European Neuropsychopharmacology (v.13, #2)

Depression is a serious and burdensome illness. Although selective serotonin reuptake inhibitors (SSRIs) have improved safety and tolerability of antidepressant treatment efficacy, the delay in the onset of action have not been improved. There is evidence to suggest that the delay in onset of therapeutic activity is a function of the drugs, rather than the disease. This suggests that research into the biological characteristics of depression and its treatments may yield faster-acting antidepressants. Emerging evidence from clinical studies with mirtazapine, venlafaxine and SSRI augmentation with pindolol suggests that these treatments may relieve antidepressant symptoms more rapidly than SSRIs. The putative mechanism of action of faster-acting antidepressant strategies presented here purports that conventional antidepressants acutely increase the availability of serotonin (5-hydroxytryptamine, 5-HT) or noradrenaline (NA), preferentially at their cell body level, which triggers negative feedback mechanisms. After continued stimulation, these feedback mechanisms become desensitised and the enhanced 5-HT availability is able to enhance 5-HT and/or NA neurotransmission. Putative fast-onset antidepressants, on the other hand, may uncouple such feedback control mechanisms and enhance 5-HT and/or NA neurotransmission more rapidly. Further studies are required to characterise in detail the interactions between NA and 5-HT systems and to definitively establish the early onset of candidate antidepressants such as mirtazapine, venlafaxine and pindolol augmentation.
Keywords: Depression; Antidepressant; Onset of action; Mirtazapine; Pindolol; Venlafaxine; Serotonin; Noradrenaline;

Serum iron levels in schizophrenic patients with or without akathisia by Murat Kuloglu; Murad Atmaca; Bilal Üstündag; Halit Canatan; Omer Gecici; Ertan Tezcan (67-71).
The pathophysiology of akathisia still remains controversial. Iron deficiency was proposed to be an important factor in the development of akathisia. In the present study, it was aimed to compare levels of serum iron and linked variables in chronic akathisic (n=30), and non-akathisic patients (n=30) with schizophrenia and healthy controls (n=30) because of the controversy in the association of iron and akathisia. The Barnes Akathisia Scale for akathisia and Simpson–Angus Rating Scale for extrapyramidal side effects were used. Serum iron and linked variables and hematological profile of the patients and control subjects were determined. Serum iron levels were significantly lower both in akathisic and non-akathisic groups compared to the control group (P<0.001). Moreover, akathisic patients had significantly lower iron levels than non-akathisic patients (P<0.05). Total iron binding capacity was significantly higher in patients with akathisia compared to the control group (P<0.01). Although non-akathisic patients had a mild increase in total iron binding capacity, it was not statistically significant compared to the control group (P>0.05). Ferritin levels were determined to be significantly lower in both groups compared to the control group (P<0.01). In addition, there was a significant difference in ferritin levels between the patients with and without akathisia (P<0.05). In conclusion, our results support the hypothesis that an association between akathisia and iron metabolism exists.
Keywords: Serum iron; Akathisia; Ferritin; Total iron binding capacity;

Milnacipran in the treatment of bulimia nervosa: a report of 16 cases by Nadia El-Giamal; Martina de Zwaan; Ursula Bailer; Alexandra Strnad; Petra Schüssler; Siegfried Kasper (73-79).
Controlled trials in patients with bulimia nervosa have demonstrated efficacy of antidepressant medications with serotonergic function (e.g. fluoxetine) as well as noradrenergic function (e.g. desipramine). Sixteen out-patients with bulimia nervosa according to DSM-IV criteria were treated in a drug surveillance with 100 mg of milnacipran, a specific serotonin and noradrenaline reuptake inhibitor (SNRI). Ten patients completed the 8-week observation period. The reasons for premature attrition were improvement in one patient (no. 12), a generalized exanthema in one patient (no. 7), severe nausea in one patient (no. 8) and non-compliance due to non-drug-related reasons in three patients (no. 1, 2, and 16). An intent-to-treat analysis exhibited a significant reduction in weekly binge eating and vomiting frequency from baseline to the end of treatment. Three patients stopped binge eating and purging completely during the last week of treatment. Furthermore, there was a concomitant decrease of depression ratings (HAMD, BDI). Our preliminary data give rise to the notion that milnacipran may be promising in the treatment of bulimia nervosa.
Keywords: Bulimia nervosa; Treatment; Milnacipran; Serotonin and noradrenaline reuptake inhibitor;

Nizatidine for prevention of weight gain with olanzapine: a double-blind placebo-controlled trial by Patrizia Cavazzoni; Yoko Tanaka; Suraja M. Roychowdhury; Alan Breier; David B. Allison (81-85).
Weight gain is associated with treatment with olanzapine and other psychotropic agents. Nizatidine, a histamine H-2 receptor antagonist, has been proposed to have weight-reducing effects. This double-blind trial evaluated the efficacy of nizatidine in limiting weight gain in patients with schizophrenia and related disorders who were treated with olanzapine for up to 16 weeks. After an initial screening period, 175 patients were randomized to receive olanzapine (5–20 mg) with either placebo or nizatidine (150 mg b.i.d. or 300 mg b.i.d.). Significantly less weight gain was observed on average at weeks 3 and 4 with olanzapine+nizatidine 300 mg b.i.d. (P<0.05) compared to olanzapine+placebo, but the difference was not statistically significant at 16 weeks. Nizatidine was well-tolerated and did not adversely affect clinical outcomes. Nizatidine 300 mg b.i.d. may have an early transient effect in limiting the weight gain, but this potential early effect appeared to be diminished or eliminated by 16 weeks.
Keywords: Olanzapine; Nizatidine; Weight gain; H-2 blockade;

Alternation learning in OCD/schizophrenia patients by Haggai Hermesh; Abraham Weizman; Shai Gur; Gil Zalsman; Roni Shiloh; Joseph Zohar; Ruth Gross-Isseroff (87-91).
In continuation of our previous studies on orbitofrontal cortex function in obsessive compulsive disorder (OCD) we studied a group of OCD patients with schizophrenia in comparison with a group of schizophrenia patients. In order to test orbitofrontal cortex function we again used an alternation learning task. We found no difference between the two groups in the performance of this task. The relationship between severity of OC symptoms and alternation learning was curvilinear. Thus, in the low range of symptom severity the correlation between alternation learning and symptom severity was negative, while in the high range it was positive. The positive correlation in the severely affected patients is essentially the same as that found in severe “pure” OCD patients, which we have previously reported. We conclude that the data indicate independent orbitofrontal cortex function in OCD, irrespective of comorbidity.
Keywords: Obsessive compulsive disorder; Schizophrenia; Orbitofrontal cortex; Alternation learning;

Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder by Sı&#x0302;an M.J. Hemmings; Craig J. Kinnear; Dana J.H. Niehaus; Johanna C. Moolman-Smook; Christine Lochner; James A. Knowles; Valerie A. Corfield; Dan J. Stein (93-98).
There is increasing evidence that the aetiology of obsessive-compulsive disorder (OCD) has a marked genetic component, although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. This study investigated the role of attractive candidate genes in the serotonergic and dopaminergic pathways in the development of OCD. The distribution of selected polymorphic variants in the serotonin receptor type 2A and 1Dβ (5-HT2A , 5-HT1Dβ ), dopamine transporter (DAT), dopamine receptor type 4 (DRD4) and monoamine-oxidase A (MAO-A) genes were analysed in 71 OCD cases and 129 control individuals in the genetically homogeneous Afrikaner population, by means of case-control association studies. Although no statistically significant genotypic or allelic associations were detected, the data yielded interesting preliminary results that warrant further discussion and investigation.
Keywords: Obsessive-compulsive disorder; Genetics; Association studies; Afrikaner;

Polyunsaturated fatty acid deficit in patients with bipolar mania by Chih-Chiang Chiu; Shih-Yi Huang; Kuan-Pin Su; Mong-Liang Lu; Ming-Chyi Huang; Chiao-Chicy Chen; Winston W. Shen (99-103).
The aim of this study is to test the hypothesis that there is a depletion of polyunsaturated fatty acids of erythrocyte membranes in patients with bipolar disorder and to connect the previous therapeutic and psychoimmunological findings. Fatty acid compositions of erythrocyte membranes in 20 bipolar manic patients and 20 healthy controls were analyzed by thin-layer chromatography and gas chromatography. The major finding was significantly reduced arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) compositions in bipolar patients as compared to normal controls with P values of 0.000 and 0.002, respectively. There were no differences in total omega-3 and omega-6 polyunsaturated fatty acids. This abnormality may be related to the mechanisms of action of mood stabilizers and the previous findings on the abnormal psychoimmunology of patients with bipolar disorder. Larger sample sizes of medicated patients or drug-free manic, well-controlled designs on the diet and smoking, and fatty acid composition measurements during full remission after the index episode are warranted in future studies.
Keywords: Omega-3 polyunsaturated fatty acids (PUFA’s); Pregnancy; Bipolar mania; Arachidonic acid (AA); Ecosapentaenoic acid (EPA); Docosahexaenoic acid (DHA); Taiwan;

CSF testosterone in 43 male suicide attempters by Gunnar Gustavsson; Lil Träskman-Bendz; J.Dee Higley; Åsa Westrin (105-109).
Several studies have shown a relationship between high testosterone and violent aggressive behaviour. The general aim of this study was to gain knowledge of the importance of testosterone in suicide attempters. Testosterone in cerebrospinal fluid (CSF) was analysed in men with a recent suicide attempt, diagnostically subdivided into groups according to DSM-III-R axis I and II diagnosis and mode of suicidal behaviour. In general, our patients had lower CSF testosterone levels than aggressive violent patients in other studies. Patients with depression NOS or dysthymia showed higher CSF testosterone levels than the rest. Significant positive correlation between testosterone and irritability or a negative correlation with social desirability was found in diagnostic subgroup of patients, specifically axis II, cluster B personality disorders. The results suggest that suicide attempts may be mediated by different biological variables than aggression.
Keywords: Testosterone; Depressive disorder; Personality disorder; Suicide, attempted; Aggressiveness;

The effects of a single dose of zolpidem (10 mg), zopiclone (7.5 mg) and flunitrazepam (1 mg) on motor activity the following 3 nights were compared to those of a placebo in a double-blind, crossover study. Thirty-three healthy subjects received medication between 10.30 and 11.30 p.m. and were asked to rise between 7.30 and 8.30 a.m. During the night under treatment, flunitrazepam, zopiclone and zolpidem significantly reduced motor activity. Changes in motor activity are quantitatively compatible with the hypothesis of reduced light sleep and wakefulness after sleep onset. During the first or second post-drug night, for zolpidem and zopiclone the opposite effect was observed, i.e. increased activity compared with placebo. These modifications cannot be explained by modified sleep structure. This last result underlines our inadequate understanding of the underlying mechanisms of motor activity during sleep. However, being sensitive and easy to use, actigraphy is an ideal technique to assess the effect of hypnotics on large populations and for long duration studies.
Keywords: Zolpidem; Zopiclone; Flunitrazepam; Actigraphy; Side-effect; Sleep;

SSRIs antidepressant activity is influenced by Gβ3 variants by Alessandro Serretti; Cristina Lorenzi; Cristina Cusin; Raffaella Zanardi; Enrico Lattuada; David Rossini; Roberta Lilli; Adele Pirovano; Marco Catalano; Enrico Smeraldi (117-122).
The aim of the present study was to test a possible effect of the G-protein β3-subunit (Gβ3) C825T gene variant on the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) in a sample of major and bipolar depressives, with or without psychotic features. Four hundred and ninety inpatients were treated with fluvoxamine 300 mg/day (n=362) or paroxetine 40 mg/day (n=128) and either placebo or pindolol in a double-blind design for 6 weeks. The severity of depressive symptoms was weekly assessed with the Hamilton Rating Scale for Depression. Gβ3 allelic variants were determined in each subject using a PCR-based technique. Subjects with Gβ3 T/T variants showed better response to treatment (P=0.009) and this effect was independent from analyzed demographic and clinical variables. These results confirm preliminary reports and shed further light on the genetics of the response to antidepressant treatments.
Keywords: Pharmacogenetics; Paroxetine; Fluvoxamine; Mood disorders; Antidepressant treatment;

Effect of the 5-HT2 antagonist mianserin on cognitive dysfunction in chronic schizophrenia patients: an add-on, double-blind placebo-controlled study by Michael Poyurovsky; Danny Koren; Inna Gonopolsky; Michael Schneidman; Camil Fuchs; Abraham Weizman; Ronit Weizman (123-128).
Preponderance of serotonin 5-HT2A antagonism over dopamine D2 blockade exerted by atypical antipsychotics may contribute to their cognitive-enhancing effect. In a double-blind placebo-controlled study we examined the effect of add-on mianserin (15 mg/day), an agent with marked 5-HT2A antagonism, on cognitive functioning in 30 chronic hospitalized DSM-IV schizophrenia patients stabilized on typical antipsychotics. The Automated Neuropsychological Assessment Metrics (ANAM) battery was used to assess learning, memory and sustained attention; Wisconsin Card Sorting Test (WCST) to assess executive function at baseline and endpoint (4 weeks). Clinical assessment included appropriate rating scales. The mianserin group overperformed the placebo group on selective ANAM memory/learning tests, reflected in moderate-to-high effect size values. No between-group differences were revealed in WCST and clinical ratings. Conclusions: Improved performance on selective neurocognitive tests with addition of the 5-HT2A antagonist mianserin to typical antipsychotics indicates a possible role of the 5-HT system in cognitive-enhancing effects. The effect of flexible doses of mianserin on cognitive deficits in a broader schizophrenia population merits further investigation.
Keywords: Schizophrenia; Cognition; 5-HT2A antagonist; Mianserin;

Clonazepam in the long-term treatment of patients with unipolar depression, bipolar and schizoaffective disorder by Dietmar Winkler; Matthäus Willeit; Rainer Wolf; Mara Stamenkovic; Johannes Tauscher; Edda Pjrek; Anastasios Konstantinidis; Shird Schindler; Christian Barnas; Siegfried Kasper (129-134).
The value of a long-term treatment with clonazepam in the prophylaxis of affective disorder is discussed controversially in the scientific literature. Altogether there are only a few reports on the use of this compound as a mood stabilizer, most of them describing patients suffering from bipolar affective disorder. The aim of this investigation was to evaluate clonazepam as a phase prophylactic medication in affective disorder. We conducted a retrospective chart review in 34 out-patients of our lithium clinic (15 suffering from unipolar depression, 15 from bipolar disorder, four from schizoaffective disorder), who had been treated with clonazepam as a long-term medication. Clonazepam was either given as monotherapy, or as in the case of lithium non-responders, as adjunctive therapy. Patients with unipolar depression had significantly (P=0.026) less depressive episodes after initiation of treatment with clonazepam. Patients with bipolar disorder did not benefit from this therapy. Neither manic/hypomanic phases nor depressive episodes were reduced in this group of patients. Interestingly, clonazepam also reduced affective phases in our four schizoaffective patients on a trend level. Our results indicate that patients with unipolar depression may benefit from a maintenance treatment with clonazepam. Due to methodological limitations our results need to be replicated in controlled double-blind randomized clinical trials.
Keywords: Clonazepam; Mood-stabilizer; Maintenance treatment; Depression; Bipolar disorder; Schizoaffective disorder;

Manic symptoms associated with quetiapine treatment by Lefteris Lykouras; Panagiotis Oulis; John Hatzimanolis (135-136).
This case illustrates the induction of manic-like symptoms in a 26-year-old male patient with DSM-IV paranoid schizophrenia following treatment with quetiapine. The only drug he had received prior to quetiapine was risperidone which was occasionally taken in the previous 3 years. The manic symptoms remitted after quetiapine withdrawal.
Keywords: Quetiapine; Manic symptoms; Schizophrenia; Atypical antipsychotic;