European Neuropsychopharmacology (v.12, #5)

Drug treatment of conduct disorder in young people by Priscille Gérardin; David Cohen; Philippe Mazet; Martine F Flament (361-370).
Although conduct disorder (CD) is the most common psychiatric disorder in youth from the community and encompasses one third to one half of all referrals to child and adolescent clinics, there is no licensed drug, to date, for treatment of CD, neither in Europe nor in the US. The aims of this paper are to review research data available on the use of medication for CD in young people and to identify future directions for research. We review 17 controlled studies and six open trials. Investigated compounds mainly belong to three classes of psychotropic drugs: mood stabilizers, neuroleptics and stimulants (six, five and six controlled studies, respectively). Lithium is the most documented treatment (3/4 positive studies). Conventional neuroleptics have been most commonly prescribed (3/3 positive studies), atypical neuroleptics appear promising (2/2 positive studies). Methylphenidate improves some CD symptoms, even in the absence of ADHD (6/6 positive studies). Sparse research has been conducted on response to antidepressants. The evidence for an effective role of pharmacotherapy in CD is still limited. Treatment should be multimodal and individualized to each patient’s specific condition.
Keywords: Conduct disorder; Aggressiveness; Drug treatment; Child; Adolescent;

The aim of the present study was to determine optimum conditions for studying promazine and perazine metabolism in rat liver microsomes, and to investigate the influence of specific cytochrome P-450 inhibitors on 5-sulfoxidation and N-demethylation of these neuroleptics. Based on the developed method, the metabolism of neuroleptics in liver microsomes was studied at linear dependence of product formation on time, and protein and substrate concentrations (incubation time: 10 min; concentration of microsomal proteins: promazine—0.7 mg ml−1, perazine—0.5 mg ml−1; substrate concentrations: promazine—25, 40 and 75 nmol ml−1, perazine—20, 35, 50 nmol ml−1). A Dixon analysis of the metabolism of neuroleptics showed that quinine (a CYP2D1 inhibitor), metyrapone (a CYP2B1/B2 inhibitor) and α-naphthoflavone (a CYP1A1/2 inhibitor) affected, whereas erythromycin (a CYP3A inhibitor) and sulfaphenazole (a CYP2C inhibitor) did not change the neuroleptic biotransformation. N-Demethylation of promazine was competitively inhibited by quinine (K i=20 μM) and metyrapone (K i=83 μM), while that of perazine—by quinine (K i=46.5 μM), metyrapone (K i=46 μM) and α-naphthoflavone (K i=78.8 μM). 5-Sulfoxidation of promazine was inhibited only by quinine (K i=28.6 μM), whereas that of perazine—by quinine (K i=10 μM) and metyrapone (K i=96 μM). The results obtained are compared with our previous findings of analogous experiments concerning thioridazine, and with the data on other phenothiazines and species. In summary, it is proposed that N-demethylation of the mentioned phenothiazine neuroleptics in the rat is catalyzed by the isoenzymes CYP2D1, CYP2B2 and CYP1A2 (CYP1A2 does not refer to promazine). 5-Sulfoxidation of these drugs may be mediated by different isoenzymes, e.g. CYP2D1 (promazine and perazine), CYP2B2 (perazine) and CYP1A2 (thioridazine). Isoenzymes belonging to subfamilies CYP2C and CYP3A do not seem to be involved in the metabolism of the investigated neuroleptics in the rat. The results obtained point to the drug structure and species differences in the contribution of cytochrome P-450 isoenzymes to the metabolism of phenothiazines.
Keywords: Promazine; Perazine; Thioridazine; Metabolism; Cytochrome P-450 isoenzymes; Specific inhibitors;

Typical and atypical antipsychotic drugs (APD) show differential effects in brain on both dopamine output and activation of Fos-like immunoreactivity (FLI) in dopamine nerve terminal regions. Typical APD increase dopamine output preferentially in the core and atypical APD increase dopamine output preferentially in the shell of the nucleus accumbens (NAC). Whereas both typical and atypical APD increase FLI in NAC, typicals cause FLI activation in the striatum and atypicals cause FLI activation in the prefrontal cortex. Clinically, low doses of haloperidol cause less side-effects than higher doses, and low-dose haloperidol has been suggested as a cost-effective alternative to atypical APD. Here, in vivo voltammetry in anaesthetised, pargyline-pretreated rats was used to measure dopamine output in the two subdivisions of the NAC and, in addition, immunohistochemistry was used to assess FLI activation in dopamine target areas, following acute haloperidol administration. Haloperidol, 0.001 and 0.01 mg/kg i.v., caused a significantly higher dopamine output in the core than in the shell of the NAC. Moreover, haloperidol 0.05 and 0.5, but not 0.005, mg/kg s.c. increased FLI in the NAC and the striatum, but not in the medial prefrontal cortex. Thus, even extremely low doses of haloperidol generate, in principle, the same biochemical effects in brain as higher doses, and these effects remain different from those of atypical APD. These biological data indicate that clinical differences between haloperidol and atypicals are qualitative rather than dose-dependent. Consequently, our results do not support the use of low-dose haloperidol as replacement for atypical APD in the treatment of schizophrenia.
Keywords: Schizophrenia; Voltammetry; Immunohistochemistry; Fos protein; Nucleus accumbens shell; Nucleus accumbens core;

Effects of 5-HT1B receptor ligands microinjected into the accumbal shell or core on the sensitization to cocaine in rats by Edmund Przegaliński; Joanna Siwanowicz; Iwona Papla; Małgorzata Filip (387-396).
The present study was designed to find out whether 5-HT1B receptors located in subareas of the nucleus accumbens played a role in cocaine sensitization in rats, and whether pharmacological activation of these receptors could modify this drug effect. Male Wistar rats implanted bilaterally with cannulae into the accumbens shell or core were microinjected with GR 55562 (an antagonist of 5-HT1B receptors) or CP 93129 (an agonist of 5-HT1B receptors). The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. GR 55562 (0.1–10 μg/side), administered for 5 days into the accumbens shell, but not into the core, prior to cocaine dose-dependently attenuated cocaine sensitization. When injected for 5 days into either the accumbens shell or core before cocaine, CP 93129 (0.1–10 μg/side) had no effect on the development of cocaine sensitization. To examine the effects of GR 55562 and CP 93129 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. No change in cocaine sensitization was observed after injection of GR 55562 (0.1–10 μg/side) to the either accumbens subregion or after injection of CP 93129 (0.1–10 μg/side) into the core. However, an intra-accumbens shell injection of CP 93129 (10–30 μg/side) increased sensitization to cocaine, and this enhancement was attenuated after local injection of GR 55562 (1 μg/side). Our findings indicate that behavioral sensitization to cocaine may be modulated by 5-HT1B receptor ligands in the accumbens shell, but not into the core. They suggest that the inhibition of 5-HT1B receptors in the accumbens shell attenuates the development, whereas their pharmacological activation enhances the expression of cocaine sensitization.
Keywords: Cocaine; Behavioral sensitization; 5-HT1B receptors; CP 93129; GR 55562; Nucleus accumbens; Rats;

We study the brain regional distribution of putrescine after excitotoxic damage. After status epilepticus induced by kainic acid (9 mg/kg, i.p.) we found an increase of putrescine in all the regions analyzed. Three kind of regions can be identified according to the magnitude and persistence of the abnormal concentration of putrescine: hippocampus and cortex (9-fold 1 day, still increased 2-fold 2 weeks after injection), cerebellum and medulla oblongata+pons (2-fold 1 day after injection) and the other regions (7–8-fold 1 day, still increased 2–3-fold 1 week after injection). The histological damage was: severe, absent and moderate or low, respectively. After ataxia induced by kainic acid injection (2.34 nmols) into the cerebellum, putrescine also rises in all regions; a high concentration (9-fold) and severe damage was found in the injected cerebellar hemisphere. In conclusion, in the models studied, putrescine increases in all the regions analyzed. However, the highest concentrations and the most severe damage were found in the target regions.
Keywords: Polyamines; Kainic acid; Epilepsy; Ataxia; Rat brain;

Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens by Everett H Ellinwood; Colin Davidson; Guo-Zhong Yu; George R King; Tong H Lee (407-415).
One therapeutic paradigm for cocaine abuse is a 24-h ‘agonist’ treatment which reduces reinforcing effects in a manner similar to the methadone maintenance model for heroin. However, 24-h dosing of dopamine (DA) agonists may induce side effects of insomnia and psychosis, as well as anergia and anhedonia which may actually potentiate abuse. Thus, it is important to determine the daily dose duration of potential treatments such as direct (e.g. pramipexole) and indirect (e.g. GBR 12909) DA agonists, that may induce cross-tolerance with cocaine. We gave a cocaine challenge (15 mg/kg i.p.) on withdrawal day 7 and recorded ambulations and a behavioral rating. We found that 20- and 24-, but not 16-h, daily dosing with cocaine (40 mg/kg), for 14 days, induced tolerance. Pramipexole (4 mg/kg), administered for 24 but not 12 h per day, for 14 days, induced cocaine cross-tolerance while GBR 12909 (18 mg/kg), administered i.p. over 24 or 16 h a day, for 7 days, did not. Thus daily dosing duration is an important variable in consideration of stimulant abuse treatment.
Keywords: Cocaine; Tolerance; Dosing duration; GBR 12909; Pramipexole; Behavior;

Classical antidepressant therapy has mainly used selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), but tianeptine appears to possess effects on 5-hydroxytryptamine (5-HT, serotonin) levels in the synaptic cleft contradictory to those of SSRIs. The mechanism behind its antidepressant effects is still unclear. The effect of tianeptine on the electrophysiological characteristics of neurons in the dorsal raphe, where serotonergic neurons mainly originate from, were investigated by the patch-clamp method in the present study. Tianeptine was shown to inhibit the ion currents induced by the inhibitory neurotransmitters GABA and glycine as well as the inwardly rectifying K+ current induced by 5-HT and 8-hydroxy-2 (di-n-propylamino) tetraline hydrobromide (8-OH-DPAT), a 5-HT1A agonist. Tianeptine, however, exerted no effect on the ion current induced by the excitatory neurotransmitter glutamate. These results indicate that tianeptine has an inhibitory effect on ion currents evoked by GABA, glycine, and inwardly rectifying K+ current induced by 5-HT in the dorsal raphe. This action may increase the excitability of serotonergic neurons of the dorsal raphe.
Keywords: Tianeptine; 5-Hydroxytryptamine; γ-Amino-n-butyric acid; Glycine; Glutamate; Patch clamp;

[11C]Mirtazapine for PET neuroimaging: radiosynthesis and initial evaluation in the living porcine brain by Katalin Marthi; Dirk Bender; Albert Gjedde; Donald F Smith (427-432).
We radiolabelled mirtazapine, a tetracyclic, atypical, antidepressant drug, for positron emission tomography (PET) and evaluated its regional kinetics in the living porcine brain. We produced [N-methyl-11C]mirtazapine with a radiochemical-purity >98% in a 21% decay-corrected radiochemical yield by alkylation of N-desmethyl mirtazapine with [11C]methyl iodide, followed by HPLC purification and formulation. [N-Methyl-11C]mirtazapine entered the brain readily and, under baseline conditions, it had an apparent volume of distribution (V e′) of 9–13 in the basal ganglia, thalamus, and frontal cortex. Reference region and graphical analyses based on a one-compartment model showed that the binding of [N-methyl-11C]mirtazapine was reversible, with an apparent binding potential of more than two in thalamus and frontal cortex. Infusion of unlabelled mirtazapine markedly displaced [N-methyl-11C]mirtazapine from binding sites in the basal ganglia, thalamus and frontal cortex, but not in reference regions (cerebellum and olfactory tubercle). Thus, [N-methyl-11C]mirtazapine showed rapid passage into the living brain, slow metabolism in blood, and reversible, competitive binding, which may make it useful for PET neuroimaging of neuroreceptors involved in antidepressant actions.
Keywords: [11C]Mirtazapine; PET neuroimaging; Antidepressant; Tetracyclic drug; Porcine brain;

Stereochemistry is now influencing most areas of pharmacotherapy, with a growing awareness in the field of psychiatry and, more specifically, depression. This is due to the fact that the enantiomers of many chiral drugs may have distinct pharmacological, pharmacokinetic and/or pharmacogenetic profiles. Consequently, in some instances there may be an advantage in using a single enantiomer over the racemic form—thus providing a basis for the development of new therapeutic agents, as well as the potential to improve current treatments. This review highlights some of the potential advantages and disadvantages that using single enantiomers might offer. The principles are exemplified through reference to the stereoselective properties of several established chiral psychotropic drugs, including thioridazine, methadone, trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. Emphasis is given to the treatment of depression and how the potential of one pure enantiomer—escitalopram, the S-enantiomer of the selective serotonin reuptake inhibitor citalopram—appears to be fulfilling its preclinical promise in the clinic.
Keywords: Enantiomer; Depression; Antidepressant; SSRI; Citalopram; Escitalopram;

Effect of 5-HT in mianserin-pretreated rats on the structure of feeding behavior by J.M Mancilla-Dı́az; R.E Escartı́n-Pérez; V.E López-Alonso; S.E Cruz-Morales (445-451).
The present study examined the effects of intra-PVN serotonin injection in mianserin-pretreated rats at the onset of the dark phase of light cycle on the structure of feeding behavior. The drugs were injected into the paraventricular nucleus (PVN) of the hypothalamus. The animals were maintained in a self-selection feeding paradigm and provided with freely available and separate sources of protein, carbohydrate, fat and water. The suppressive effect of 5-HT on carbohydrate intake was attenuated by mianserin at the beginning of the active (dark) feeding period. Mianserin-pretreatment increased the duration of carbohydrate and protein intake, but it was unable to block the effect of 5-HT on meal frequency and local rate of carbohydrate consumption. The present data suggests that carbohydrate intake may be in part mediated by postsynaptic 5-HT2A/2C receptors. However, the temporal characteristics of carbohydrate ingestion are mediated by another subpopulation of 5-HT receptors in the PVN and indicates a possibly adrenergic influence.
Keywords: Serotonin; Mianserin; Food intake; Meal patterns;

Efficacy of citalopram in anorexia nervosa: a pilot study by Secondo Fassino; Paolo Leombruni; Giovanni Abbate Daga; Annalisa Brustolin; Giuseppe Migliaretti; Franco Cavallo; Giovanni G Rovera (453-459).
Introduction: Anorexia nervosa (AN) still lacks a defined treatment. Since fluoxetine proved effective in weight-restored anorexics, this pilot study evaluates the efficacy of another SSRI, citalopram, in restricting-type AN. Experimental procedures: Fifty-two female anorectic outpatients were randomized in the citalopram (n=26) and waiting list (n=26) as a control group. Efficacy was assessed using Eating Disorder Inventory-2, Eating Disorder Inventory-Symptom Checklist, State-Trait Anger Expression Inventory, Beck Depression Inventory, Symptom Checklist-90 and Structured Clinical Interview for DSM-IV Axis II Disorders. Results: Thirteen patients dropped-out, thus 19 patients received citalopram and 20 remained in the control group. After 3 months of treatment, the citalopram group showed a decrease on BDI and SCL-90 Depression subscale and an improvement of baseline obsessive compulsive features on SCL-90, EDI-2 impulsiveness and Trait-anger on STAXI. Weight gain was similar in the two groups. Discussion: These preliminary results support the efficacy of citalopram in anorectics. Citalopram seems to improve depression, obsessive–compulsive symptoms, impulsiveness and Trait-anger.
Keywords: Anorexia nervosa; Selective serotonin reuptake inhibitors; Citalopram;

The role of noradrenaline and selective noradrenaline reuptake inhibition in depression by N Brunello; J Mendlewicz; S Kasper; B Leonard; S Montgomery; J.Craig Nelson; E Paykel; M Versiani; G Racagni (461-475).
Depression is a common disorder that impacts on all aspects of a person’s life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.
Keywords: Depression; Selective noradrenaline reuptake inhibition; Catecholamines; Melancholia; Efficacy; Tolerability;

No association between the serotonergic polymorphisms and incidence of nausea induced by fluvoxamine treatment by Hitoshi Takahashi; Keizo Yoshida; Kenich Ito; Kazuhiro Sato; Mitsuhiro Kamata; Hisashi Higuchi; Tetsuo Shimizu; Kunihiko Ito; Kazuyuki Inoue; Takehiko Tezuka; Toshio Suzuki; Tadashi Ohkubo; Kazunobu Sugawara (477-481).
We investigated the association between serotonergic polymorphisms and incidence of nausea, which is the most frequent side-effect of selective serotonin reuptake inhibiters (SSRIs), in 66 patients treated with fluvoxamine in a protocolized-dosing method. We focused on three polymorphisms of serotonin (5-HT) neuronal systems such as 5-HT transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR), a variable number of tandem repeat (VNTR) polymorphism in the second intron of the 5-HTT gene (STin2) and tryptophan hydroxylase (TPH) gene polymorphism in intron 7 (TPH-A218C), which have been reported to possess positive association with treatment response to SSRIs. In addition to this, the relationship between development of nausea and treatment response was also analyzed. Results suggested that these three polymorphisms did not affect the development of fluvoxamine-induced nausea, and that incidence of nausea was not a phenomenon that predicts the treatment response to fluvoxamine.
Keywords: Pharmacogenetics; Fluvoxamine; Serotonin; Nausea;

The protein kinase A in platelets from patients with panic disorder by Daniela Tardito; Raffaella Zanardi; Giorgio Racagni; Tiziana Manzoni; Jorge Perez (483-487).
Although previous studies suggested that dysfunctions in the protein kinase A (PKA) and in some of its substrates are associated with several psychiatric disorders, there is no evidence regarding the possible involvement of such components in panic disorder (PD). Thus, the aim of the present study was to investigate the levels of PKA and Rap1 in platelets from patients with such disorder. Twenty-four drug free patients with PD and 24 healthy volunteers participated to the study. Employing the Western Blot analysis, immunostaining and computer-assisted imaging, the levels of the regulatory (R, type I and type II) and the catalytic (C) subunits of PKA, and those of Rap1 were assessed in platelets from the two groups. The data show that patients with PD have significantly higher levels of platelet RI and C subunits of PKA than controls, whereas the levels of RII were unchanged. No significant differences were found in the immunolabelling of Rap1 between groups. These findings may provide clues toward understanding the involvement of cAMP signalling in anxiety disorders.
Keywords: Panic disorder; cAMP signalling; PKA; Rap1; Platelets;

Vasopressin in CSF and plasma in depressed suicide attempters: preliminary results by Jürgen Brunner; Martin E Keck; Rainer Landgraf; Manfred Uhr; Christian Namendorf; Thomas Bronisch (489-494).
Increased plasma arginine vasopressin (AVP) concentrations have been reported in depressed suicide attempters. Plasma AVP is primarily produced by the magnocellular system in response to increased plasma osmolality, and central AVP may be independently regulated. In the present study we investigated cerebrospinal fluid (CSF) and plasma AVP concentrations in depressed patients and controls. Nineteen drug-free depressed psychiatric inpatients (nine suicide attempters) and nine neurological control subjects underwent lumbar puncture and psychiatric evaluation. CSF and plasma concentrations of AVP, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol were assayed. In 15 depressed patients (eight suicide attempters), the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed to examine the hypothalamic–pituitary–adrenocortical (HPA) system. There were no differences between depressed subjects and controls in all parameters measured. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF.
Keywords: Suicide attempt; Depression; Vasopressin; Monoamine metabolites; Cerebrospinal fluid; Hypothalamic–pituitary–adrenocortical system;