The CB(1) antagonist rimonabant is adjunctively therapeutic as well as monotherapeutic in an animal model of Parkinson's disease.

Acute injections of 8mg/kg of 3,4-dihydroxy-l-phenylalanine (l-DOPA) or 0.05mg/kg rimonabant equally improved contralateral forepaw stepping in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions, and their combination improved stepping more than either drug alone. However, 0.05mg/kg rimonabant did not alter the changes in stepping produced by acute injections of a dyskinesic dose of 35mg/kg l-DOPA. Thus, not only is a cannabinoid antagonist monotherapeutic in this animal model of Parkinson's disease, but it also enhances the therapeutic effect of a moderate, but not a high, dose of l-DOPA.

Treatment strategies in achieving remission in major depressive disorder.

OBJECTIVE: This paper discusses strategies for achieving remission in major depressive disorder, summarizing the results of comparative studies of various antidepressants. METHOD: Antidepressant efficacy was determined as either response or remission, measured using the Hamilton Depression Rating Scale, the Clinical Global Impressions scale and other widely used instruments. RESULTS: Study results suggest an advantage to pharmacotherapy that interacts with more than one neurotransmitter system, either as single mixed-activity drugs (e.g. clomipramine, mirtazapine and venlafaxine extended-release) or combinations of medications that are individually specific for a single neurotransmitter system. CONCLUSION: Remission should be the goal of antidepressant therapy. Treatment strategies include increasing the dosage of the chosen antidepressant; switching to an antidepressant with a different mechanism of action; augmenting one antidepressant with another agent; or using combination therapy. A substantial body of data indicates that for a subset of depressed patients, activation of multiple neurotransmitter systems is beneficial in achieving remission.

Social anxiety: an often silent disorder.

Social anxiety disorder (SAD) is a chronic, often debilitating disorder with a high potential for comorbid conditions. Despite being among the most common of psychiatric disorders it is often under-recognized. This case illustrates the treatment of a patient who had initially presented for treatment of major depressive disorder, but was later discovered to also have SAD. Treatment of the SAD, which had predated the major depressive disorder, resulted in a markedly improved outcome. Discussions of treatment options including pharmacotherapy and psychotherapy are presented.

Clinician perspective on achieving and maintaining remission in depression.

The majority of large-scale clinical trials of depression focus on response, typically defined as a 50% reduction in symptoms, as the endpoint. Response in the absence of remission places patients at greater risk for relapse, decreases their level of functioning, and erodes quality of life. Most importantly, both research and our clinical experience suggest that remission, or "getting well," is an attainable goal for patients with major depressive disorders. Pharmacotherapy, psychotherapy, and combination regimens are all treatment options. Recent studies across a range of patient populations have demonstrated the benefit of affecting multiple transmitter systems over a single antidepressant mechanism. Pooled data from more than 2000 patients comparing venlafaxine, a serotonin-norepinephrine reuptake inhibitor, and selective serotonin reuptake inhibitors suggest that the dual mechanism of action of venlafaxine provides significantly greater efficacy in achieving remission. Ultimately, achieving a good clinical outcome is desirable, but sustaining the mood state is, perhaps, more important. Studies of venlafaxine show it is possible to prevent more relapses and recurrences of depression with dual-mechanism treatment than with placebo. These data highlight the need for setting appropriately aggressive goals and working closely with our patients to achieve them. By doing so, we create the best opportunity for restoring patients to "wellness" and, ultimately, a normal and fulfilling life.

Efficacy, safety, and tolerability of venlafaxine XR in generalized anxiety disorder.

Generalized anxiety disorder (GAD) is a common and chronic disorder with a low rate of spontaneous remission. A complication in treatment selection is the high rates of co-morbid major depressive disorder in this population. A number of treatments exist to treat GAD. The most recent medication to gain an indication for GAD is venlafaxine XR, a serotonin/norepinephrine reuptake inhibitor that is also approved for the treatment of major depressive disorder. More than 2,000 patients with GAD have been studied in outpatient trials of venlafaxine XR with demonstrated efficacy, tolerability and safety of this compound. This article reviews these studies, both short term and longer (6 month) continuation trials. The response to venlafaxine XR in this population, combined with good tolerability, makes this agent an appropriate first-line medication for GAD. In general, treatment with antidepressants, though associated with a longer onset of action than benzodiazepines, does not produce physiological dependency, and is useful in a patient population with a high prevalence of mood disorders.

Social phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Perforant path stimulation in rats produces seizures, loss of hippocampal neurons, and a deficit in spatial mapping which are reduced by prior MK-801.

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.

Medial septal lesions in rats enhance locomotor sensitization to amphetamine.

RATIONALE: The mesolimbic dopamine (DA) system appears to play a major role in the locomotor activating and sensitizing effects of several addictive drugs. However, less is known about the neural structures that may modulate this system. OBJECTIVE: We examined the effects of medial septal lesions on the locomotor activating and sensitizing effects of amphetamine in between-subjects (experiment 1) and within-subjects (experiment 2) experiments. RESULTS: Repeated injections of 0.6 mg/kg (experiment 1) or 1.0 mg/kg (experiment 2) amphetamine over six sessions produced more locomotion in the lesioned rats than in the sham-operated controls. This repeated exposure to amphetamine subsequently increased the locomotor response to 0.2 mg/kg (experiment 2) and 0.4 mg/kg (both experiments) amphetamine in the lesioned rats, such that these sensitized, lesioned rats moved more in response to these doses than unsensitized, lesioned rats and sensitized controls did. Both experiments also indicated that this prior sensitization enhanced the locomotor response to 0.4 mg/kg amphetamine more in the lesioned rats than in the control rats when compared with the response produced by saline following sensitization or by the same dose of amphetamine prior to sensitization. In contrast, prior exposure to amphetamine decreased the locomotor response to 4.0 mg/kg amphetamine in the lesioned rats (experiment 1). CONCLUSIONS: Although medial septal lesions occasionally enhance locomotor responses to moderate doses of amphetamine prior to sensitization, a main effect of these lesions is to further enhance the effects of locomotor sensitization to amphetamine. Implications for drug addiction are discussed.

Acute corticosterone replacement reinstates performance on spatial and nonspatial memory tasks 3 months after adrenalectomy despite degeneration in the dentate gyrus.

Long-term adrenalectomy (ADX) causes loss of spatial memory and of dentate gyrus cells. These effects are prevented by chronic replacement of corticosterone (CORT). The effects of acute replacement 3 months after ADX in rats classified as ADX or incomplete ADX (INC) on the basis of saline intake, weight, and plasma CORT levels were investigated. ADX rats swam longer and farther to find a platform in a spatial water-maze task (Exp. 1) and were impaired on a nonspatial object-recognition task (Exp. 2) compared with INC and SHAM rats. In both experiments, ADX decreased the size of the dentate gyrus, and replacement with CORT either 5 or 10 days prior to and during testing restored the performance of ADX rats without affecting the size of the dentate. CORT did not affect INC and SHAM rats. Thus, the adverse effects of ADX on memory may not be due to damage in the dentate, and the effects of CORT replacement may operate outside the hippocampus.

Dose-response relationship with venlafaxine.

Considerations when selecting a first-line antidepressant agent include the potential for achieving greater response with increasing dosages, thereby allowing greater flexibility in dosing. The efficacy and dose-response of venlafaxine, a novel serotonin and norepinephrine reuptake inhibitor, was evaluated in two placebo-controlled studies. Both studies demonstrated that venlafaxine was efficacious (as determined by the Hamilton Rating Scale for Depression, the Montgomery-Asberg Depression Rating Scale, and the Clinical Global Impressions scale scores), as well as safe and tolerable when administered either twice or three times daily in the treatment of outpatients who had major depression. In addition, evidence of a dose-response relationship was shown in both studies.

Temporal factors in the effect of restraint stress on morphine-induced behavioral sensitization in the rat.

The role of associative factors in the effect of 15 min/day of restraint stress on morphine-induced behavioral sensitization was examined. Male rats were initially given seven systemic (10 mg/kg, IP) or intraventral tegmental area (VTA, 5 micrograms/side) [corrected] injections of morphine, and were exposed to restraint, either just prior to drug injection (Paired-Stress) or 24 h after injection (Unpaired-Stress), or to no restraint (Control). In subsequent tests for behavioral sensitization to low doses of morphine (0.75 or 3.0 mg/kg, IP), animals in the Paired-Stress condition were more active than animals in the Unpaired-Stress or Control conditions. These results indicate that temporal and possibly associative factors may contribute to stress-induced changes in sensitization to the behavioral activating effects of opioids.

Venlafaxine in social phobia.

Social phobia is a prevalent anxiety disorder with potentially significant dysfunction and a high rate of comorbid depression. Treatment with an antidepressant is often indicated. Venlafaxine's dual activity at both serotonin and norepinephrine transporters suggests that it might be efficacious in treating social phobia, particularly in patients who do not respond to selective serotonin reuptake inhibitors (SSRIs). This report describes an open-label trial of venlafaxine in 9 patients with social phobia. Eight patients had previously been treated with an SSRI and had either been unable to tolerate the medication or failed to respond to it. Eight patients had a marked improvement on venlafaxine. The results from this chart review suggest that venlafaxine may be a valuable treatment for social phobia. Clearly, larger double-blind placebo-controlled studies are needed. Patients with social phobia may do better with a starting dose smaller than the one in the package insert.

Lesions of the dorsomedial amygdala, but not the nucleus accumbens, reduce the aversiveness of morphine withdrawal in rats.

Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal. Together, these findings suggest that the neural structures that mediate the rewarding effects of opiates may be at least partially distinct from the structures that mediate the aversive effects of opiate withdrawal.

Medial septal lesions disrupt spatial, but not nonspatial, working memory in rats.

In Experiment 1, rats with small medial septal lesions were less able than were control rats to remember the location of the arm of a Y maze they had been forced to enter on the preceding sample run. Moreover, as the retention interval between the sample and choice runs on this spatial delayed nonmatching-to-sample (DNMTS) task was increased to 1 and 2 min, the magnitude of the deficit increased. In contrast, these same lesioned rats were not deficient in Experiment 2 in their ability to remember the object they had encountered in the straight alley on the sample run. In fact, when the retention interval was increased to 1 min on this nonspatial DNMTS task, the rats with medial septal lesions were more accurate than were the controls. This pattern of results did not appear to be due to task difficulty, recovery of function, or sequence of training. Rather, these results indicate that damage to the septohippocampal system disrupts spatial working memory more than it disrupts nonspatial working memory.