The 25th Annual Meeting of the Canadian College of Neuropsychopharmacology

CCNP Heinz Lehmann Award lecture

This year the CCNP Heinz Lehmann Award went to Dr. H. Steiger (McGill University, Montreal), whose talk was titled “Eating disorders and the serotonin connection: states, traits and trauma.” The eating disorders anorexia and bulimia have a multidimensional (biopsychosocial) pathogenesis, and Dr. Steiger argued that the study of the serotonergic system in eating disorders illustrates the convergence of biological, psychological and social factors. Although eating disorders are traditionally classified in terms of anorexia or bulimia, another way of looking at them is to classify them in terms of restricters, characterized by too much dieting and overly inhibited eating behaviour and bingers–purgers who demonstrate more impulsive behaviour and emotional instability, characteristics that have been associated with low serotonin function. One factor that may alter serotonin function is dieting, as relatively nonintensive dieting over only 3 weeks has been shown to decrease the prolactin response to the serotonergic agent fenfluramine. This suggests that decreased food intake may be a factor that lowers serotonin function in both restricters and bingers–purgers. However, 2 studies suggest that serotonergic abnormalities may play a larger role in the latter group. Platelet paroxetine binding (a measure of the serotonin transporter) was lower in low-impulsive bulimics than in normal-eating controls, but was even lower in impulsive bulimics. In a second study, subjects were divided into 4 groups depending on how impulsive and compulsive they were, and their prolactin response to the serotonin receptor agonist m-chlorophenylpiperazine (mCPP) was measured. The high impulsive, low compulsive group showed a markedly lower prolactin response than the other groups.

Altered serotonin function in eating disorders may also be associated with developmental stressors. Thus, bulimic women who were abused in childhood had a somewhat lower prolactin response to mCPP than bulimic women who were not abused in childhood. Interestingly, the prolactin responses of women who were abused but did not have eating disorders were just as low.

Serotonergic anomalies that occur in patients with eating disorders may have implications for their stress tolerance, impulse control, capacity for mood regulation and ability to control eating behaviour. These characteristics are under partial genetic control, so genetic, developmental (abuse) and environmental (dieting) factors may all contribute to the dysregulated serotonergic system that promotes behavioural and mood dysregulation in some patients with eating disorders. This raises the possibility that in less impulsive patients, symptom-focused, nutritionally oriented therapies may prove adequate, whereas impulsive patients may not respond unless the more fundamental dysregulation of the serotonergic system is tackled through pharmacological support.

CCNP Innovations in Neuropsychopharmacology Award lecture

This year, the CCNP Innovations in Neuropsychopharmacology Award was given to Dr. S. Lal (McGill University, Montreal), who summarized some of his work under the title “Some historical notes on that most extraordinary compound synthesized by Matthiessen and Wright in the year of our Lord, 1869.” The extraordinary compound is apomorphine, and Dr. Lal’s talk combined history, science and humour in a most effective way. Apomorphine was synthesized by heating morphine with hydrochloric acid, and immediately after its synthesis, studies in humans and dogs established that it was an emetic and also produced stereotyped behaviour. In the late nineteenth century, its use as an emetic led to the realization that it also has a sedative effect. This was used clinically, and in the early part of the twentieth century its use in the treatment of alcoholic delirium led to the further observation that it was decreasing anxiety and craving. As a result, for several decades Dent’s Oral Apomorphine was used for the treatment of alcoholism. In the 1960s, Dr. Lal and his colleague, Dr. E.K. Schlatter, were using it to treat a patient for alcohol dependence, and the patient claimed that the drug caused an erection, although he had been impotent for 4 years. This led to the first publication on apomorphine as an inducer of penile erections. Subsequent research led to the marketing of apomorphine in July 2001 to treat impotence.

The success of apomorphine in the treatment of Parkinson’s disease in the 1930s was later explained by the discovery, in 1970, of its action as an agonist at DA receptors. The 1970s also saw the use, pioneered by Dr. Lal, of apomorphine as a neuroendocrine probe. In humans, it stimulates the release of growth hormone and inhibits the release of prolactin, even in patients with prolactinemia. Other effects in humans include a suppression of photosensitive epilepsy. At low doses, it suppresses yawning, but at high doses, it stimulates this behaviour.

Although apomorphine has been given extensively to humans, it has not been found to either cause or exacerbate psychosis. This obviously is not consistent with the simple DA theory of schizophrenia and has led to the suggestion that apomorphine may be acting primarily presynaptically to inhibit DA function in humans. The data on yawning suggests that it may act presynaptically at low doses, but probably postsynaptically at higher doses; its therapeutic effect in Parkinson’s disease is a clear indication that it can act postsynaptically in humans. Apomorphine is more specific than amphetamine for its effect on dopaminergic systems, and amphetamine definitely can cause psychosis. Thus, enhanced DA function may be necessary but not sufficient for the production of psychosis.

CCNP Young Investigator Award lectures

This year, the CCNP Young Investigator Award was shared by 2 researchers who work on very different topics, but have adjacent offices, Dr. S. Kar and Dr. C.D. Walker (both from McGill University, Montreal).

Dr. S. Kar spoke on “Amyloid beta peptides and cholinergic neurons: functional interrelations and relevance to Alzheimer’s disease pathology.” He first presented an overview of the pathology of Alzheimer’s disease characterized by the deposition of β-amyloid (Aβ) plaques, neurofibrillary tangles and loss of cholinergic neurons in patients’ brains. Dr. Kar showed data on the modulatory/toxic relationship of Aβ peptides with cholinergic neurons in several model systems including brain slices, cultured septal neurons, transgenic mice and age-impaired rats. His results show that picomolar concentrations of Aβ potently inhibit acetylcholine release and choline uptake in the cortex and hippocampus, but not in the striatum of adult rats. Moreover, cholinergic neurons of aged cognitively impaired rats show greater sensitivity to the release-inhibiting actions of Aβ than those of aged unimpaired rats. In cultured septal neurons, micromolar concentration of Aβ induces tau phosphorylation and cell death. Dr. Kar also presented data showing alterations in some cholinergic markers in the brains of amyloid precursor protein and presenilin-1 double transgenic mice. To conclude, he stated that the sensitivity of cholinergic neurons toward Aβ peptides suggests a potential mechanistic link between the deposition of Aβ and vulnerability of these neurons in Alzheimer’s disease.

Dr. C.D. Walker’s talk was titled “Interactions between mother and pups in regulation of stress responsiveness.” Her research focuses on the complex bidirectional relations that regulate stress in mothers and their infants, and she illustrated some of the relations from her work on rats. Nutrition is one of the variables. Mothers fed a high-fat diet produce milk with a higher fat content. This, in turn, increases the body fat stores of the pups, and fat stores produce leptin, a hormone whose target is the brain. Although leptin was originally studied for its effect on hunger and satiety, it also influences the hypothalamic-pituitary-adrenal (HPA) axis. Rat pups of mothers fed high-fat diets show decreased adrenocorticotropic hormone (ACTH) output in response to stress. When leptin is injected into rat pups to produce a level of leptin similar to that produced by a high-fat diet in the mother, it also reduces ACTH output, and this seems to be related to increased glucocorticoid feedback efficiency. Specifically, there is increased expression of glucocorticoid receptor mRNA and protein in the hippocampus. These receptors are important in the negative feedback control of the HPA axis.

Another change that may contribute to the altered stress response is the activation of a messenger called suppressor of cytokine signalling 3 (SOCS-3), which, among other functions, is involved in feedback inhibition of the HPA axis. Other changes produced by leptin include a decrease in NPY mRNA and an increase in pro-opiomelanocortin (POMC) mRNA. Although these changes might be expected to decrease food intake, it is not altered, suggesting that other compensatory mechanisms exist. Use of a DNA microarray on hippocampal tissue indicates that there are changes in the expression of a variety of other genes. These include the NR1 subunit of the N-methyl-d-aspartate (NMDA) receptor, so the changes are very wide ranging. This work illustrates how maternal diet can alter what is happening in the brains of the pups during postnatal development. It also demonstrates that high-fat diets can be beneficial during early development, and this may have important clinical implications.

The other side to the interaction between mother and pup is the effects that pups can have on the mother. In lactating mothers, ACTH response to stress is, in general, lowered. However, the salience of a stressor can alter the response. Activation of the HPA axis is greater to a male intruder when the pups are present (presumably because of the potential threat to the pups) than when they are absent. Similarly, the presence of pups eliminates the blunted ACTH response to the smell of fox urine seen in lactating mothers in the absence of pups. Work is currently under way to see how the salience of the stimulus to the security of the baby influences the stress response of human mothers.

The SNRI story in antidepressants: dual action or more of the same

Dr. F.P. Bymaster (Lilly Research Laboratories, Indianapolis) opened the session with a talk titled “Preclinical investigations of the blockade of monoamine transporters by dual-uptake inhibitors.” The important question is whether inhibition of uptake of both serotonin (5-HT) and noradrenaline is better than inhibition of either one alone. In support of this idea, the antidepressant action of fluoxetine plus desipramine is better than either alone. The locus ceruleus and the raphe nuclei each project to the other, providing a possible basis for the superiority of dual-action drugs. Different dual-action drugs have different relative affinities for the 2 transporters. Although duloxetine and milnacipran have relatively similar affinities for the 2, venlafaxine and clomipramine have greater affinity for the serotonin transporter. However, intracerebral dialysis studies in rats indicate that duloxetine, venlafaxine and clomipramine all stimulate the release of both noradrenaline and serotonin. Milnacipran has less effect on both systems, possibly due to poor penetration into the brain.

Dr. J.H. Meyer (University of Toronto) talked about “Lessons from PET investigations of serotonin transporter occupancy.” The aim of his work was to define the relation between receptor occupancy and clinical effect. Using a tracer that binds with good reproducibility to the serotonin transporter, the ability of fluoxetine, sertraline, venlafaxine, citalopram and paroxetine to displace the ligand was studied. The drugs were given to healthy volunteers for 4 weeks. The minimum therapeutic dose resulted in a range of occupancy of the transporter between 75% and 83%. Increasing the dose of the drug increased occupancy in a nonlinear fashion, with some degree of flattening of the curve at higher doses. It remains to be seen to what extent increasing the occupancy of the serotonin transporter above about 80% will do to the clinical efficacy of uptake inhibitors.

Dr. J.-M. Le Mellédo (University of Alberta, Edmonton) introduced new complexities in the action of selective serotonin reuptake inhibitors (SSRIs) in his talk on “Effect of selective serotonin reuptake inhibitors on cholesterol and nitric oxide.” In depression, and to some extent anxiety disorders, there is an increased risk of cardiovascular disease. However, the mechanism responsible is unknown, and there is no clear evidence for the efficacy of antidepressant treatments in modifying the risk of cardiovascular disease. High levels of low-density lipoprotein cholesterol (LDL-C) are a risk factor in cardiovascular disease, and this may be mediated in part by decreased nitric oxide (NO) production. Paroxetine, but not nortriptyline, decreases NO production, and a variety of SSRIs increase LDL-C levels in patients with panic disorder on long-term treatment. Levels fall again on drug discontinuation. A greater understanding is needed of how mental state and serotonin and noradrenaline reuptake inhibitors modify these risk factors for cardiovascular disease.

Dr. S.H. Kennedy (University of Toronto) reviewed the evidence concerning the efficacy of SSRIs and dual-action drugs. Overall, SSRIs and tricyclic antidepressants (TCAs) may be equally effective, but TCAs have an edge in severely depressed patients, although more patients stop taking TCAs because of side effects. Several studies indicate that the dual-uptake inhibitor venlafaxine is more effective than SSRIs and imipramine, although it is less clear that venlafaxine is better than other TCAs. A single study indicates that the dual-action drug duloxetine is superior to fluoxetine. A single study suggests that, in patients not responding to fluoxetine, dosage escalation is more effective than augmentation with desipramine or lithium. Overall, although some evidence favours the efficacy of dual-action drugs, the evidence is not entirely consistent.

Rapid response to antidepressants

This symposium was omitted from the 2001 meeting report but is included here because it remains timely. The symposium critically assessed evidence suggesting that some drug combinations might elicit a rapid antidepressant response. The speakers emphasized the clinical importance of developing more rapid treatments, and the research is notable for using evidence- and mechanism-based treatment development strategies.

Dr. M.T. Isaac (University Hospital Lewisham, London, UK) opened the session with a talk titled “Assessing the rate of onset of antidepressants: some methodological issues.” He noted that in the UK, an estimated $2/person/yr was spent on antidepressants, that $60 million/yr was spent on general practitioner consultations, and that direct economic costs related to depression had been estimated at $900 million/yr. A comparable figure for the US was $44 billion/yr. Benefits of a rapid treatment response includes rapid symptom relief, decreased suicide risk, destigmatization of the disorder, decreased economic costs and faster return to productive functioning. Most studies, though, are not designed to detect speed of clinical response. It was suggested that studies better designed for this purpose would include predetermined criteria of treatment response, more frequent clinical assessments (especially during the first 2 weeks of treatment), aggressive dosing schedules and larger samples. Clinical samples for initial studies should be relatively homogenous, severely ill and without comorbid Axis II or substance use disorders. Both the “placebo” and “treatment” arms of such studies can include treatment because the experimental manipulation is the addition of a putative augmenting agent. Data from 2 new studies were presented. In the first, treatment with paroxetine was compared with that of paroxetine plus the mixed 5-HT_1A/β-noradrenergic receptor antagonist pindolol (which increases synaptic levels of 5-HT and noradrenaline). The combination treatment produced a statistically significant acceleration of treatment response. Patients who exhibited this accelerated response had fewer past episodes of treated depression than those who did not. The second study compared the effect of the dual 5-HT and noradrenaline reuptake inhibitor milnacipran with that of milnacipran plus pindolol. By 6 weeks, a positive treatment response was seen in 58% of the milnacipran plus placebo group and in 95% of those in the combination treatment group. Dr. Isaac cautioned that the size of the sample was modest (39/group).

Dr. D. Bakish (Ottawa Psychopharmacology Clinic) spoke on “Changes in clinical trial research patients: a comparison of baseline characteristics of 2 samples of depressed patients, pre- and post-SSRIs.” His presentation addressed the possibility that patient populations participating in clinical trials might have changed during the past decade, either as a result of changing recruitment strategies or cohort effects. Patients recruited by the same clinicians at the same clinic for studies conducted in 1988 and 1998 were compared. In the 1988 study, patients were recruited primarily from GP referrals. In 1998, they were recruited from newspaper advertisements. There were no group differences in sex distribution, ethnic background, age at referral, marital status or family history of psychosis. However, fewer individuals in the latter sample reported use of nicotine (58% v. 18%), but more used alcohol (58% v. 72%). In the 1998 sample, age of onset of first episode was younger (32 v. 27 yr), number of past episodes was higher (2 v. 6) and delay in seeking treatment was longer (patients reported trying more “alternative” medicines before seeking medical help). The 1998 sample also reported a more frequent family history of major depression, bipolar depression and anxiety disorders, less frequent comorbid diagnoses (71% v. 20%) and lower HAM-D scores (26 v. 22), and they were less likely to have received previous pharmacotherapy (28% v. 5%). The overall picture suggested a patient sample with more severe forms of the disorder earlier in the course of their illness.

Dr. P. Blier (University of Florida, Gainesville) discussed “Neurobiological bases for rapid onset pharmacotherapies of major depression.” He began by emphasizing that the development of rapid treatments for depression was definitely possible — such treatments already exist (e.g., sleep deprivation and electroconvulsive therapy). Given that acute tryptophan depletion and α-methyl-p-tyrosine challenge studies indicate a role of both 5-HT and noradrenaline in the clinical efficacy of different antidepressants, it seems plausible that increasing activity in both systems simultaneously might lead to a more efficacious and rapid response. Examples of encouraging early results using this strategy include treatment with an SSRI plus pindolol and dual 5-HT–noradrenaline reuptake inhibitors. Dr. Blier noted that recent preclinical studies in rats and PET studies in humans indicate that even high doses of pindolol preferentially block presynaptic (not postsynaptic) 5-HT_1A receptors. In addition, a long-known rapid treatment strategy — sleep deprivation — may have greater clinical applicability than previously thought; a recent study suggests that 3 nights of sleep deprivation distributed over 9 days leads to a clinical remission that can be maintained by lithium.

Preliminary animal studies suggest that combining an SSRI with the α₂-antagonist mirtazapine leads to significantly greater increases in noradrenergic and serotonergic cell firing than that produced by either drug alone. In humans, a double-blind study suggests that coadministration of paroxetine and mirtazapine leads to a superior clinical response than either treatment alone. As well, in patients who did not respond to monotherapy, adding the other treatment elicited a treatment response within 2 weeks. The combination therapy did not increase the number of side effects or the number of patients who dropped out.

The last speaker, Dr. I.M. Anderson (University of Manchester, UK) talked about “A faster fix: what’s the evidence for antidepressants?” He reported meta-analyses of 5 proposed rapid treatment response antidepressant strategies. The first compared treatment with an SSRI to that with the dual 5-HT–noradrenaline reuptake inhibitor mirtazapine. At 2 weeks, 5 of 5 studies supported the greater efficacy of mirtazapine; at 6 weeks, the 2 were equally effective. There was no difference in number of side effects or the rate of subject drop-out. Amitriptyline was as effective as mirtazapine. Lithium versus placebo augmentation of TCAs was supported in the meta-analysis of 7 studies, with superior treatment efficacy apparent at 2 and 4–6 weeks. However, the treatment drop-out rate was higher in the lithium groups. A meta-analysis of 6 double-blind pindolol–SSRI studies supported the augmentation strategy, with superior treatment responses evident at both 2 and 4–6 weeks. There were no differences in drop-out rates. Finally, benzodiazepine augmentation of treatment with tricyclics was supported in an analysis of 9 studies; superior clinical efficacy was seen at 2 weeks, and fewer people dropped out. At 6 weeks of treatment, both benzodiazepine and placebo augmentation strategies were equally effective, suggesting that benzodiazepine augmentation elicited a more rapid response but not a higher proportion of positive responses.

Trends in the pharmacological treatment of generalized anxiety disorder

Dr. F. Kapczinski (Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil) reported on “New trends in the pharmacological treatment of generalized anxiety disorder: a meta-analysis of the use of antidepressants.” Generalized anxiety disorder (GAD), he noted, has a lifetime prevalence of approximately 4% and shows substantial comorbidity with major depressive disorder (60%), dysthymia (40%), panic disorder (25%), agoraphobia (25%) and simple phobia (35%). GAD can be associated with a high level of impairment and low level of life satisfaction. Antidepressants are commonly prescribed, but a meta-analysis to assess efficacy had not been previously conducted. The reported analysis was limited to studies of patients without comorbid Axis I disorders. Imipramine, venlafaxine and paroxetine all improved GAD symptoms. A small study (n = 11) suggests that sertraline might be exceptionally effective in children and adolescents. The side-effect profile was not different from that reported to occur during the treatment of patients with major depression, and drop out rates were not elevated, compared with placebo. The one ineffective antidepressant was clomipramine, the only tricyclic to have clinical efficacy for obsessive–compulsive disorder. These results suggest that both SSRIs and most TCAs are clinically effective in the treatment of GAD; the lack of clinical efficacy of clomipramine, though, suggests some pharmacologic specificity.

Dr. S. Chiu (University of Western Ontario, London) reported on an “Open-label study of gabapentin in panic disorder with alcohol dependence.” As Dr. Chiu noted, there is a high rate of comorbidity between anxiety and substance abuse disorders. A variety of peripheral indices and functional neuroimaging studies suggest that both anxiety and alcohol abuse disorders have overlapping disturbances to GABAergic function, possibly leading to dysregulated dopaminergic and serotonergic neurotransmission. Recent clinical trials support the clinical efficacy of gabapentin in panic disorder and substance abuse alone. In Dr. Chiu’s study of patients with comorbid panic disorder and alcohol dependence (n = 16), 12 weeks of treatment with gabapentin significantly reduced alcohol craving and both Hamilton Anxiety and Clinical Global Index scores. The dropout rate was 25%. These promising initial results will be followed up in a large double-blind study.

Dr. M. Leyton (McGill University, Montreal) reviewed “Serotonin and anxiety: evidence from tryptophan depletion studies.” Forty-eight relevant acute tryptophan depletion (ATD) studies were identified. In psychopathology-free subjects, 21 of 22 studies found no effect of ATD alone on anxiety. In comparison, 5 of 10 studies found that ATD potentiated the effect of anxiogenic challenges (1 of 3 studies with carbon dioxide, 2 of 4 with public speaking stress, 1 of 1 with the α₂-antagonist, yohimbine, 0 of 1 studies with a CCK-4 agonist, and 1 of 1 where both serotonin and catecholamine precursors were depleted simultaneously). Patients with a demonstrated vulnerability to anxiety were not more vulnerable to the effects of ATD. In 6 of 6 studies in patients with a history of anxiety disorders, ATD had no effect. In comparison, ATD potentiated the effect of coadministered anxiogenic challenges in 4 of 4 patient studies (3 with carbon dioxide and 1 with the benzodiazepine receptor antagonist flumazenil). Patients with a history of mood disorders reported increased anxiety after ATD alone (5 of 8 studies), but this co-occurred with the transient reappearance of depressive symptoms and was not specific to anxiety. Together, the results suggest that low serotonin neurotransmission is not a sufficient substrate of anxiety, but transient decreases might increase vulnerability to anxiogenic challenges. SSRIs may be clinically effective in anxiety disorders, not by directly inhibiting anxiety, but instead by increasing resilience to anxiogenic events, perhaps by increasing mechanisms related to coping.

Dr. V.A.-M.I. Tanay (University of Alberta, Edmonton) described the “Effects of anxiolytics on the regulation of GABA-A receptors.” She reviewed studies investigating effects of antidepressant and anxiolytic drugs on GABA-A receptor subunit gene expression. GABA-A receptors are composed of 5 subunits, each with a range of subtypes (e.g., α, β, γ, ∂, E, π) and isoforms (e.g., α1-6, β1-3, γ1-3). The mRNA expression of each subunit can vary, affecting receptor binding characteristics and postsynaptic signalling. Dr. Tanay’s studies suggest that alprazolam, but not imipramine, buspirone or phenelzine, induces relatively rapid (2–3 days) increases in α3, β1 and γ2 mRNA expression. Imipramine and phenelzine also increased β1 and γ2 mRNA expression, but this was only seen after administration for 21 days, consistent with their delayed onset on clinical effectiveness. Preliminary studies have tentatively identified transcription factors affected by benzodiazepine administration. One, but not 3 weeks of diazepam administration increased ΔfosB expression. Activator-1 protein expression, which is regulated in part by Fos expression (via dimerization of Fos plus Jun), is also transiently altered by repeated diazepam administration, with increases evident at day 7 but not days 3 or 21. If the present results are replicated with a wider range of anxiolytic drugs, the changes in mRNA expression might provide an effective screening tool for novel medications and identify postsynaptic mechanisms related to anxiolytic efficacy.

Neurotransmitter interactions in psychotherapeutic drug action

In his talk entitled “Therapeutic action of antipsychotic drugs: insights from cellular mechanisms of incentive learning,” the first speaker in the session, Dr. R. Beninger (Queen’s University, Kingston), discussed data from his laboratory suggesting new mechanisms of action of antipsychotic drugs. Psychotic symptoms in schizophrenia result from excess DA transmission, and all antipsychotic drugs are blockers of DA D₂ receptors. Given that DA in animals is shown to enhance a type of learning called incentive learning, Dr. Beninger argued that psychotic symptoms of schizophrenia result from an excess of incentive learning. Animal studies have shown that DA-mediated incentive learning involves modification of corticostriatal glutamatergic synapses, which in turn is mediated by protein kinases PKA and PKC. In support of his hypothesis, he observed that blockers of PKA and PKC impair incentive learning. He concluded by suggesting that effective treatments for the positive symptoms of schizophrenia may come from better understanding of the cellular pathways mediating incentive learning.

Dr. D. Self (University of Texas Southwestern Medical Center, Dallas) presented data suggesting that “AMPA glutamate–dopamine receptor interactions regulate relapse to cocaine seeking.” Craving and relapse to cocaine dependence is believed to be mediated by the mesolimbic DA system. His previous data show that D₂ receptor activation triggers, whereas D₁ receptor stimulation blocks, cocaine seeking in animals. He presented data suggesting that overexpression of AMPA receptor subunits GluR1 and GluR2 in the nucleus accumbens with the HSV viral vector diminishes cocaine seeking and facilitates extinction. Further, overexpression of AMPA subunits enhances locomotor responses to D₁ but attenuates responses to D₂ receptor agonists. It also blocks the induction of locomotor sensitization to repeated cocaine treatments. The effects of D₁ receptors on cocaine seeking may possibly be mediated by GluR1 phosphorylation. His results suggest that AMPA glutamate and DA receptors in the nucleus accumbens regulate cocaine seeking via complex interactions involving different subtypes of DA receptors.

Dr. G. Debonnel (McGill University, Montreal) discussed “Interactions between neurosteroids and the serotonergic system: potential clinical implications for the treatment of depression.” He began by reminding the audience that although serotonin is known to be implicated in the etiology and treatment of affective disorders, ovarian hormones also influence mood. As the therapeutic efficacy of antidepressant drugs is believed to result from an augmentation of serotonergic activity, Dr. Debonnel tested the hypothesis that ovarian hormones might also increase serotonergic transmission. He presented data showing that basal firing activity of serotonergic neurons differs between male and female rats and rises dramatically during pregnancy. Long-term (7–21 days) treatment of female rats with several steroids increased firing activity by more than 50%. He ended the talk with the suggestion that research on the effects of ovarian hormones on serotonergic activity may be a new avenue for the development of drugs to treat depression.

Dr. G.A. Higgins’ (Schering Plough Research Institute, Kenilworth, NJ) talk entitled “The 5-HT_2C receptor — one of the more important 5-HT receptor subtypes” summarized data from several studies suggesting that, of over a dozen 5-HT receptors, the 5-HT_2C subtype may be more relevant for behaviour and therapeutic drug actions than was hitherto appreciated. For example, in contrast to other 5-HT receptor subtype knock-out mice, 5-HT_2C knock-outs display an obvious phenotype: they are obese and prone to seizures. Furthermore, 5-HT_2C activation can explain many of the effects of nonselective 5-HT agonists, such as mCPP and the indirect agonist dexfenfluramine. He also pointed out that the 5-HT_2C receptor is the only G-protein coupled receptor known to undergo RNA editing, generating further diversity and functional modifications in this receptor subtype.

Neuroprotection and neuropsychiatric disorders

Dr. L.T. Young (McMaster University, Hamilton) spoke about “Antidepressants, mood stabilizers and neuroprotection.” He reviewed evidence that episodes of depression might induce neural damage that increases susceptibility to subsequent episodes and, also, that antidepressants and mood stabilizers might have neuroprotective effects. Neuroimaging studies suggest tissue volume and glial density loss in the subgenual prefrontal cortex of patients with familial recurrent mood disorders. Post-mortem studies suggest decreased cortical cyclic AMP regulatory binding (CREB) levels and blunted adenyl cyclase activity. In comparison, animal studies suggest that various antidepressant treatments and mood stabilizers increase cyclic AMP activity; CREB levels; brain-derived neurotrophic factor (BDNF) mRNA expression; and GRP78 transcription, mRNA and immunoreactivity. These changes are associated with neurogenesis and protection from glutamate-induced neurotoxicity. The overall picture suggests that genetic vulnerability to mood disorders might include susceptibility to stress-induced transmitter and excitatory amino acid release induced neurotoxicity. Neuroprotective effects of antidepressants and mood stabilizers might account for both treatment and prophylactic efficacy.

Dr. X.-M. Li (University of Saskatchewan) summarized evidence about the “Neuroprotective effects of atypical antipsychotics” including clozapine, risperidone, olanzapine and quetiapine. Accumulating evidence suggests that schizophrenia is, in part, a neurodevelopmental disease associated with progressive structural abnormalities, including ventricular enlargement and reduced temporal lobe volume. Most of the tissue loss occurs during the first 2 decades, but loss continues and may contribute to increasing severity of symptoms. Early treatment appears to improve subsequent illness course. Studies by Li and colleagues suggest that, in vitro, atypical antipsychotics reduce neurotoxin-induced cell death, possibly by increasing neuroprotective enzyme expression such as copper-zinc superoxide dismutase (SODI) and Bc12, by decreasing p75 mRNA expression or by preventing stress-induced decreases in neurotrophic factors (e.g., BDNF). In vivo, the 2 first atypical antipsychotics to be tested, olanzapine and quetiapine, prevent β-amyloid-induced neurotoxicity.

Dr. K.G. Todd (University of Alberta, Edmonton) reported on “Neuroprotective effects of monoamine oxidase inhibitors and their analogues in chronic and acute models of neuronal cell death.” The studies used 2 models of cell death, a thiamine-deficiency model, Wernicke’s encephalopathy and cerebral ischemia. The monoamine oxidase inhibitor (MAOI), deprenyl, and its analog, N-methyl,N-propargyl-2-phenylethylamine (MPPE), had neuroprotective effects both in vitro and in vivo. The effect was independent of their actions on monoamines and may be due to actions as a free radical scavenger, decreasing oxidative stress. The MAOI phenelzine and its structural analog, phenylthylidenehydrazine (PEH), increased GABA levels, possibly decreasing excitatory amino acid induced neurotoxicity. Both phenelzine and PEH reduced ischemia-induced cell loss, and this effect was seen as long as 16 hours after the induced stroke. The findings may indicate novel mechanisms relevant to the long-term treatment of mood disorders, the acute treatment of stroke and protection from stroke-related vulnerability to depression.

Dr. S. Bastianetto (McGill University, Montreal) talked about “Natural extracts and phytonutrients as neuroprotective agents.” Some evidence suggests that diets rich in vegetables, fruits and red wine might protect against age-related neurologic disorders, perhaps related to antioxidant properties of flavinols. A Ginkgo biloba extract, EGb 761, also has flavinoids. Some evidence suggests that it increases cerebral blood flow and has antineurotoxic effects against β-amyloids and nitric oxide. In Europe, it has been prescribed as a treatment for Alzheimer’s disease. Green tea has been proposed to lower the incidence of Parkinson’s disease. This could be related to its antioxidant polyphenols (e.g., catechins) and an ability to diminish stress-induced ischemia-related cell death. Red wine continues to be implicated as having some protective effects against coronary heart disease; more recent evidence suggests that polyphenols in red wine (e.g., resveratrol, quercetin, (+)-catechin) might also protect against stroke and dementia.

Linking functional genomics and proteomics in mental disorders

In his opening remarks, Dr. R.K. Mishra (McMaster University, Hamilton) argued that cDNA microarray and proteomic technologies are powerful new methods for identifying abnormally expressed genes and proteins in schizophrenia. He briefly discussed the methodologies involved and presented data from his laboratory showing changes in the expression of novel genes after antipsychotic treatments in rats. For example, the atypical drug clozapine causes upregulation of a protease inhibitor nexin, whereas haloperidol increases expression of synapsin 2A in the striatum.

Dr. L.K. Srivastava (McGill University, Montreal) presented data on “Cellular and molecular changes in the prefrontal cortex of adult rats following neonatal hippocampal lesions.” Excitotoxic lesions of the ventral hippocampus in 7-day-old rats led to the adult onset of a variety of behaviours analogous to those seen in patients with schizophrenia. Cellular and neurochemical abnormalities in this “animal model” of schizophrenia point to an involvement of the prefrontal neurons and mesolimbic DA circuits. He presented data on gene expression changes in the prefrontal cortex and nucleus accumbens of adult rats that received neonatal lesions. Using Clontech cDNA membrane arrays, he showed that gene expression changes in these animals belong to 3 main clusters (i.e., synaptic terminal proteins, signal transduction elements and Ca2+ binding proteins). He emphasized that further studies are warranted to assign the gene changes to specific behavioral abnormalities in the neonatally lesioned animals.

Dr. P.R. Albert (University of Ottawa) spoke on “Molecular approaches to understanding depression.” First he discussed the evidence for a role of 5-HT_1A receptors in the therapeutic action of SSRIs and pointed that a better knowledge of the regulation of the 5-HT_1A gene is important for understanding the etiology and treatment of depression. His laboratory sequenced the promoter of the 5-HT_1A gene and identified a nonselective strong promoter regulated by a series of upstream repressor elements. He has also identified a C/G polymorphism in one of the repressers and found that the G-allele, which fails to repress the promoter, is enriched in depressed patients. Two novel proteins, Freud-1 and clone 76D, present in serotonergic neurons, interact with the upstream elements of 5-HT_1A gene and control its expression. He concluded by presenting a model that predicts increased expression of somatodendritic 5-HT_1A receptors in depression.

In his talk entitled “Gene expression, mood disorders and their treatment,” Dr. L.T. Young (McMaster University, Hamilton) emphasized the important roles of signal transduction pathways and transcription factors in the action of mood stabilizers and antidepressants. Using different model systems, such as post-mortem brain tissues, lymphoblasts from lithium responsive patients, as well as cell lines treated with mood stabilizers, his laboratory is examining gene expression changes relevant to mood disorders. With cDNA arrays, he has identified many differentially expressed genes in patients with mood disorders, one of which, TGFβ1, present in glial cells, is especially important. Other genes such as SSR, RAB and MTTF were also identified in lymphoblasts of lithium-responsive patients. Lamotrigine-treated cultured rat hippocampal cells show differential expression of the β3 subunit of GABA-A receptor as well as somatostatin. Using Affymetrix DNA chip arrays, he also showed gene expression changes induced by lithium or valproate in primary rat cerebral cortical neurons. Many of these genes function in cell death and regeneration (Bcl-xB, IGFBP) and signal transduction.

Seminal ideas in Canadian neuropsychopharmacology

In this symposium to mark the 25th anniversary of the CCNP, 4 eminent Canadian scientists recounted key developments in neuropsychopharmacology in Canada.

Dr. Y.D. Lapierre (University of Ottawa) described the circumstances that lead to the CCNP’s formation. During the 1950s and ‘60s, an exceptional group of Canadian clinical and preclinical neurobiologists identified many of the first psychotropic medications, brain pathways involved in neurological diseases and neurocircuits mediating reward. The excitement generated by these discoveries led to the initiation of large multicentre drug trials. In Europe and the United States, the clear need to promote research and provide a collegial forum for the rapid exchange of new findings led to the formation of the Collegium Internationale Neuropsychopharmacologicum (CINP). Soon afterward, European and American offshoots were formed, the ECNP and ACNP. During a reportedly “well-lubricated meal” in the Laurentians (18–19 Oct. 1976), an exuberant group, including Yvon Lapierre, Bill Dewhurst, Joe McClure, Maurice Dongier and Heinz Lehmann, proposed the idea of forming a college of Canadians. When the idea still appealed to them the next morning, it was decided to canvas researchers across the country. The response was enthusiastic, and in 1977 a gathering was held in association with the American Psychiatric Association. Forty people attended, encouraging all involved to pursue things further. The following year (20–21 Apr. 1978), the first formal independent meeting was held at St. Mary’s Hospital in Montreal. A steering committee was formed, Yvon Lapierre agreed to be the first president, and the CCNP was born. Heinz Lehmann agreed to have an award named after him. Since then, the organization has grown and has played an important role in fostering Canadian researchers, encouraging young scientists and advocating important issues in biological psychiatry.

In 1982, the CCNP started its awards program with the first annual Heinz Lehmann Award to highlight excellence in research in neuropsychopharmacology in Canada. To encourage these goals further, it was proposed, around the 10th anniversary, to hold, whenever possible, meetings in collaboration with companion organizations from other countries. These joint meetings continue, fostering international collaborations, the exchange of ideas and a friendly collegial environment. In 1992, the Journal of Psychiatry & Neuroscience became the official CCNP publication. Since then, the journal has grown and now has a very respectable citation factor (i.e, 2.5) approaching the top third of publications in psychiatry and neuroscience. What seemed 25 years ago an audacious proposal is now a thriving tradition.

Dr. P.M. Milner (McGill University, Montreal) described the circumstances surrounding the discovery of electrical brain self-stimulation. Professor Milner noted that until the 1950s, the primary model of the brain depicted it as a series of electrical circuits. Two neurotransmitters had received some attention (norepinephrine and acetylcholine), but psychotropic drugs were commonly thought to act on neurons as a whole. Most behavioural research was strictly behaviourist, viewing neurobiological research as uninformative. An interest in rethinking these perspectives was fostered by a series of events. In 1934, Penfield established the Montreal Neurological Institute (MNI). At the MNI, Herbert Jasper and Francis McNaughton developed seminar courses in electrophysiology and neuroanatomy. In 1949, Donald Hebb, the new Chair of McGill Psychology, published The Organization of Behaviour, and encouraged people to think seriously about a physiological psychology. These influences were absorbed by a group of young researchers, including Brenda Milner, Seth Sharpless and Peter Milner. Steeped in these influences, Peter Milner formulated a hypothesis that stimulation of the reticular formation could alter goal-directed behaviour; in essence, an arousal theory of motivation and reinforcement. As these ideas were being tested, Jim Olds arrived as a post-doctoral fellow. Olds was a social psychologist by training, but Hebb encouraged him to look at Milner’s research. Milner in turn, taught Olds stereotaxic surgery, and he proceeded to implant rats with electrodes aimed at the reticular formation. Milner notes that up to that point, radiofrequency electrical stimulation showed little evidence of promoting positive reinforcement. One of Olds’ rats, however, behaved quite differently. This “particular rat,” Milner later wrote, “would advance, sniffing and searching, whenever the stimulation was turned on, and would stop or turn back when it was switched off” (Neurosci Biobehav Rev 1989;13:61–7). An x-ray of the rat’s head indicated that the electrode had missed its intended site and ended up in the septal area or more probably the anterior hypothalamus. It soon became clear that this rat, and others with electrodes intentionally implanted in this region, would choose to receive brain stimulation. This provided an elegant refutation of the then-dominant theory of reinforcement; in drive-reduction theory, motivational states were aversive, not something to work for. It was also clear that a search for a neurochemistry of reward could begin.

Dr. T.L. Sourkes (McGill University, Montreal) summarized a career that began during this same dynamic nascent period in neuropsychopharmacology and led to, among other things, the identification of the nigrostriatal DA pathway, the discovery of its role in Parkinson’s disease and the first clinical trials with l-dopa. At the beginning of his career in the early 1950s, Professor Sourkes assessed the effects of various aromatic amino acid homologues. α-Methyldopa, he showed in vitro, inhibited dopa decarboxylase. When assessed clinically at NIH, its most distinct effect was markedly reduced blood pressure. Further trials led to α-methyldopa becoming the first antihypertensive drug. By the late 1950s, Sourkes’ research had turned to investigations of possible biochemical disturbances in patients with diseases of the basal ganglia. His earlier work with catecholamine metabolic pathways served him well, and in 1961, he reported that patients with Parkinson’s disease excreted low levels of DA. Given that his animal studies indicated that l-dopa increased brain DA levels, he assessed the potential clinical efficacy of administering the catecholamine precursor to patients. The result was a striking reduction of Parkinsonian symptoms and the first treatment for the disease.

This remarkable progress — from the identification of striatal degeneration in post-mortem tissue, to the observation of low DA excretion, to an effective treatment — had occurred in the absence of much knowledge about DA in the brain. Given this, Sourkes and his colleague Louis Poirier examined the striatum and its afferents further. Their studies identified the nigrostriatal DA pathway and brought the research program full circle. Subsequent studies assessed the properties of other α-methylamino acids, including α-methyltryptophan. The ability of α-methyltryptophan to enter the serotonin metabolic pathway led to the suggestion that α-methyltryptophan might serve as a PET tracer to index serotonin synthesis. One of Professor Sourkes’ colleagues, Mirko Diksic, took up the idea. The full list of his trainees includes an impressive number of accomplished CCNP members, including André Villeneuve, Serge Gauthier, Samarthji Lal and Simon Young.

Dr. Edward Kingstone (St. Michael’s Hospital, Toronto) described the introduction of lithium as a treatment for bipolar manic depression. Professor Kingstone first reported clear evidence of the clinical efficacy of lithium carbonate in 1960. However, despite the recent successes with antipsychotics and first-generation antidepressants (monoamine oxidase inhibitors and tricyclics), there was pronounced resistance to the compound’s use. This resistance reflected an interesting earlier history. A decade earlier, John Cade noted that the urine of bipolar patients was toxic when given to guinea pigs. Lithium prevented this toxicity. This observation encouraged Cade to conduct an open-label clinical trial. In 1949, he reported that lithium reduced manic symptoms. The unusual route of discovery noted, the observation of clinical efficacy was clearly important. However, the breakthrough received a blow when in the same year Corcoran and colleagues reported that lithium chloride, which was being used as a salt substitute in low sodium diets, could have significant toxicity. Ten years later, Dr. Kingstone readdressed the question and conducted a clinical trial with lithium carbonate. The results supported both the efficacy and safety of the new compound. However, memories of the dangers of lithium salts led to great reluctance to adopt lithium carbonate as a treatment, and widespread use did not begin until the early 1970s. At present, lithium carbonate is seen by many as the gold standard in the treatment of bipolar disorders.

CCNP the next generation: CCNP Travel Awardees’ presentations

The symposium “CCNP the next generation” consisted of 6 short talks from research trainees who had submitted the best abstracts. The first talk, titled “Antipsychotic drugs induce BDNF mRNA expression in rat hippocampus,” was from O. Bai (University of Saskatchewan, Saskatoon). Neurotrophins may be involved in the mechanism of action of antipsychotics. In this study, rats were given haloperidol, clozapine or olanzapine for 28 days and BDNF mRNA was measured in the hippocampus. Although haloperidol lowered the levels, the atypical antipsychotics increased it, suggesting that they may exert a neuroprotective effect.

The next talk, “Experience-dependent AMPA receptor plasticity in the nucleus accumbens: modulation of cocaine seeking behaviour,” was by K.-H. Choi (University of Texas Southwestern Medical Center, Dallas). The AMPA glutamate receptor subunits GluR1 and GluR2 were overexpressed in the shell of the nucleus accumbens during extinction training in rats trained to self-administer cocaine. This did not alter cocaine-seeking behaviour induced by cocaine, but reduced cocaine seeking behaviour induced by stress. This suggests that AMPA receptor activation may reduce stress-induced relapse in former cocaine addicts.

R.L.H. Clements (University of Alberta, Edmonton) spoke on “Interaction of NMDA blockade and DA D_2/3 receptor stimulation as measured by locomotor activity and electrical self-stimulation of the ventral tegmental area in rats.” Two studies, using the NMDA receptor antagonist MK-801 and the D_2/3 receptor agonist 7-OH-DPAT, were conducted in rats to examine the interactions between DA and glutamate in the mesolimbic pathway. D_2/3 receptor activation blocked hyperactivity induced by NMDA, whereas NMDA attenuated the rewarding effects (measured though electrical self-stimulation) of dopaminergic stimulation.

S.S. Cui (University of Saskatchewan, Saskatoon) gave the next talk titled “Role of amygdala in the action of oxytocin against cannabinoid withdrawal syndrome.” Rats were given the potent cannabinoid HU210 for 5 days, and 4 hours after the last dose they received the cannabinoid antagonist AM281 to produce the cannabinoid withdrawal syndrome. Injection of oxytocin in the bilateral central amygdaloid nucleus inhibited the withdrawal syndrome.

T. O’Donnell (University of Alberta, Edmonton) spoke on “DEX-CRH double challenge in depressed women with and without histories of interpersonal trauma: preliminary data.” Although neuroendocrine dysregulation differs to some extent in major depression and post-traumatic stress disorder, many women who have had interpersonal trauma (IT) display symptoms of both disorders. In this study, depressed women with or without IT underwent a double challenge with dexamethasone and corticotropin-releasing hormone (CRH). The double challenge shows increased sensitivity in depressed patients compared with dexamethasone challenge alone. ACTH and cortisol responses to the challenge showed great intersubject variability, but the arginine vasopressin response to CRH challenge was greater in women with a history of IT than in those without such a history.

The final talk, titled “Gender differences in the modulation of the firing activity of dorsal raphe nucleus serotonergic neurons by neurosteroids” was from M. Robichaud (McGill University, Montreal). The effect of various neurosteroids on the firing of serotonin neurons in the dorsal raphe nucleus of male and female rats was studied. Seven days of treatment with 5β-pregnane-3,20-dione, 5α-pregnane-3α-01,20-one, DHEA or 17β-estradiol increased the firing of serotonin neurons in female rats from 56% to 106% but had no effect in male rats. A time-course study showed that the increase in firing with 5β-pregnane-3,20-dione was greatest at 7–14 days but diminished toward baseline levels at 21 days. On the other hand, firing increased steadily over 21 days with administration of DHEA. These changes may be relevant to the mood changes in women during periods of ovarian steroid fluctuation.