Comparative effects of nefazodone and fluoxetine on sleep in outpatients with major depressive disorder.

BACKGROUND: Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep. METHODS: This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8. RESULTS: Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine. CONCLUSIONS: Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

A comparison of nefazodone and fluoxetine on mood and on objective, subjective, and clinician-rated measures of sleep in depressed patients: a double-blind, 8-week clinical trial.

BACKGROUND: Previous small trials have suggested that nefazodone does not suppress rapid-eye-movement (REM) sleep or increase REM latency in depressed patients, in contrast to fluoxetine. The effects of nefazodone and fluoxetine on sleep architecture and on clinician- and patient-rated sleep measures were directly compared in this 8-week, multicenter, double-blind, randomized, parallel-group study. METHOD: Forty-four outpatients with moderate to severe, nonpsychotic major depressive disorder (DSM-III-R) and insomnia were randomly assigned to receive nefazodone (Days 1-7, 200 mg/day; Days 8-56, 400 mg/day) or fluoxetine (Days 1-56, 20 mg/day). Sleep measures were obtained at baseline, while patients were unmedicated, and at Weeks 2, 4, and 8 of treatment. RESULTS: In 43 evaluable patients (23 nefazodone, 20 fluoxetine), nefazodone and fluoxetine demonstrated similar antidepressant efficacy. All significant values were p < .05. Fluoxetine significantly decreased sleep efficiency and REM sleep and increased number of awakenings, Stage 1 sleep, and REM latency compared with baseline. In contrast, nefazodone significantly decreased percentage of awake and movement time and did not alter sleep efficiency or number of awakenings, Stage 1 or REM sleep, or REM latency compared with baseline. Nefazodone was associated with significantly less change from baseline for sleep efficiency, number of awakenings, percentage of awake and movement time, percentage of REM and Stage 1 sleep, and REM latency compared with fluoxetine. Both fluoxetine- and nefazodone-treated patients also showed significant improvement in some clinician- and patient-rated sleep disturbance scores, but nefazodone-treated patients improved to a significantly greater extent than fluoxetine-treated patients in most measures. CONCLUSION: While nefazodone and fluoxetine showed equivalent antidepressant efficacy, more objective, subjective, and clinician-rated measures of sleep disturbance were improved during treatment with nefazodone than with fluoxetine. These results suggest that antidepressant effects of medications can occur independently of drug-induced changes in objective, subjective, and clinician-rated measures of sleep. Further studies, including parallel placebo-controlled comparisons with nefazodone, are needed to further test this hypothesis.

Restriction of enhanced [2-14C]deoxyglucose utilization to rhinencephalic structures in immature amygdala-kindled rats.

Sixteen-day-old albino rat pups were kindled to varying degrees of seizure severity with amygdala stimulations spaced 15 to 20 min apart. Subsequently, each rat pup was injected (ip) with 10 microCi of [2-14C]-deoxyglucose, and received several additional kindled seizures at regular intervals throughout the following 80 min, at which time it was killed and processed for deoxyglucose autoradiography. Increased seizure severity was associated with correspondingly increased deoxyglucose utilization in many rhinencephalic limbic structures. However, unlike adults, rat pups did not show discernibly increased neocortical, thalamic, or substantia nigra utilization. We postulate that the apparent confinement of seizure activity to limbic structures in pups is related to their relative lack of postictal seizure refractoriness, as well as to other indices of increased seizure susceptibility in immature animals.

Mammalian optic nerve regeneration following the application of electric fields.

Previous studies have shown that the application of electric fields to the damaged mammalian nervous system is efficacious in promoting regeneration of peripheral nervous system axons. The present experiments were undertaken to determine whether exogenously applied electric fields can induce regenerative responses in the damaged mammalian central nervous system (CNS). In these studies, chronically delivered direct current was applied to the optic nerve, orienting the cathode distal to the lesion site. Histologic analyses at 3 weeks revealed that the damaged optic nerve did exhibit a regenerative response following treatment. We believe that this represents the first report of regenerative effects on the mammalian visual system using chronic DC electric fields, and we suggest that such galvanic treatment may be used alone or as an adjunct to promoting regeneration of the injured mammalian central nervous system.

Facilitated regeneration in the rat peripheral nervous system using applied electric fields.

The efficacy of applied electric fields in promoting regeneration of the transected and frozen rat sciatic nerve was studied. Three groups were studied at 6, 12, and 18 days post-lesion; nerves treated with 1.5 microA of direct current where the cathode was oriented distal to the lesion, nerves treated with the anode distal to the lesion, or no current delivered to the nerve. Regeneration in this severely damaged mammalian peripheral nerve model was quantitated by counting fluorescent antibody profiles to neurofilament protein distal to the lesion site. The results indicated that only cathodal current, applied distal to the lesion, significantly increased the rate of regeneration compared to controls. Such results help to elucidate mechanisms by which electric fields can facilitate regeneration in the mammalian nervous system.

Unilateral peri-substantia nigra catecholaminergic lesion and amygdala kindling.

Recent evidence suggests that the substantia nigra (SN) may be involved in the modulation of kindled seizures in adult rats. In this report we investigated the role of the dopaminergic nigrostriatal pathway in mediating the SN effect on seizures by lesioning this pathway with unilateral infusions of 6-hydroxydopamine (6-OHDA) in the vicinity of the right SN with or without desmethylimipramine pretreatment. Our data suggest that the facilitation of amygdala kindling observed following 6-OHDA lesion in the vicinity of the ipsilateral SN is due to norepinephrine depletion of the ipsilateral forebrain. Selective destruction of the nigrostriatal dopaminergic neurons neither facilitates nor inhibits the development of amygdala-kindled convulsions in adult rats.

Perinatal hypoxia and subsequent development of seizures.

Perinatal asphyxia has been implicated in the pathogenesis of persistent convulsive disorders later in life. Whether epilepsy is the result of oxygen deficiency alone or is due to the combined effect of hypoxia and ischemia is not known. In this report we studied the role of perinatal hypoxia alone on the development of epilepsy. One day and ten days old rat pups were exposed to prolonged hypoxia (6% O2). The subsequent susceptibility to focally elicited (kindled) or generalized (flurothyl) seizures was determined in the fourth week of age. Rats exposed to hypoxia were not more susceptible to the development of either type of seizures when compared to controls. Since the equivalent degree of hypoxia used for the 1 day old rat has previously been shown to result in lasting neurochemical and behavioral alterations and the degree of hypoxia used for the 10 day rat was lethal in over 35% of the animals, it is suggested that oxygen deficiency in and of itself may not be sufficient to lead to the development of epilepsy.

Unidirectional interaction between flurothyl seizures and amygdala kindling.

In this report, the interaction between flurothyl convulsions and electrical kindling of the amygdala was investigated. Three flurothyl convulsions decreased the afterdischarge threshold of the amygdala and enhanced the rate of development of electrical kindling without affecting the intensity of postictal refractoriness. On the other hand, 3 generalized kindled convulsions did not alter the flurothyl convulsive threshold. The data suggest that the influence of generalized convulsions on future seizure susceptibility may depend on the agents used to induce the convulsions.

Ventromedial thalamic lesions and seizure susceptibility.

Recent data indicate that the substantia nigra is an important site in a circuitry involved in the modification of various experimental seizures with neocortical and limbic involvement. Since there are no direct nigral projections to either area, we assumed that the nigral effects on seizures are relayed by other sites such as the thalamus. To evaluate this hypothesis we produced bilateral high-radiofrequency thermocoagulative lesions of the ventromedial (VM) thalamic nuclei which receive the nigral efferents in the rat. We determined the susceptibility of lesioned and control adult rats to the development of flurothyl seizures 2 and 4 weeks later. The latency to the onset of a generalized seizure was considered as the convulsive threshold. There were no differences in the mean latencies between the groups. The results suggest that bilateral destruction of the VM thalamic nuclei does not modify the susceptibility to the development of flurothyl seizures in the rat.

Infantile status epilepticus and future seizure susceptibility in the rat.

The long-term effects of infantile seizures on the development of seizures in adulthood were studied in rats. Infantile seizures of varying severity were induced with intraperitoneal injections of kainic acid in 15-day-old rats. In adulthood the seizure susceptibility of the rats was determined by kindling the left amygdala and by measuring their ability to resist recurrent seizures. The results suggest that infantile status epilepticus is associated with a very high mortality; however in the surviving rats, infantile seizures even as severe as status epilepticus do not cause neuronal brain damage and do not predispose to the development of convulsions later in life.

Effect of a single brief seizure on subsequent seizure susceptibility in the immature rat.

To determine whether a single seizure permanently affects the brain's susceptibility to further seizures, 27-day-old rats were subjected to a single seizure induced by either an electroshock or the administration of pentylenetetrazol. Three days following the seizure, the rats, along with age- and weight-matched control rats, underwent kindling. The rate of kindling did not differ between the control rats and those rats that had previously experienced a single electroshock or pentylenetetrazol-induced seizure. At the present time, there is no conclusive evidence that a single brief seizure results in permanently increased susceptibility to future convulsions.

Nigral muscimol infusions facilitate the development of seizures in immature rats.

Since recent data utilizing GABAergic stimulation of the substantia nigra (SN) suggest that the SN is a crucial site in a circuitry involved in the modification of seizures in adult rats, the role of the SN was investigated in seizures of rat pups. Bilateral nigral infusions of the GABA agonist muscimol partially protected adult rats against flurothyl-induced seizures, while similar infusions actually facilitated the development of flurothyl seizures in 15-day-old rat pups. These results suggest that age-related differences in the nigral GABA sensitive system may account for the increased susceptibility to generalized seizures of the developing brain.

Kainic-acid-induced seizures: a developmental study.

Developmental dose-response curves for kainic-acid-induced seizures were generated in rats. Rats at 15-18 days (pups), 33-37 days ( pubescents ) and over 90 days (adults) were administered kainic acid intraperitoneally. Seizures were elicited in all 3 age groups, but some of the behavioral manifestations differed in the pups. This group also had the lowest convulsive threshold, the most severe seizures and the highest mortality. Forelimb convulsions and status epilepticus were associated with the occurrence of necrotic lesions in the adults and pubescents but not in the pups. Deoxyglucose (DG) autoradiographic studies of the convulsing rats disclosed differences in the DG uptake pattern of the substantia nigra across the 3 age groups. Increases in the DG uptake were present in the two older age groups but not in the pups. Since recent data have implicated the substantia nigra as a crucial site in a seizure modifying circuitry in adult animals, our results suggest that the lack of substantia nigra involvement in the pups may account for the early generalization and the increased severity of seizures in this age group.

Maturational changes in postictal refractoriness and seizure susceptibility in developing rats.

The ability of the central nervous system to suppress recurrent seizures as a function of age was determined in rats. Eight electrical stimulations were delivered to the amygdala at 2-minute intervals in adult and suckling rats that were previously kindled from the left amygdala. During this 16-minute period, prolonged and severe convulsions were repeatedly elicited in the 16-day-old rat pups, whereas convulsions were not always elicited in adult rats. The results suggest that immature rats are more prone to develop status epilepticus than adult rats. Subsequently, the rat pups and implanted but not stimulated littermates were allowed to grow. At maturity, all the surviving animals were kindled from the contralateral (right) amygdala. The previously kindled rats developed seizures significantly faster than did their littermates. However, their respective abilities to suppress recurrent seizures did not differ at 150 and 210 days of age, being similar to the seizure suppression abilities of naive controls and significantly greater than those evidenced in infancy. We conclude that the propensity to develop single seizures in adulthood is directly related to infant seizure history, whereas the ability to suppress multiple seizures is a dynamic process that is modified by age, being minimal early in life and enhanced with maturation independently of history of infantile convulsions.

Increased seizure susceptibility of the immature brain.

The ability of the CNS to generate seizures as a function of age was investigated utilizing the kindling model of epilepsy. Hourly electrical, low intensity stimulations of the amygdala induced kindling in adult rats, but stimulations delivered at 15 min intervals failed to or markedly retarded the development of kindled convulsions. In contrast, both types of stimulation induced consistent prolongation of the afterdischarges and repeated generalized seizures in suckling rat pups. The rate of development of the kindled convulsions in the pups was similar, irrespective of whether the stimulations were delivered at 15 or 60 min intervals, indicating that short (less than 15 min) seizure refractory periods exist in the immature brain. The data suggest that seizure susceptibility changes with age and is greater early in life.

Kindling in developing rats: persistence of seizures into adulthood.

The effects of kindling induced in developing rat pups were re-examined when the rats reached maturity. Eighteen-day-old rats, implanted with bipolar electrodes, were separated into the following 4 groups: the fully kindled group consisted of pups that developed generalized convulsions; the partially kindled group of pups that consistently displayed afterdischarges and occasionally behavioral focal seizures; the afterdischarge group of pups in which the afterdischarge threshold was measured and the non-stimulated group of pups implanted but not stimulated. Subsequently, the electrodes were removed and the rats were allowed to grow. At 65-70 days, the surviving rats and age matched controls were rekindled. The vulnerability to kindled convulsions at maturity, as expressed by the kindling rates, correlated directly with the severity of previous kindled seizures, but did not correlate with the presence of long standing gliotic lesions. These findings suggest that the neural alterations evoked by kindling persist and are not modified by the dynamic changes that occur with growth.