HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder.

INTRODUCTION: This retrospective analysis compared sensitivity to change on the 17-item and 6-item Hamilton Rating Scales For Depression (HAM-D (17) and HAM-D (6), respectively) in relation to antidepressant dose and baseline depression severity. METHODS: Data were derived from 6 randomized, double-blind, placebo-controlled, 8-week trials of fixed-dose desvenlafaxine (50, 100, 200 or 400 mg/d) for major depressive disorder. HAM-D (17) and HAM-D (6) effect sizes were assessed. RESULTS: HAM-D (17) effect sizes were negative (favoured placebo) for higher desvenlafaxine doses (200-400 mg/d) at week 1, but were positive for all doses after week 2, with no clear dose-response pattern. However, HAM-D (6) effect sizes were positive for all doses at all weeks. Effect sizes were consistently greater for HAM-D (6) vs. HAM-D (17), regardless of time spent under therapy. Effect sizes were greater for HAM-D (6) vs. HAM-D (17) for all desvenlafaxine doses among patients with baseline HAM-D (17) <25, but not among patients with baseline HAM-D (17) ≥ 25. DISCUSSION: The HAM-D (6) demonstrated greater sensitivity to change and robustness than the HAM-D (17), supporting the greater homogeneity of the HAM-D (6).

S22153, a melatonin antagonist, dissociates different aspects of photoperiodic responses in Syrian hamsters.

In the Syrian hamster, short photoperiod (SP) induces changes in several physiological functions (body mass, reproduction, hibernation), and these responses involve the pineal hormone melatonin. The present study investigated the effects of a melatonin antagonist, S22153, on photoperiodic adaptation of male Syrian hamster. When constantly released from subcutaneous implants, S22153 had no effect on body or testes masses of animals kept in long photoperiod. S22153 decreased the total hibernation duration observed in animals exposed to SP and low temperature. The decrease in hibernation duration was due to a marked reduction in the number and duration of hypothermic bouts. Moreover, S22153 significantly inhibited the increase of interscapular brown adipose tissue (BAT) mass induced by SP. However, neither the gonadal atrophy nor the body mass increase induced by SP were affected by S22153. These results show that S22153 affects only part of the physiological changes controlled by SP and cold. Whether the decreases in BAT mass and hibernation duration are linked still remains an open question.

Long-term daily melatonin infusion induces a large increase in N-acetyltransferase activity, hydroxyindole-O-methyltransferase activity, and melatonin content in the Harderian gland and eye of pinealectomized male Siberian hamsters (Phodopus sungorus).

The effects of long-term daily melatonin infusions on the melatonin synthetic pathway in the Harderian glands and eyes of male Siberian hamsters were studied. Hamsters were pinealectomized (PX) and infused daily for 8 hr with either melatonin (6 microg/hr) or vehicle for 7 days in short photoperiod (SP, 10L:14D), followed by 14 wk in either SP (SP group) or in constant darkness (DD group). After the infusion period (15 wk), the infusion was stopped and animals were transferred into SP for 3 wk. The hamsters were then killed at midday or midnight. Exogenous melatonin infusion caused an increase in the Harderian gland weight, which was still evident 3 wk after the end of the treatment. In addition, exogenous melatonin increased endogenous melatonin concentrations (4-fold) and hydroxyindole-O-methyltransferase (HIOMT) activity (2-fold). N-acetyltransferase (NAT) activity, however, was not increased, and no day/night difference in melatonin content and HIOMT activity was observed in the Harderian glands. In the eye, melatonin infusions significantly increased day and night-time melatonin levels (up to 3-fold) and both NAT and HIOMT activities (up to 3.5-fold). This effect of melatonin treatment was observed in both SP and DD groups. These observations demonstrate that exogenously-infused melatonin at relatively high doses activates the synthesis of endogenous melatonin in the Harderian gland and eye of the Siberian hamster. Circulating levels of melatonin were also markedly increased, indicating that in these conditions melatonin may be released from extra-pineal sites.

Entrainment of rat circadian rhythms by melatonin does not depend on the serotonergic afferents to the suprachiasmatic nuclei.

Daily administration of melatonin (MEL) can entrain rat circadian rhythms free-running in constant darkness. The high MEL doses needed to obtain entrainment suggest the implication of other neural mechanisms than simply an effect on the hormone's specific receptors detected in the SCN. Administration of serotonin receptor agonists can phase-shift the rodent circadian clock, and MEL is known to modulate release and reuptake of serotonin in nerve endings. This raises the question of a critical involvement of 5-HT-fibres in the entraining properties of MEL. The aim of the present study was to test this hypothesis. Bilateral neurotoxic (5,7-dihydroxytryptamine) lesions of the serotonergic fibres in the SCN were performed in animals kept in LD 12:12. Following the post-operative period, the animals were transferred to constant darkness to free-run. MEL was then administered by a 1 h daily infusion. Both well lesioned and intact animals entrained to MEL. No differences were observed between lesioned and control animals on parameters such as the phase-angles between MEL onset and activity onset, and core body temperature acrophase, respectively. Entrainment of rat circadian rhythms to exogenous MEL is thus not directly dependent on the 5-HT fibres in the SCN.

Role of the thalamic intergeniculate leaflet and its 5-HT afferences in the chronobiological properties of 8-OH-DPAT and triazolam in syrian hamster.

The 5-HT(1A/7) receptor agonist 8-hydroxy-2-[di-n-propylamino]-tetralin (8-OH-DPAT) has chronobiological effects on the circadian system and, in the Syrian hamster, it is known that serotonergic (5-HT) projections connecting the median raphe nucleus to the suprachiasmatic nuclei (SCN) of the hypothalamus are a prerequisite for the expression of 8-OH-DPAT-induced phase advance of locomotor activity rhythm. We examined the possible involvement of the thalamic intergeniculate leaflet (IGL) in the phase-shifting properties of 8-OH-DPAT injections at CT7. Bilateral electrolytic lesions of the IGL blocked phase-shift responses to 8-OH-DPAT of the activity rhythm. Phase changes induced by injections of 8-OH-DPAT at CT7 and triazolam (Tz), a short-acting benzodiazepine, at CT6 were also studied after bilateral chemical lesion of the 5-HT fibres connecting the dorsal raphe nucleus (DR) to IGL. Destruction of 5-HT fibres within the IGL blocked the phase-shift response to Tz, but not the phase-shift response to 8-OH-DPAT. In conclusion, (a) IGL is essential for the phase-shifting effect of peripheral 8-OH-DPAT injections; (b) 5-HT fibres connecting DR to IGL are necessary for the expression of the phase-shifting effect of Tz but not of 8-OH-DPAT.

Influence of the mode of daily melatonin administration on entrainment of rat circadian rhythms.

In previous entrainment studies, melatonin (MEL) was administered by handling the animal, but because such handling may act as a confounding variable, the results from these studies are equivocal. The authors used MEL administration techniques that do not involve direct handling of the animal. Long Evans rats were used, and core body temperature (CBT) and wheel-running activity were recorded. One group of rats received a daily 1-h time-fixed infusion of MEL or the vehicle via a subcutaneous catheter. Animals in a second group had timed access to drinking water involving daily presence of drinking water containing MEL or the vehicle for 2 h at a fixed time of the day. Following entrainment to LD 12:12, both groups were transferred to constant darkness to free-run under vehicle administration. MEL was then administered, and entrainment occurred when activity onset coincided with MEL onset. Under both regimens, entrainment of wheel-running and CBT rhythms showed equal phase-relation to the onset of MEL administration, and free-running reoccurred when MEL was withdrawn. The authors concluded that MEL administration via drinking water and via infusion represent efficient ways to synchronize free-running rhythms in rats.

Organization of rat circadian rhythms during daily infusion of melatonin or S20098, a melatonin agonist.

Daily administration of melatonin or S20098, a melatonin agonist, is known to entrain the free-running circadian rhythms of rats. The effects of the duration of administration on entrainment were studied. The animals demonstrated free-running circadian rhythms (running-wheel activity, body temperature, general activity) in constant darkness. Daily infusions of melatonin or S20098 for 1, 8, or 16 h entrained the circadian rhythms to 24 h. Two daily infusions of 1 h (separated by 8 h) entrained the activity peak within the shorter time interval. The entraining properties of melatonin and S20098 were similar and were affected neither by pinealectomy nor by infusion of 1- or 8-h duration. However, with 16-h infusion, less than half of the animals became entrained. Once entrained, the phase angle between the onset of infusion and the rhythms (onset of activity or acrophase of body temperature) increased with the duration of infusion. Before entrainment, the free-running period increased with the duration of infusion, an effect that was not predictable from the phase response curve.

In Syrian hamsters, 5-HT fibres within the suprachiasmatic nuclei are necessary for the expression of 8-OH-DPAT induced phase-advance of locomotor activity rhythm.

8-Hydroxy-2-[di-n-propylamino]-tetralin) (8-OH-DPAT), a 5-HT1A/7 receptor agonist, has a chronobiological effect on the circadian system. To identify how the 8-OH-DPAT exerts this effect, we specifically destroyed the serotonergic (5-HT) fibres connecting the median raphe nuclei (RN) to the suprachiasmatic nuclei (SCN) of the hypothalamus by using microinjections of a neurotoxin 5,7-dihydroxytryptamine into the SCN. After administration of 8-OH-DPAT (0.1 ml, 5 mg/kg) at circadian time 7, the control and the 'partially-lesioned' animals showed a large phase-advance whereas in the 'well-lesioned' hamsters the phase-advances were significantly reduced or absent. The present study demonstrates that, in the Syrian hamster, the 5-HT fibres connecting the RN to the SCN are essential for the phase-shifting action of peripheral 8-OH-DPAT injections, and that the drug does very probably not exert its chronobiological effect directly onto SCN neurons but through receptors localized on median raphe nucleus neurons.

The photoperiodic response in Syrian hamsters depends upon a melatonin-driven rhythm of sensitivity to melatonin.

The pineal gland conveys photoperiodic information to the brain through its daily pattern of melatonin (MEL) secretion. The duration of MEL secretion is proportional to the duration of the night. To determine the mechanism by which MEL transduces photoperiod, we used a protocol of daily MEL infusion given to sexually active pinealectomized Syrian hamsters. A long MEL signal (10 h) inhibited sexual activity, whereas a 5-hour infusion had no effect. However, animals given a 2.5-hour infusion twice separated by an interval of 3 h produced complete gonadal atrophy. Changes in the time interval between infusions blocked the potency of the MEL infusion, suggesting a tight temporal relationship between MEL signals. Additionally, the infusions were as effective whether applied during the day or during the night, in both long and short photoperiods. These data suggest that there is a rhythm of sensitivity to MEL involved in the photoperiodic response which is entrained by MEL itself.

Environmental control of the seasonal variations in the daily pattern of melatonin synthesis in the European hamster, Cricetus cricetus.

Nocturnal patterns of pineal melatonin concentrations were measured at hourly intervals in the European hamster, Cricetus cricetus, maintained under different natural or experimental environmental conditions. There were pronounced variations in the night peak of pineal melatonin both in the duration and the amplitude of the melatonin peak and in the onset and decline of melatonin synthesis. The duration of the melatonin peak increased proportionally with increased dark period. The amplitude increased abruptly from LD 16/8 to LD 15/9 and remained constant in all other photoperiods. The onset of synthesis started 6:00 hours after the onset of darkness in LD 16/8, 15/9, and 14/10, while it started 4:00 hours after dark onset in shorter photoperiods (LD 12/12 and 10/14). This result is opposite to that observed in the rat. The decline of synthesis was delayed as darkness increased and was directly related to lights on in long photoperiods, while it was endogenous in short photoperiods. Temperature, under a long photoperiod, also seems to be implicated in the regulation of the amplitude of the melatonin peak.

The photoperiodic response in Syrian hamster depends upon a melatonin-driven circadian rhythm of sensitivity to melatonin.

The pineal gland, via the daily pattern of melatonin (MEL) secretion, is directly involved in the conduction of photoperiodic information. The duration of MEL secretion is proportional to the duration of the dark period and, whatever the photoperiod is, MEL synthesis occurs 3 or 4 h after the dark onset in Syrian hamsters. In order to determine the relative importance of the duration or the coincidence hypothesis, a daily infusion protocol was used in sexually active pinealectomized hamsters. Long duration of MEL infusion (10 h) completely inhibit testes whereas short duration infusion (5 h) had no effect. When the animals were infused twice within 2 h 30 min separated by 3 h, they presented a complete gonadal atrophy, similar to the one observed with the 10 h infusion. Measurement of plasma MEL during the infusion and separation periods revealed that MEL reached physiological nighttime values during the infusion period and fell to daytime values 1 h after the end of an infusion period. Thus, the results could not be due to a time additive action of the two MEL pulses. An intermediate response was observed when the 2 signals were applied across the light/dark transition. Gonadal regression did not occur when the 2 periods of infusion were separated by 5 h 30 min. The efficiency of this type of infusion was not dependent on the ambiant photoperiod since similar results were obtained in long and short photoperiods. The infusion was also as effective during the day as well as during the night. These results suggest that there is a rhythm of sensitivity to MEL, based on the coincidence hypotheses, that are important for transmission of photoperiodic information. This rhythm of sensitivity to MEL seems to be entrained by MEL itself, since the efficiency of the two pulses of MEL is not dependent of time of application and/or of photoperiod.

Effects of different doses and durations of melatonin infusions on plasma melatonin concentrations in pinealectomized Syrian hamsters: consequences at the level of sexual activity.

The effect of different doses and durations of melatonin infusions on plasma melatonin concentrations has been studied in pinealectomized Syrian hamsters maintained under short photoperiod at either 7 degrees C or 18 degrees C. The effects of the infusions on plasma melatonin concentrations and on gonadal activity were compared. The results show that the minimal effective quantity of infused melatonin that induced gonadal atrophy was 40 ng/h at 7 degrees C and 20 ng/h at 18 degrees C. An infusion of 8 hr duration per day is necessary to inhibit sexual activity, while an infusion of 6 hr duration was ineffective. This finding suggests that the critical duration of melatonin infusion is between 6 and 8 hr. Despite the various doses of melatonin infused, plasma melatonin concentrations measured in the middle of the infusion period did not differ significantly from concentrations measured in intact animals. This finding suggests that the metabolism of infused melatonin increases as the dose of melatonin increases. Moreover, the different physiological effects observed after the various melatonin infusions cannot be explained by variations in plasma melatonin concentrations.