Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.

Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.

The present study demonstrates that chronic, but not acute, adminstration of several different classes of antidepressants, including serotonin- and norepinephrine-selective reuptake inhibitors, increases the expression of cAMP response element binding protein (CREB) mRNA in rat hippocampus. In contrast, chronic administration of several nonantidepressant psychotropic drugs did not influence expression of CREB mRNA, demonstrating the pharmacological specificity of this effect. In situ hybridization analysis demonstrates that antidepressant administration increases expression of CREB mRNA in CA1 and CA3 pyramidal and dentate gyrus granule cell layers of the hippocampus. In addition, levels of CRE immunoreactivity and of CRE binding activity were increased by chronic antidepressant administration, which indicates that expression and function of CREB protein are increased along with its mRNA. Chronic administration of the phosphodiesterase (PDE) inhibitors rolipram or papaverine also increased expression of CREB mRNA in hippocampus, demonstrating a role for the cAMP cascade. Moreover, coadministration of rolipram with imipramine resulted in a more rapid induction of CREB than with either treatment alone. Increased expression and function of CREB suggest that specific target genes may be regulated by these treatments. We have found that levels of brain-derived neurotrophic factor (BDNF) and trkB mRNA are also increased by administration of antidepressants or PDE inhibitors. These findings indicate that upregulation of CREB is a common action of chronic antidepressant treatments that may lead to regulation of specific target genes, such as BDNF and trkB, and to the long-term effects of these treatments on brain function.

We have isolated 145 fertile mutants of C. elegans that are defective in egg laying and have characterized 59 of them genetically, behaviorally and pharmacologically. These 59 mutants define 40 new genes called egl. for egg-laying abnormal. Most of the other mutants are defective in previously identified genes. The egl mutants differ with respect to the severity of their egg-laying defects and the presence of behavioral or morphological pleiotropies. We have defined four distinct categories of mutants based on their responses to the pharmacological agents serotonin and imipramine, which stimulate egg laying by wild-type hermaphrodites. These drugs test the functioning of the vulva, the vulval and uterine muscles and the hermaphrodite-specific neurons (HSNs), which innervate the vulval muscles. Mutants representing 14 egl genes fail to respond to serotonin and to imipramine and are likely to be defective in the functioning of the vulva or the vulval and uterine muscles. Four mutants (representing four different genes) lay eggs in response to serotonin but not to imipramine and appear to be egg-laying defective because of defects in the HSNs; three of these four were selected specifically for these drug responses. Mutants representing seven egl genes lay eggs in response to serotonin and to imipramine. One egl mutant responds to imipramine but not to serotonin. The remaining egl mutants show variable or intermediate responses to the drugs. Two of the HSN-defective mutants, egl-1 and her-1(n695), lack HSN cell bodies and are likely to be expressing the normally male-specific program of HSN cell death. Whereas egl-1 animals appear to be defective specifically in HSN development, her-1(n695) animals exhibit multiple morphological pleiotropies, displaying partial transformation of the sexual phenotype of many cells and tissues. At least two of the egl mutants appear to be defective in the processing of environmental signals that modulate egg laying and may define new components of the neural circuitry that control egg laying.

The mechanism by which cholera toxin (CT) is internalized from the plasma membrane before its intracellular reduction and subsequent activation of adenylyl cyclase is not well understood. Ganglioside GM1, the receptor for CT, is predominantly clustered in detergent-insoluble glycolipid rafts and in caveolae, noncoated, cholesterol-rich invaginations on the plasma membrane. In this study, we used filipin, a sterol-binding agent that disrupts caveolae and caveolae-like structures, to explore their role in the internalization and activation of CT in CaCo-2 human intestinal epithelial cells. When toxin internalization was quantified, only 33% of surface-bound toxin was internalized by filipin-treated cells within 1 h compared with 79% in untreated cells. However, CT activation as determined by its reduction to form the A1 peptide and CT activity as measured by cyclic AMP accumulation were inhibited in filipin-treated cells. Another sterol-binding agent, 2-hydroxy-beta-cyclodextrin, gave comparable results. The cationic amphiphilic drug chlorpromazine, an inhibitor of clathrin-dependent, receptor-mediated endocytosis, however, affected neither CT internalization, activation, nor activity in contrast to its inhibitory effects on diphtheria toxin cytotoxicity. As filipin did not inhibit the latter, the two drugs appeared to distinguish between caveolae- and coated pit-mediated processes. In addition to its effects in CaCo-2 cells that express low levels of caveolin, filipin also inhibited CT activity in human epidermoid carcinoma A431 and Jurkat T lymphoma cells that are, respectively, rich in or lack caveolin. Thus, filipin inhibition correlated more closely with alterations in the biochemical characteristics of CT-bound membranes due to the interactions of filipin with cholesterol rather than with the expressed levels of caveolin and caveolar structure. Our results indicated that the internalization and activation of CT was dependent on and mediated through cholesterol- and glycolipid-rich microdomains at the plasma membrane rather than through a specific morphological structure and that these glycolipid microdomains have the necessary components required to mediate endocytosis.

Antidepressants increase proliferation of neuronal progenitor cells and expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. We investigated the role of BDNF signaling in antidepressant-induced neurogenesis by using transgenic mice with either reduced BDNF levels (BDNF+/-) or impaired trkB activation (trkB.T1-overexpressing mice). In both transgenic strains, chronic (21 d) imipramine treatment increased the number of bromodeoxyuridine (BrdU)-positive cells to degree similar to that seen in wild-type mice 24 h after BrdU administration, although the basal proliferation rate was increased in both transgenic strains. Three weeks after BrdU administration and the last antidepressant injection, the amount of newborn (BrdU- or TUC-4-positive) cells was significantly reduced in both BDNF+/- and trkB.T1-overexpressing mice, which suggests that normal BDNF signaling is required for the long-term survival of newborn hippocampal neurons. Moreover, the antidepressant-induced increase in the surviving BrdU-positive neurons seen in wild-type mice 3 weeks after treatment was essentially lost in mice with reduced BDNF signaling. Furthermore, we observed that chronic treatment with imipramine or fluoxetine produced a temporally similar increase in both BrdU-positive and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeled neurons in the dentate gyrus, indicating that these drugs simultaneously increase both neurogenesis and neuronal elimination. These data suggest that antidepressants increase turnover of hippocampal neurons rather than neurogenesis per se and that BDNF signaling is required for the long-term survival of newborn neurons in mouse hippocampus.

Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.

We investigated the effectiveness of two brief psychotherapies, interpersonal psychotherapy and cognitive behavior therapy, for the treatment of outpatients with major depression disorder diagnosed by Research Diagnostic Criteria. Two hundred fifty patients were randomly assigned to one of four 16-week treatment conditions: interpersonal psychotherapy, cognitive behavior therapy, imipramine hydrochloride plus clinical management (as a standard reference treatment), and placebo plus clinical management. Patients in all treatments showed significant reduction in depressive symptoms and improvement in functioning over the course of treatment. There was a consistent ordering of treatments at termination, with imipramine plus clinical management generally doing best, placebo plus clinical management worst, and the two psychotherapies in between but generally closer to imipramine plus clinical management. In analyses carried out on the total samples without regard to initial severity of illness (the primary analyses), there was no evidence of greater effectiveness of one of the psychotherapies as compared with the other and no evidence that either of the psychotherapies was significantly less effective than the standard reference treatment, imipramine plus clinical management. Comparing each of the psychotherapies with the placebo plus clinical management condition, there was limited evidence of the specific effectiveness of interpersonal psychotherapy and none for cognitive behavior therapy. Superior recovery rates were found for both interpersonal psychotherapy and imipramine plus clinical management, as compared with placebo plus clinical management. On mean scores, however, there were few significant differences in effectiveness among the four treatments in the primary analyses. Secondary analyses, in which patients were dichotomized on initial level of severity of depressive symptoms and impairment of functioning, helped to explain the relative lack of significant findings in the primary analyses. Significant differences among treatments were present only for the subgroup of patients who were more severely depressed and functionally impaired; here, there was some evidence of the effectiveness of interpersonal psychotherapy with these patients and strong evidence of the effectiveness of imipramine plus clinical management. In contrast, there were no significant differences among treatments, including placebo plus clinical management, for the less severely depressed and functionally impaired patients.

The mechanisms underlying the initiation/onset of, and the recovery from, depression are still largely unknown; views that neurogenesis in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms have gained currency over the years although the original evidence has been challenged. In this study, an unpredictable chronic mild stress protocol was used to induce a depressive-like phenotype in rats. In the last 2 weeks of stress exposure, animals were treated with the antidepressants fluoxetine, imipramine, CP 156,526 or SSR 1494515, alone or combined with methylazoxymethanol, a cytostatic agent used to arrest neurogenesis. We found that antidepressants retain their therapeutic efficacy in reducing both measured indices of depression-like behavior (learned helplessness and anhedonia), even when neurogenesis is blocked. Instead, our experiments suggest re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus and prefrontal cortex, rather than neurogenesis, as the basis for the restoration of behavioral homeostasis by antidepressants.

We have earlier shown that microglia, the immune cells of the CNS, release microparticles from cell plasma membrane after ATP stimulation. These vesicles contain and release IL-1beta, a crucial cytokine in CNS inflammatory events. In this study, we show that microparticles are also released by astrocytes and we get insights into the mechanism of their shedding. We show that, on activation of the ATP receptor P2X7, microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATP-induced shedding and IL-1beta release are markedly reduced by the inhibition of acid sphingomyelinase, and completely blocked in glial cultures from acid sphingomyelinase knockout mice. We also show that p38 MAPK cascade is relevant for the whole process, as specific kinase inhibitors strongly reduce acid sphingomyelinase activation, microparticle shedding and IL-1beta release. Our results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells and define key molecular effectors of microparticle formation and IL-1beta release, thus, opening new strategies for the treatment of neuroinflammatory diseases.

OBJECTIVE

The recurrence of an affective disorder in people who initially recover from major depressive disorder was characterized by using the unique longitudinal prospective follow-up data from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies.

METHODS

Up to 15 years of prospective follow-up data on the course of major depressive disorder were available for 380 subjects who recovered from an index episode of major depressive disorder and for 105 subjects who subsequently remained well for at least 5 years after recovery. Baseline demographic and clinical characteristics were examined as predictors of recurrence of an affective disorder. The authors also examined naturalistically applied antidepressant therapy.

RESULTS

A cumulative proportion of 85% (Kaplan-Meier estimate) of the 380 recovered subjects experienced a recurrence, as did 58% (Kaplan-Meier estimate) of those who remained well for at least 5 years. Female sex, a longer depressive episode before intake, more prior episodes, and never marrying were significant predictors of a recurrence. None of these or any other characteristic persisted as a predictor of recurrence in subjects who recovered and were subsequently well for at least 5 years. Subjects reported receiving low levels of antidepressant treatment during the index episode, which further decreased in amount and extent during the well interval.

CONCLUSIONS

Few baseline demographic or clinical characteristics predict who will or will not experience a recurrence of an affective disorder after recovery from an index episode of major depressive disorder, even in persons with lengthy well intervals. Naturalistically applied levels of antidepressant treatment are well below those shown effective in maintenance pharmacotherapy studies.

The hippocampus is one of several brain areas thought to play a central role in affective behaviors, but the underlying local network dynamics are not understood. We used quantitative voltage-sensitive dye imaging to probe hippocampal dynamics with millisecond resolution in brain slices after bidirectional modulation of affective state in rat models of depression. We found that a simple measure of real-time activity-stimulus-evoked percolation of activity through the dentate gyrus relative to the hippocampal output subfield-accounted for induced changes in animal behavior independent of the underlying mechanism of action of the treatments. Our results define a circuit-level neurophysiological endophenotype for affective behavior and suggest an approach to understanding circuit-level substrates underlying psychiatric disease symptoms.

DNA methylation regulates gene transcription and has been suggested to encode psychopathologies derived from early life stress. We found that methylation regulated the expression of the Crf (also known as Crh) gene and that chronic social stress in adult mice induced long-term demethylation of this genomic region. Demethylation was observed only in the subset of defeated mice that displayed social avoidance and site-specific knockdown of Crf attenuated the stress-induced social avoidance.

BACKGROUND

Panic disorder (PD) may be treated with drugs, psychosocial intervention, or both, but the relative and combined efficacies have not been evaluated in an unbiased fashion.

OBJECTIVE

To evaluate whether drug and psychosocial therapies for PD are each more effective than placebo, whether one treatment is more effective than the other, and whether combined therapy is more effective than either therapy alone.

METHODS

Randomized, double-blind, placebo-controlled clinical trial conducted in 4 anxiety research clinics from May 1991 to April 1998.

METHODS

A total of 312 patients with PD were included in the analysis.

METHODS

Patients were randomly assigned to receive imipramine, up to 300 mg/d, only (n=83); cognitive-behavioral therapy (CBT) only (n=77); placebo only (n=24); CBT plus imipramine (n=65); or CBT plus placebo (n=63). Patients were treated weekly for 3 months (acute phase); responders were then seen monthly for 6 months (maintenance phase) and then followed up for 6 months after treatment discontinuation.

METHODS

Treatment response based on the Panic Disorder Severity Scale (PDSS) and the Clinical Global Impression Scale (CGI) by treatment group.

RESULTS

Both imipramine and CBT were significantly superior to placebo for the acute treatment phase as assessed by the PDSS (response rates for the intent-to-treat [ITT] analysis, 45.8%, 48.7%, and 21.7%; P=.05 and P=.03, respectively), but were not significantly different for the CGI (48. 2%, 53.9%, and 37.5%, respectively). After 6 months of maintenance, imipramine and CBT were significantly more effective than placebo for both the PDSS (response rates, 37.8%, 39.5%, and 13.0%, respectively; P=.02 for both) and the CGI (37.8%, 42.1%, and 13.0%, respectively). Among responders, imipramine produced a response of higher quality. The acute response rate for the combined treatment was 60.3% for the PDSS and 64.1% for the CGI; neither was significantly different from the other groups. The 6-month maintenance response rate for combined therapy was 57.1% for the PDSS (P=.04 vs CBT alone and P=.03 vs imipramine alone) and 56.3% for the CGI (P=.03 vs imipramine alone), but not significantly better than CBT plus placebo in either analysis. Six months after treatment discontinuation, in the ITT analysis CGI response rates were 41.0% for CBT plus placebo, 31.9% for CBT alone, 19.7% for imipramine alone, 13% for placebo, and 26.3% for CBT combined with imipramine.

CONCLUSIONS

Combining imipramine and CBT appeared to confer limited advantage acutely but more substantial advantage by the end of maintenance. Each treatment worked well immediately following treatment and during maintenance; CBT appeared durable in follow-up. JAMA. 2000;283:2529-2536

Inescapable, but not escapable, stress inhibits the induction of Long Term Potentiation (LTP) in the CA1 region of hippocampus, a process that is dependent upon activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Since inescapable stress also produces a syndrome of behavioral depression sensitive to clinically effective antidepressants, we examined the actions of functional antagonists at the NMDA receptor complex in animal models commonly used to evaluate potential antidepressants. A competitive NMDA antagonist (2-amino-7-phosphonoheptanoic acid [AP-7]), a non-competitive NMDA antagonist (Dizolcipine [MK-801]), and a partial agonist at strychnine-insensitive glycine receptors (1-aminocylopropanecarboxylic acid [ACPC]) mimicked the effects of clinically effective antidepressants in these models. These findings indicate that the NMDA receptor complex may be involved in the behavioral deficits induced by inescapable stress, and that substances capable of reducing neurotransmission at the NMDA receptor complex may represent a new class of antidepressants. Based on these findings, the hypothesis that pathways subserved by the NMDA subtype of glutamate receptors are involved in the pathophysiology of affective disorders may have heuristic value.

Ketamine is a non-competitive antagonist to the phencyclidine site of N-methyl-d-aspartate (NMDA) receptor. Clinical findings point to a rapid onset of action for ketamine on the treatment of major depression. Considering that classic antidepressants may take long-lasting time to exhibit their main therapeutic effects, the present study aims to compare the behavioral effects and the BDNF hippocampus levels of acute administration of ketamine and imipramine in rats. To this aim, rats were acutely treated with ketamine (5, 10 and 15 mg/kg) and imipramine (10, 20 and 30 mg/kg) and animal behavioral was assessed in the forced swimming and open-field tests. Afterwards, BDNF protein hippocampal levels were assessed in imipramine- and ketamine-treated rats by ELISA-sandwich assay. We observed that ketamine at the doses of 10 and 15 mg/kg, and imipramine at 20 and 30 mg/kg reduced immobility time compared to saline group, without affecting locomotor activity. Interesting enough, acute administration of ketamine at the higher dose, but not imipramine, increased BDNF protein levels in the rat hippocampus. In conclusion, our findings suggest that the increase of hippocampal BDNF protein levels induced by ketamine might be necessary to produce a rapid onset of antidepressant action.

Here, we characterized behavioral abnormalities induced by prolonged social isolation in adult rodents. Social isolation induced both anxiety- and anhedonia-like symptoms and decreased cAMP response element-binding protein (CREB) activity in the nucleus accumbens shell (NAcSh). All of these abnormalities were reversed by chronic, but not acute, antidepressant treatment. However, although the anxiety phenotype and its reversal by antidepressant treatment were CREB-dependent, the anhedonia-like symptoms were not mediated by CREB in NAcSh. We found that decreased CREB activity in NAcSh correlated with increased expression of certain K(+) channels and reduced electrical excitability of NAcSh neurons, which was sufficient to induce anxiety-like behaviors and was reversed by chronic antidepressant treatment. Together, our results describe a model that distinguishes anxiety- and depression-like behavioral phenotypes, establish a selective role of decreased CREB activity in NAcSh in anxiety-like behavior, and provide a mechanism by which antidepressant treatment alleviates anxiety symptoms after social isolation.

Rats and mice when forced to swim in a restricted space will rapidly cease attempts to escape and become immobile. Previous experiments have shown that immobility was selectively reduced by antidepressant agents. The present experiments show that important differences exist between strains in both the amount of immobility observed and the effects of imipramine. Strain differences should therefore be taken into account in attempts to replicate results from one laboratory to another.

BACKGROUND

The endocannabinoid anandamide may be involved in the regulation of emotional reactivity. In particular, it has been shown that pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH), which catalyzes the intracellular hydrolysis of anandamide, elicits anxiolytic-like and antidepressant-like effects in rodents.

METHODS

We investigated the impact of chronic treatment with the selective FAAH inhibitor, URB597 (also termed KDS-4103), on the outcomes of the chronic mild stress (CMS) in rats, a behavioral model with high isomorphism to human depression.

RESULTS

Daily administration of URB597 (.3 mg kg(-1), intraperitoneal [IP]) for 5 weeks corrected the reduction in body weight gain and sucrose intake induced by CMS. The antidepressant imipramine (20 mg kg(-1), once daily, IP) produced a similar response, whereas lower doses of URB597 were either marginally effective (.1 mg kg(-1)) or ineffective (.03 mg kg(-1)). Treatment with URB597 (.3 mg kg(-1)) resulted in a profound inhibition of brain FAAH activity in both CMS-exposed and control rats. Furthermore, the drug regimen increased anandamide levels in midbrain, striatum, and thalamus.

CONCLUSIONS

URB597 exerts antidepressant-like effects in a highly specific and predictive animal model of depression. These effects may depend on the ability of URB597 to enhance anandamide signaling in select regions of the brain.

The Hamilton Anxiety Scale (HAM-A) was tested for reliability and validity in two different samples, one sample (n = 97) defined by anxiety disorders, the other sample (n = 101) defined by depressive disorders. The reliability and the concurrent validity of the HAM-A and its subscales proved to be sufficient. Internal validity tested by latent structure analysis was insufficient. The major problems with the HAM-A are that (1) anxiolytic and antidepressant effects cannot be clearly distinguished; (2) the subscale of somatic anxiety is strongly related to somatic side effects. The applicability of the HAM-A in anxiolytic treatment studies is therefore limited. More specific anxiety scales are needed.

OBJECTIVE

The authors examined gender differences in treatment response to sertraline, a selective serotonin reuptake inhibitor (SSRI), and to imipramine, a tricyclic antidepressant, in chronic depression.

METHODS

A total of 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were randomly assigned to 12 weeks of double-blind treatment with sertraline or with imipramine after placebo washout.

RESULTS

Women were significantly more likely to show a favorable response to sertraline than to imipramine, and men were significantly more likely to show a favorable response to imipramine than to sertraline. Gender and type of medication were also significantly related to dropout rates; women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the study. Gender differences in time to response were seen with imipramine, with women responding significantly more slowly than men. Comparison of treatment response rates by menopausal status showed that premenopausal women responded significantly better to sertraline than to imipramine and that postmenopausal women had similar rates of response to the two medications.

CONCLUSIONS

Men and women with chronic depression show differential responsivity to and tolerability of SSRIs and tricyclic antidepressants. The differing response rates between the drug classes in women was observed primarily in premenopausal women. Thus, female sex hormones may enhance response to SSRIs or inhibit response to tricyclics. Both gender and menopausal status should be considered when choosing an appropriate antidepressant for a depressed patient.

We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.

Caenorhabditis elegans concentrates its food, bacteria, by pharyngeal pumping. The rate of pumping is affected by the presence of bacteria. Using a new assay that allows measurement of pumping rate in a population of worms suspended in liquid by measuring their uptake of microscopic iron particles, we have confirmed and quantitated this effect. Furthermore, we demonstrated that starvation stimulates pumping. Worms that had been deprived of bacteria for more than 4 hours pumped in the absence of bacteria under conditions in which well-fed worms did not. Furthermore, starved worms responded to lower amounts of bacteria than did fed worms. The assay was also useful for measuring effects of drugs on pumping. Of about 30 chemicals screened, 5 had clear effects. The neurotransmitter serotonin and the serotonin uptake inhibitor imipramine stimulated pumping, while the serotonin antagonist gramine inhibits. Imipramine stimulation is greatly decreased in cat-1 and cat-4 mutants, which have low levels of serotonin. Muscimol, an agonist for the neurotransmitter GABA, and ivermectin, whose site of action may also be the GABA receptor, both inhibit pumping. Qualitative observations suggested a role for acetylcholine in the regulation of pumping.