Antidepressant-induced Dopamine Receptor Dysregulation: A Valid Animal Model of Manic-Depressive Illness.

BACKGROUND: Mania seems to be associated with an increased dopamine (DA) transmission. Antidepressant treatments can induce mania in humans and potentiated DA transmission in animals, by sensitizing DA D2 receptors in the mesolimbic system. We have suggested that the sensitization of D2 receptors may be responsible of antidepressant-induced mania. This review aims to report the experimental evidence that led to the hypothesis that antidepressant-induced DA receptors dysregulation can be considered an animal model of bipolar disorder. METHODS: We reviewed papers reporting preclinical and clinical studies on the role of DA in the mechanism of action of antidepressant treatments and in the patho-physiology of mood disorders. RESULTS: A number of preclinical and clinical evidence suggests that mania could be associated with an increased DA activity, while a reduced function of this neurotransmission might underlie depression. Chronic treatment with imipramine induces a sensitization of DA D2 receptors in the mesolimbic system, followed, after drug discontinuation, by a reduced sensitivity associated with an increased immobility time in forced swimming test of depression (FST). Blockade of glutamate NMDA receptors by memantine administration prevents the imipramine effect on DA receptors sensitivity and on the FST. CONCLUSION: We suggest that chronic treatment with antidepressants induces a behavioural syndrome that mimics mania (the sensitization of DA receptors), followed by depression (desensitization of DA receptors and increased immobility time in the FST), i.e. an animal model of bipolar disorder. Moreover the observation that memantine prevents the "bipolar-like" behavior, suggests that the drug may have an antimanic and mood stabilizing effect. Preliminary clinical observations support this hypothesis.

Failure of memantine to "reverse" quinpirole-induced hypomotility.

AIM: To evaluate antidepressant-like effect of memantine in a rat model. METHODS: Male Wistar rats were treated intraperitoneally with either vehicle, memantine (10 mg/kg) or imipramine (20 mg/kg), for 3 wk. Twenty-four hour after the last treatment animals were challenged with quinpirole (0.3 mg/kg s.c.) and tested for motor activity. After 1 h habituation to the motility cages, the motor response was recorded for the following 45-min and the data were collected in 5-min time bins. RESULTS: As expected, chronic treatment with imipramine potentiated the locomotor stimulant effect of quinpirole. On the contrary, chronic memantine administration failed to induce the behavioral supersensitivity to the dopamine agonist. CONCLUSION: The results show that memantine, at variance with antidepressant treatments, fails to induce dopaminergic behavioral supersensitivity. This observation is consistent with the results of preclinical and clinical studies suggesting that memantine does not have an acute antidepressant action but does have an antimanic and mood-stabilizing effect.

Three-year, naturalistic, mirror-image assessment of adding memantine to the treatment of 30 treatment-resistant patients with bipolar disorder.

BACKGROUND: Developing safe and effective long-term treatments for bipolar disorder remains a major challenge. Given available treatments, patients with bipolar disorder remain unwell in half of long-term follow-up, mostly in depression. As memantine, an N-methyl-D-aspartate (NMDA)-glutamate receptor antagonist used to treat dementia, has been proposed for testing in bipolar disorder, we carried out a 3 + 3-year, mirror-image, chart-review study of the effects of adding memantine to stably continued, but insufficiently effective, ongoing mood-stabilizing treatments. METHOD: Outpatients diagnosed with DSM-IV-TR bipolar disorder (I or II), followed intensively at the Lucio Bini Mood Disorder Center, Rome, Italy, had responded consistently unsatisfactorily to standard treatments (lithium, anticonvulsants, antipsychotics, antidepressants, and electroconvulsive therapy) for ≥ 3 years (2005-2013). Memantine (20-30 mg/d) was added clinically to otherwise stable regimens for another 3 years. On the basis of chart review, we compared morbidity measures and Clinical Global Impressions scale for Bipolar Disorder (CGI-BP) score before versus during memantine treatment. RESULTS: The 30 bipolar I (n = 17) and II (n = 13) subjects showed consistent morbidity for 3 years before memantine, but improved progressively (r = 0.28, P < .01) over 3 years with memantine (23 ± 4.8 mg/d). Markedly decreased (all P values ≤ .01) were (1) percentage of time ill (total, mania, or depression; averaging -75.0%), (2) CGI-BP severity scores (-67.8%), (3) duration of new episodes (-58.6%), and (4) episodes/year (-55.7%). Subjects with previous rapid or continuous cycling were particularly improved (t = 2.61, P = .016). Adverse effects were mild and rare. CONCLUSIONS: Memantine added substantial long-term benefits by preventing or ameliorating depressive as well as mania-like morbidity in previously consistently poorly responsive patients with bipolar disorder. Further testing in randomized, controlled trials is required.

Memantine prevents "bipolar-like" behavior induced by chronic treatment with imipramine in rats.

A great deal of evidence suggests that virtually all antidepressant treatments induce a dopaminergic behavioral supersensitivity. We have suggested that this effect may play a key role not only in the antidepressant effect of these treatments, but also in their ability to induce a switch from depression to mania. In 2003-4 we found that the sensitization of dopamine receptors induced by imipramine is followed, after imipramine withdrawal, by a desensitization of these receptors associated with a depressive-like behavior assessed in the forced swimming test. The dopamine receptor sensitization can be prevented by MK-801, an NMDA receptor antagonist, but not by currently used mood stabilizers (lithium, carbamazepine, valproate). These observations led us to suggest - and later confirm - with preliminary clinical observations that memantine may have an acute antimanic and a long-lasting mood-stabilizing effect in treatment-resistant bipolar disorder patients. Here we present data showing that memantine prevents not only the dopamine receptor sensitization induced by imipramine, as observed with MK-801, but also the ensuing desensitization and the associated depressive-like behaviorq observed after antidepressant withdrawal.

Memantine: New prospective in bipolar disorder treatment.

UNLABELLED: We review preclinical and clinical evidences strongly suggesting that memantine, an old drug currently approved for Alzheimer's dementia, is an effective treatment for acute mania and for the prevention of manic/hypomanic and depressive recurrences of manic-depressive illness. Lithium remains the first line for the treatment and prophylaxis of bipolar disorders, but currently available treatment alternatives for lithium resistant patients are of limited and/or questionable efficacy. Thus, research and development of more effective mood stabilizer drugs is a leading challenge for modern psychopharmacology. We have demonstrated that 21 d administration of imipramine causes a behavioural syndrome similar to a cycle of bipolar disorder, i.e., a mania followed by a depression, in rats. Indeed, such treatment causes a behavioural supersensitivity to dopamine D2 receptor agonists associated with an increase sexual activity and aggressivity (mania). The dopamine receptor sensitization is followed, after imipramine discontinuation, by an opposite phenomenon (dopamine receptor desensitization) and an increased immobility time (depression) in the forced swimming test of depression. Memantine blocks the development of the supersensitivity and the ensuing desensitization associated with the depressive like behavior. On the basis of these observations we have suggested the use of memantine in the treatment of mania and in the prophylaxis of bipolar disorders. To test this hypothesis we performed several naturalistic studies that showed an acute antimanic effect and a long-lasting and progressive mood-stabilizing action (at least 3 years), without clinically relevant side effects. To confirm the observations of our naturalistic trials we are now performing a randomized controlled clinical trial. Finally we described the studies reporting the efficacy of memantine in manic-like symptoms occurring in psychiatric disorders other than bipolar. LIMITATIONS: A randomized controlled clinical trial is needed to confirm our naturalistic observations. CONCLUSION: We believe that this review presents enough pharmacological and clinical information to consider the administration of memantine in the treatment of bipolar disorders that no respond to standard mood stabilizers.

Memantine in the treatment and prophylaxis of bipolar type II mood disorder and co-morbid eating disorder: a case report.

We have recently reported that memantine has a clinically relevant antimanic and long-lasting mood-stabilizing effect in treatment- resistant bipolar disorders, both as augmenting agent and as a monotherapy. Moreover, we observed an acute antimanic and sustained mood-stabilizing effect also in "naïve" bipolar type I disorder. Here we report a case history of a young woman suffering from bipolar type II mood disorder, associated with a very severe eating disorder, showing an acute antimanic and a long-term prophylactic effect of memantine on bipolar disorder and comorbid eating disorder.

Memantine in the treatment and prophylaxis of bipolar II disorder and comorbid fibromyalgia: a case report.

We have recently reported that memantine has a clinically relevant antimanic and long-lasting mood-stabilizing effect in treatment-resistant bipolar disorders, both as augmenting agent and as monotherapy. We have also observed an acute antimanic and sustained mood-stabilizing effect in a small number of patients with bipolar I disorder who had had minimal previous pharmacotherapy. In this article, we report the case of a young woman suffering from bipolar II disorder with associated fibromyalgia, in whom memantine showed an acute antimanic and a long-term prophylactic effect on both bipolar disorder as well as the associated fibromyalgia syndrome.

The role of memantine in the treatment of psychiatric disorders other than the dementias: a review of current preclinical and clinical evidence.

Memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease with a good safety profile, is increasingly being studied in a variety of non-dementia psychiatric disorders. We aimed to critically review relevant literature on the use of the drug in such disorders. We performed a PubMed search of the effects of memantine in animal models of psychiatric disorders and its effects in human studies of specific psychiatric disorders. The bulk of the data relates to the effects of memantine in major depressive disorder and schizophrenia, although more recent studies have provided data on the use of the drug in bipolar disorder as an add-on. Despite interesting preclinical data, results in major depression are not encouraging. Animal studies investigating the possible usefulness of memantine in schizophrenia are controversial; however, interesting findings were obtained in open studies of schizophrenia, but negative placebo-controlled, double-blind studies cast doubt on their validity. The effects of memantine in anxiety disorders have been poorly investigated, but data indicate that the use of the drug in obsessive-compulsive disorder and post-traumatic stress disorder holds promise, while findings relating to generalized anxiety disorder are rather disappointing. Results in eating disorders, catatonia, impulse control disorders (pathological gambling), substance and alcohol abuse/dependence, and attention-deficit hyperactivity disorder are inconclusive. In most psychiatric non-Alzheimer's disease conditions, the clinical data fail to support the usefulness of memantine as monotherapy or add-on treatment However, recent preclinical and clinical findings suggest that add-on memantine may show antimanic and mood-stabilizing effects in treatment-resistant bipolar disorder.

The sustained mood-stabilizing effect of memantine in the management of treatment resistant bipolar disorders: findings from a 12-month naturalistic trial.

BACKGROUND: We have recently provided preliminary clinical observations indicating that memantine, as augmenting agent, was associated with a meaningful antimanic and mood-stabilizing effect in treatment-resistant bipolar disorders. To further investigate the therapeutic and prophylactic action of the drug we administered memantine, as augmenting agent, to 40 treatment-resistant bipolar disorder patients, monitored and evaluated for 12 months. METHODS: The sample population encompassed 40 treatment-resistant bipolar disorder patients monitored for 12 months. Memantine, at the dose of 10-30 mg/day, was added to the ongoing treatment, which was left unmodified. The severity of the patients' condition before memantine and the changes after memantine addition were evaluated on the Clinical Global Impression Bipolar (CGI-BP) Overall Bipolar Illness Scale. The severity of patients' condition was scored before memantine and the change was evaluated after memantine addition at 6 and 12 months. LIMITATIONS: The present study has the limitations of an open clinical study and the observed effects require testing in a blinded, randomized, controlled trial which is planned. RESULTS: The average CGI-BP score of the patients was 6.7 (SD=0.58, range: 5-7) before the addition of memantine. After 6 months of memantine treatment, 72.5% of patients were very much or much improved. Among the rapid cyclers 68.4% of patients reached stability, defined by the absence of recurrences. Patients very much or much improved were 72.5% at 12 months; while 12.5% discontinued memantine or were lost to follow-up. CONCLUSIONS: The results confirm our previous observations and strongly suggest that memantine, as augmenting agent, was associated with a clinically substantial antimanic and sustained mood-stabilizing effect, with excellent safety and tolerability profile.

Clozapine increases reward evaluation but not overall ingestive behaviour in rats licking for sucrose.

RATIONALE: Clozapine and the "atypical" antipsychotics are less prone than neuroleptics to induce extrapyramidal motor effects, worsening of the negative symptoms of schizophrenia and dysphoria. This is paralleled by preclinical evidence showing reduced suppression of behaviours aimed at the pursuit of reward, with increased measures of reward efficacy. Serotonin 5-HT2 receptors seem to play a role in determining this profile. OBJECTIVE: We investigated the effects of clozapine on the microstructure of ingestive behaviour, which might reveal behavioural dimensions, such as reward evaluation and behavioural activation, which might be relevant in explaining its atypical profile. Moreover, we investigated the possibility that coadministration of the typical antipsychotic haloperidol and the 5-HT2A/2C receptor antagonist ritanserin might mimic clozapine effects. MATERIALS AND METHODS: The effects of clozapine (0.5, 1 and 5 mg/kg) and of the coadministration of haloperidol (0.05 mg/kg) and ritanserin (0.5 and 3 mg/kg) have been examined on the microstructure of licking for a 10% sucrose solution in rats. RESULTS: Clozapine failed to affect whole ingestion as revealed by the lack of effect on lick number. However, it increased reward evaluation at the dose of 1 mg/kg, as revealed by increased mean bout size. Haloperidol resulted in a decreased bout size. Ritanserin failed to exert any effects either alone or when coadministered with haloperidol. CONCLUSION: The ability of clozapine to increase reward evaluation might contribute to explain its atypical profile both in the clinical setting and in preclinical studies. These results suggest that 5-HT2A/2C receptors are not involved in the observed effect.

Dopamine on D2-like receptors is involved in reward evaluation in water-deprived rats licking for NaCl and water.

The analysis of licking microstructure provides measures, size and number of licking bouts, which might reveal, respectively, reward evaluation and behavioural activation. Based on the ability of the dopamine D2-like receptor antagonist raclopride to reduce bout size and to induce an "extinction mimicry effect" on bout number, we suggested that the level of activation of reward-associated responses is updated, or "reboosted", on the basis of a dopamine D2-like receptor-mediated evaluation process occurring during the consummatory transaction with the reward. Here we investigate the effects of the dopamine D2-like receptor antagonist raclopride (0, 25, 125, and 250microg/kg) on the microstructure of licking for water and sodium chloride solutions (0.075M, 0.15M, and 0.3M) in 12h water-deprived rats. In each session, rats were exposed to brief contact tests (1min) for each solution. Bout size, but not bout number, was decreased at the highest NaCl concentration. Raclopride reduced lick number owing to reduced bout size, while bout number was either not affected or even increased depending on the dose. These results are in agreement with the previous observations on sucrose licking, and suggest the involvement of dopamine D2-like receptors in an evaluation process occurring during the consummatory transaction with the reward.

Dopamine is involved in the antidepressant-like effect of allopregnanolone in the forced swimming test in female rats.

Evidence from both animal and human studies suggests a role for dopamine in the therapeutic effect of antidepressant drugs. Consistently, dopamine receptor antagonists antagonize the effect of antidepressant drugs in different experimental models of depression. Neurosteroids, and in particular allopregnanolone, seem to be involved both in the pathophysiology of depression and in the mechanism of action of antidepressant drugs, and their role seems to be particularly important in the understanding of mood disturbances related to the different phases of the reproductive life in women. The aim of this study was to investigate the possible role of dopamine on the antidepressant-like effect of allopregnanolone in a model of depression. Thus, we examined (i) the behaviour of female Sprague-Dawley rats in the forced swimming test during estrus and diestrus and their response to allopregnanolone treatment (0.5, 1 and 2 mg/kg), and (ii) the effect of the dopamine D1-like and D2-like receptor antagonists SCH 23390 (0.01 and 0.025 mg/kg) and raclopride (0.05 and 0.2 mg/kg) on the antidepressant-like effect of allopregnanolone (2 mg/kg) in the same experimental model. We failed to observe differences in depressive-like behaviour between estrous phases, and allopregnanolone administration in both estrus and diestrus resulted in an antidepressant-like effect consisting in an increase of swimming behaviour. The allopregnanolone effect was unaffected by a dose of the dopamine D1-like receptor antagonist SCH 23390 displaying a marked inhibitory effect on basal activity, while it was turned into a potentiation of the depressive-like behaviour of the forced swimming condition by treatment with the higher dose of raclopride. The present results indicate an involvement of dopamine transmission in the allopregnanolone antidepressant-like effect in the forced swimming model of depression, and suggest that this effect depends mainly on stimulation of dopamine D2-like receptors.

A possible role for the endocannabinoid system in the neurobiology of depression.

The present review synthetically describes the currently advanced hypotheses for a neurobiological basis of depression, ranging from the classical monoaminergic to the more recent neurotrophic hypothesis. Moreover, the Authors review the available preclinical and clinical evidence suggesting a possible role for the endocannabinoid system in the physiopathology of depression. Indeed, in spite of the reporting of conflicting results, the pharmacological enhancement of endocannabinoid activity at the CB1 cannabinoid receptor level appears to exert an antidepressant-like effect in some animal models of depression. On the contrary, a reduced activity of the endogenous cannabinoid system seems to be associated with the animal model of depression, namely the chronic mild stress model. Moreover, a few studies have reported an interaction of antidepressants with the endocannabinoid system. With regard to clinical studies, several authors have reported an alteration of endocannabinoid serum levels in depression, while post mortem studies have demonstrated increased levels of endocannabinoids associated to a concomitant hyperactivity of CB1 receptor in the prefrontal cortex of suicide victims. No clinical trials carried out using cannabinoids in the treatment of affective disorders have been published to date, although anecdotal reports have described both antidepressant and antimanic properties of cannabis as well as the ability of cannabis to induce mania that has also been documented. These findings are discussed, leading us to conclude that, although data available are sufficient to suggest a possible involvement of the endogenous cannabinoid system in the neurobiology of depression, additional studies should be performed in order to better elucidate the role of this system in the physiopathology of depression.

Chronic valproate fails to prevent imipramine-induced behavioural sensitization to the dopamine D2-like receptor agonist quinpirole.

Based on experimental evidence suggesting a relationship between dopamine and mania, we proposed the antidepressant-induced dopaminergic supersensitivity as a model of antidepressant-related mania. We have previously shown the ability of carbamazepine, but not lithium, to prevent this phenomenon. Here we show that sodium valproate (50 mg/kg/day for 3 weeks) fails to prevent imipramine (20 mg/kg/day for 3 weeks)-induced sensitization to the locomotor response to the dopamine D2-like receptor agonist quinpirole (0.15 mg/kg). Since lithium, carbamazepine and valproate are all considered poorly effective in the treatment of antidepressant-related mania, the validity of the proposed model should be disproved by the carbamazepine results, to which, however, a pharmacokinetic mechanism might have concurred.

Dopamine D3 receptor antisense oligodeoxynucleotide potentiates imipramine-induced dopaminergic behavioural supersensitivity.

Chronic antidepressant treatments result in the potentiation of dopaminergic transmission in the mesolimbic dopamine system revealed as an increased motor response to dopamine D2-like agonists. On the basis of the involvement of this system in the control of motivation and reward-related behaviour, which are impaired in depression, it has been suggested that such supersensitivity might play an important role in the mechanism of action of these drugs. Several studies have provided evidence suggesting a role of dopamine D3 receptors in mediating antidepressant-induced increased motor response to dopamine agonists. To test this hypothesis, we studied the effect of the intracerebroventricular infusion of a dopamine D3 receptor antisense oligodeoxynucleotide (10 microg/3 microl, 2-3 daily injections) on the expression of imipramine-induced supersensitivity (20 mg/kg daily intraperitoneal injections for 21 days) to the motor effect of the dopamine D2-like receptor agonist quinpirole (a single 0.3 mg/kg subcutaneous injection 24-48 h after imipramine withdrawal). The results show that a treatment previously shown to reduce the synthesis of dopamine D3 receptors, rather than resulting in an inhibitory effect, potentiated the ability of imipramine to induce dopaminergic motor supersensitivity. The present results suggest that increased dopamine D3 receptor expression following antidepressant treatments is not involved in the mechanism of dopaminergic supersensitivity, and are consistent with evidence supporting an inhibitory role for dopamine D3 receptors in motor activity, both in normal and in sensitized subjects.

Long-term imipramine withdrawal induces a depressive-like behaviour in the forced swimming test.

Chronic antidepressant treatments enhance dopaminergic neurotransmission in the mesolimbic dopamine system. We suggested that this potentiation might underlie both the antidepressant therapeutic effect and the antidepressant-induced switch from depression to mania. In a recent study we have shown a reversal of the imipramine-induced dopaminergic supersensitivity after 40 days of chronic imipramine withdrawal. We interpreted this result suggesting that the mood-switches observed in bipolar patients following antidepressant treatment and subsequent withdrawal, i.e. mania followed by rebound depression, might depend upon parallel changes in the mesolimbic dopamine system sensitivity. On this basis, one might predict a depressive-like behaviour after long-term interruption of a chronic treatment with imipramine. To test this hypothesis we examined the behaviour of rats treated with chronic imipramine 40 days after treatment interruption in an animal model of depression, the forced swimming test. The results show that animals treated with chronic imipramine, 40 days after treatment interruption, display a depressive-like behaviour in the forced swimming test, as indicated by their increased immobility with respect to the control group.