Am J Psychiatry. 2007;164:617- 621.
12. Mannie ZN, Norbury R, Murphy SE, Inkster B, Harmer CJ, Cowen PJ. Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression. Br J Psychiatry. 2008;192:356-361.
13. Chan SWY, Harmer CJ, Goodwin GM, Norbury R. Risk for depression is associated with neural biases in emotional categorisation. Neuropsychologia. 2008; 46:2896-2903.
14. Chan SWY, Norbury R, Goodwin GM, Harmer CJ. Risk for depression and neural responses to fearful facial expressions of emotion. Br J Psychiatry. 2009; 194:139-145.
15. Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan. Lancet. 1997;349:915-919.
16. Hayward G, Goodwin GM, Cowen PJ, Harmer CJ. Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms. Biol Psychiatry. 2005;57:517-524.
17. McCabe C, Cowen PJ, Harmer CJ. Neural representation of reward in recovered depressed patients. Psychopharmacology. 2009;205:667-677.
18. Gorwood P, Corruble E, Falissard B, Goodwin GM. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry. 2008;165:731-739.
19. UK National Institute for Health and Clinical Excellence. Depression: management of depression in primary and secondary care – NICE Guidance. http:// guidance.nice.org.uk/CG23. Accessed December 8, 2009.
20. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.
21. Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action—systematic review and meta-analysis. Arch Gen Psychiatry. 2006;63:1217-1223.
22. Anderson IM, Ferrier IN, Baldwin RC, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology Guidelines. J Psychopharmacol. 2008;22: 343-396.
23. Rush AJ, Warden D, Wisniewski SR, et al. STAR*D Revising Conventional Wisdom. CNS Drugs. 2009;23:627-647.
24. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991.
25. Geddes JR, Carney SM, Davies C, et al. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet. 2003;361: 653-661.
26. Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM, Boyer P. A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. Am J Psychiatry. 2004;161:836-842.

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Philip GORWOOD, MD, PhD
INSERM U675
Centre de Psychiatrie
et Neurosciences
Paris-Descartes University
and Sainte-Anne Hospital
(CMME), Paris
FRANCE

Time perception involves different parameters that have cognitive dimensions, such as arousal, attention, memory, and mood. The neurobiological mechanisms of time processing seem to differentiate intervals of milliseconds (which concern motor tuning, and for which the cerebellum is mainly involved), hours and days (which define circadian rhythms, with the suprachiasmatic nuclei being in charge), and seconds and minutes (required for counting and estimating time; a complex fronto-striato-thalamic circuit probably being implicated). Perception of the speed of time is slower in depressed patients, because of abnormal subjective time experience and objective time judgment, and is probably explained by the additive effects of decreased arousal, attention, and memory processes. The possibility of a direct role of mood has also not been eliminated. Abnormal perception of time and decreased speed of the internal clock are both observed in depressed patients, and give a relevant and different insight into major depressive disorder. Although numerous clues are already available (regarding clinical and neurobiological findings), the role, mechanism, and etiology of abnormal time perception in depression has probably not been studied enough.

The capacity to analyze and adapt to the temporal parameters of a specific situation is an everyday requirement, and sometimes a life threatening necessity. We usually have to be “on time” for a large number of common activities, but fine synchrony and tuning of motor activity is particularly solicited when running away from major danger…

Time perception is needed at three major levels according to different time ranges

Temporal judgments are constructions of the brain. Defining ranges of time in time perception is particularly important, as the mechanisms seem to differ depending on the time range involved: in the circadian range, the suprachiasmatic nuclei (SCN) of the hypothalamus have a clear role, whereas the millisecond range, which may be more relevant for motor activity, may especially involve the cerebellum (em>Figure 1, page 134). To give a simple example, eating strawberries at lunch implies that (i) you have perceived that it is around midday; (ii) you took the decision to buy them; and (iii) you are able to transfer each strawberry successfully from plate to mouth.

Figure 1. Time ranges involved in the organization of behavior.

It is not surprising that time perception is a complex entity, as these three events imply the involvement of different time ranges and neurological structures, which one can more or less distinguish (Figure 1). Thus clear-cut distinctions between below-second and above-second time ranges when analyzing the neurobiology of timing may be artificial, and for some authors,¹ even misleading. Proposing certain heuristic models and trying to sum up the present knowledge about the neurobiology of timing could be helpful. Nevertheless, from the start, we should distinguish between the different aspects of timing and analyze the different elements that may be involved.

Subjective time perception is influenced by mood state

Our emotional state influences the way we feel time is passing. Everybody has experienced the fact that time drags when we are feeling bored or sad, whereas time flies when we are feeling excited or happy.

Major depressive disorder, which may represent a state of extreme sadness, is defined by a series of core symptoms that include a decrease in appetite, sleep, sexual desire, energy, and psychomotor activity. The latter aspect is quoted in nearly all instruments assessing depression, and can be analyzed by a specific instrument (the Psychomotor Retardation Rating Scale). This scale, devoted to psychomotor retardation, includes one item devoted to the “patient’s perception of the flow of time.”

Apart from these clinical aspects, the role of time perception in depression has also been analyzed at the phenomenological and psychopathological levels by Janet and Minkowski. In melancholia, according to Minkowski, time lived is slower and sometimes stops altogether: the present loses clarity, the future is diminished as change seems less and less possible, and the past looms into the present in the form of guilt and regret.

The feeling in depression that time passes more slowly has received limited attention in the literature,^2-9 and has sometimes led to negative results,^2,5,7,10 probably because accurately assessing such complex and subjective feelings brings methodological difficulties.

The discrepancies are partly explained by differences in methodology, patients, and aspects of time perception. Nevertheless, as detailed in the next paragraphs, there are six types of evidence that the internal clock of depressed patients is abnormal. Indeed; (i) the subjective feeling of slower time experienced during depression has been detected and replicated; (ii) depressed patients have been found to have more abnormal time judgment than controls for this aspect; (iii) more severely depressed patients are slower than less severe ones; (iv) a significant correlation has been reported between the severity of depression and time estimate abnormalities; (v) when depression improves, time judgment also improves; and (vi) the opposite of depression, ie, mania, is associated with an increased speed of the internal clock. Time perception is abnormal in major depressive disorder

Subjective time experience can be assessed with a visual analog scale by asking the subject to mark how slow or fast the flow of time is experienced at the moment of investigation. In at least two studies, this has been found to be significantly slower in depressed patients than controls.^3,11 After 23 depressed inpatients completed a self-rating questionnaire of time awareness, it was also found that they felt that time passed more slowly than the same number of matched nonpsychiatric controls.⁵ In another study, when compared with controls,depressed patients indicatedon a verbal reportmeasure that they experienced time as passing more slowly.⁹ Direct questioning about the speed of time is even simpler: this was carried out in a study half a century ago, and a very significantly higher incidence of the slowing down of the experience of time was reported in the depressed state compared with the recovery state.⁷ Interestingly, at the clinical level, the depressed patients reported a slowing, and some even an apparent stopping, of the passage of time, describing their experiences in evocative terms (“Every hour seems a year to me”; “It is terribly slow–interminable”; “Time? It is standing still”).⁷

An easy way to assess “time estimation” is to ask a patient to estimate the time length for a task that has a fixed time length. Twenty-five endogenous depressive patients underestimated a 30-second interval by 6 seconds, whereas 12 healthy controls overestimated this interval by more than 10.¹² In another trial, 30 severely depressed hospitalized patients overestimated 160-second, 240-second, 15-minute, and 30- minute time intervals compared with 30 controls.⁹ Depressed patients also overestimated time lengths of 12-minute spans compared with controls.¹¹

“Time production” is amore proactive compound of time judgment. The subject is asked to produce a certain time span, using active demonstration of, for example, the “go” and “stop” signals. When asked to produce a 35- and 90-second time span, depressed patients were found to produce shorter time lengths (29 and 64 seconds on average) than controls.¹¹ Grinker et al¹³ showed that patients with the most severe form of depression had the shortest estimation of standard durations of 1 and 3 seconds.

Quantitative approaches have also led to relatively homogeneous results. A feeling of being unwell was found to be accompanied by a more pronounced time estimation error.¹² With the temporal bisection task, the higher the depression score, the shorter the signal duration was judged to be.¹⁴ Grinker et al¹³ also obtained a significant correlation between the individual depression scores and time estimates in a discrimination task.

In one study, when the depression score improved with treatment, an analog scale assessing subjective time experience tended to normalize.³ Depressive patients have not only been compared with healthy controls, but also with patients with mania. Interestingly, on a visual analog scale, controls report a balanced experience of the flow of time, manic patients an enhanced experience, and depressive patients a slowed experience of time flow.¹¹ When assessing time production (giving a “stop” signal when the proposed duration is supposed to be finished), the intermediate position of controls between manic and depressed patients was only observed for a shorter duration (7 seconds), and did not reach statistical significance.¹¹

Figure 2. The scalar expectancy theory.

Time perception also involves motor, arousal, attention, and memory processes

Depression has a strong cognitive impact, but the motor components should not be neglected when assessing time perception, especially in the production of time intervals. Indeed, most of the previously described studies were based on a wide range of time lengths, from 1 or 2 seconds, to minutes, and even hours. Furthermore, they frequently rely on temporal judgment, which also requires the production and timing of a motor response (such as tapping or counting). In the knowledge that psychomotor retardation is a core feature of depression, it is difficult to dissociate the role of the motor component from that of the timing component in temporal performance, even though these two components may be related.¹⁴ Indeed, when specifically assessing the duration of movement patterns in depressed patients with melancholia, Lemke et al¹⁵ showed that the median of repetitive movements was higher in depressed patients than in the control group, regardless of the presence or absence of medication.

In order to avoid this confusing impact of motor retardation, a temporal bisection task was tested in depressed patients. In the test, two standard durations both below 2 seconds, one short and one long, are presented to subjects who have to categorize each probe (of variable duration) as being closer to the long or to the short standard duration. With this approach, a shift toward shorter durations, therefore an underestimation of time (ie, slower internal clock), was observed in depressed patients.¹⁴

A similar approach in another study initially gave the same type of results,¹⁶ but mainly for long intervals (above 1 second), probably because longer intervals require supplementary cognitive resources.

A comprehensive model of interval timing

The “scalar expectancy theory” was initially proposed by Gibbon1 and was largely developed later.¹⁷ As simplified in Figure 2, this theory is built on the idea of a neuronal pacemaker, which provides repetitive and regular pulses. Pulses are then gated (in order to define the beginning and the end of the duration to assess), and stored as an accumulated value (the number of pulses) in stored memory. The assessment of the duration of a specific task is then compared with reference memories, leading to a decision. This model was considered to successfully predict the outcomes of a large proportion of behavioral, pharmacological, and anatomical work in the field.¹⁷

This model of an internal clock has the advantage not only of being simple, but also of involving different cognitive features. Indeed, “gating” means being able to focus attention (with enough arousal ) on when to open and close the inputs, “comparing” (the number of pulses that were stored in the accumulator with reference memory) needs encoding and access tomemory contents, and “concluding,” ie, giving the stop signal as a consequence of the perception that the correct time interval has been reached, solicits motor skills. On the other hand, the scalar expectancy theory might be more relevant from a mathematical, rather than a neurobiological perspective, mainly because it is difficult to instantiate neural mechanisms that accumulate pulses over the order of minutes. This useful model was thus considered to be a “wellstructured metaphor [rather] than a diagram of the working brain.”¹⁷

^{The neurobiology of timing}
Initially, patients with a cerebellar pathology were used to pinpoint the role of the cerebellum in timing perception, but evidence has now been enriched with neuroimagery, stimulation, or inhibition using repetitive transcranial magnetic stimulation (rTMS), and electrophysiology data (for a review, see reference 18).

Other neural regions might serve as a dedicated timing system, including the basal ganglia, the supplementary motor area, and the prefrontal cortex.¹⁸ A fronto-striato-thalamic circuit, modulated by the dopamine system, would appear to be crucial for temporal processing within the range of seconds.

The basal ganglia receive the majority of their stimuli from the cortex, the thalamus, and the midbrain, and although initially reported as being involved in motor functioning, are now considered as playing an important role in motivational and cognitive aspects of brain functioning. The cortex projects glutamatergic (excitatory) afferents to the basal ganglia, mainly through the striatum (Figure 3). Striatal γ-aminobutyric acid (GABAergic; inhibitory) outputs project to the internal globus pallidus and the substantia nigra pars reticulata. These two structures provide an inhibitory influence on the thalamus, which, in turn, provides an excitatory output back to the cortex (and partly to the striatum).

Figure 3 was built on a schema usually proposed to describe the loops involved in motor activity (especially regarding the basal ganglia). The main proposed change today is that the output signal from the cortex does not represent motor activity, but the sum of individual waves of neurons that have different frequency oscillating signals. Adding together individual neurons as a model for producing an internal clock has the considerable advantage of allowing production (and recognition) of intervals of seconds or even minutes, which are far above the usual 200-millisecond intervals of neuronal activity. Indeed, mixing three neurons with 5 Hz (a peak every 200 msecs), 6 Hz, or 7 Hz oscillating signals will produce a curve at which a peak is observed every second.¹⁷ Such peaks, from milliseconds to minutes depending on the number of neurons concerned and their individual frequency, may then serve as an output signal that will reach the striatum.

Figure 3. Neuroanatomy of the timing circuit.

In terms of the role of the cortex, according to single cell activity studies, the prefrontal cortex may be more specifically involved. Increasing activity of dorsolateral prefrontal neurons was detected during the delay period of a task soliciting postponed activity.¹⁹ Furthermore, prefrontal delay neurons can have several different patterns of activity, including increasing, decreasing, and peak firing rates during the delay.²⁰

Interestingly, this model places the striatum as a core structure in the timing process, but also gives importance to the cortex and probably more specifically to the right dorsolateral prefrontal cortex. This model also favors a specific role for dopamine, which is in accordance with the fact that metamphetamine has an enhancing effect on timing function, and patients with Parkinson’s disease have a slower internal clock speed.¹⁸

Are the internal clocks identical for circadian and short-term interval timing?

When assessing time judgment, below-second and abovesecond intervals seem to be important, but what about intervals of hours and days? In order to learn associations with events that occur at particular times of the day, organisms use a specific circadian clock: the SCN. The SCN are located bilaterally in the anterior hypothalamus and are entrained to the external light-dark cycle by a neural pathway that transmits light information from the eyes through the retinohypothalamic tract.

Thus the neurobiological circuits for circadian and ultradian intervals seem to be different. Indeed, three types of distinction have been proposed between circadian and shorter interval timing.²¹ The circadian clock would be phase-based (automatically generated by the SCN), with low flexibility (the 24-hour basis can be shifted only by 1 hour a day, for example during jetlag) and constant variability, whereas the interval clock would be counter-based (adding pulses), with high flexibility (as relying on internal memory) and scalar variability (implying it has decreased precision for longer intervals).

Conclusion

The way we assess the speed of time forms part of our basic cognitive skill set, and is an important part of everyday analyses, decision making, and action. Such a core activity can be (artificially) distinguished according to time intervals. For intervals of below a second, most of the task concerns motor activity and may be more specifically orchestrated by the cerebellum. For intervals of over an hour, a specific structure is shared by many animals, ie, the SCN, allowing species to function both synchronically and in accordance with the night/day rhythm, and therefore to survive. For intervals of seconds to minutes, the timing circuit seems to be more complex, also involving cognitive skills. Whichever way neurons are organized as pacemakers (different models have been proposed, and their validity is difficult to prove), it is interesting that arousal, attention, and memory are involved, because of their ability to influence the inputs or outputs of the pacemaker. It is therefore not surprising that in major depressive disorder, which is known to be associated with poor attention and memory impairment,²² time seems to pass slower.

The specific impact of emotion has been tested, with analysis (using event-related potentials) of the way subjects react in front of neutral versus sad faces. Under emotional conditions, the P160 and P240 amplitudes have been found to be enhanced, suggesting that intentional bias for emotional stimuli attenuates the cognitive resources for time perception.23 The important role of dopamine at the neurotransmitter level, and the specific place of the prefrontal cortex in time production, both argue in favor of abnormal time perception belonging to the list of symptoms of depression; or at the least, sharing some identical neurobiological patterns. _

References

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21. Hinton SC, Meck WH. The ‘internal clocks’ of circadian and interval timing. Endeavour. 1997;21:82-87.
22. Gorwood P, Corruble E, Falissard B, Goodwin GM. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients. Am J Psychiatry. 2008;165:731-739.
23. Gan T, Wang N, Zhang Z, Li H, Luo YJ. Emotional influences on time perception: evidence from event-related potentials. Neuroreport. 2009;20:839-843.