Journal of Psychopharmacology

Nutt, David

doi: 10.1177/0269881105048885pmid: 15671122

Lythe, K. E. ;Anderson, I. M. ;Deakin, J. F. W. ;Elliott, R. ;Strickland, P. L.

doi: 10.1177/0269881105048886pmid: 15671123

Acute dietary tyrosine depletion has previously been shown to reduce dopamine neurotransmission in both animals and humans. In this study, we investigated the effects of brain dopamine depletion, through acute tyrosine and phenylalanine depletion, on plasma prolactin, mood and neuropsychological function in 12 normal subjects. In a randomized, double-blind, cross-over design, subjects received two amino-acid drinks separated by a week, a nutritionally balanced mixture (Bal) and on the other occasion a tyrosine and phenylalanine deficient mixture (TP-). The plasma ratio of tyrosine and phenylalanine to the other large neutral amino acids decreased significantly on the TP-occasion (-78.7%, p < 0.0001) and there was an increase in plasma prolactin concentration relative to the balanced drink in the seven subjects for whom results were available for both occasions (p < 0.02). Acute tyrosine depletion did not alter mood as measured by visual analogue scale ratings, and measures of memory, attention and behavioural inhibition were also unaffected. Our results are consistent with acute dietary tyrosine depletion causing a reduction in brain dopamine neurotransmission but raise questions about how robust or consistent the effects are on psychological function.

Riedel, Wim J. ;Eikmans, Karin ;Heldens, Annet ;Schmitt, Jeroen A. J.

doi: 10.1177/0269881105048887pmid: 15671124

Subchronic treatment with the selective serotonergic reuptake inhibitors (SSRIs) fluoxetine, venlafaxine and paroxetine, but not sertraline, were previously shown to specifically impair vigilance performance. The current study was designed to compare the vigilance effects of subchronic treatment with the SSRIs sertraline and citalopram in healthy volunteers, according to a placebo-controlled, double-blind, three-way cross-over design. Twenty-four healthy subjects, aged 30-50 years, of whom 21 completed the study, underwent three treatment periods of 2 weeks in which they received sertraline (50 mg on days 1-8, 100 mg on days 8-15), citalopram (20 mg on days 1-8, 40 mg on days 8-15) and placebo. Treatment periods were separated by 14 days washout periods. Vigilance performance was assessed through a 45-min Mackworth Clock Test at days 1, 8 and 15 of each treatment period. It was found that citalopram impaired vigilance performance acutely after the first 20 mg dose and subchronically after 40 mg daily doses. By contrast, no vigilance impairment was found during sertraline treatment. Sertraline is the only SSRI studied so far with no detrimental effects on vigilance. This may be due to the affinity of sertraline for the dopamine reuptake site. Because citalopram is the most specific SSRI showing this effect, it is concluded that the SSRI-induced decrement of vigilance performance is specifically associated with serotonergic reuptake inhibition.

Müller, Ulrich ;Mottweiler, Elisabeth ;Bublak, Peter

doi: 10.1177/0269881105048888pmid: 15671125

To investigate the noradrenergic modulation of working memory in humans single doses of two β-blockers [either 25 mg of propranolol (lipophilic) or 50 mg of atenolol (hydrophilic)] or placebo were administered to young healthy volunteers (16 subjects per drug condition) performing a numerical working memory task that requires either short-term maintenance or maintenance plus manipulation of visually presented four-number sequences. Higher manipulation costs (i.e. process-specific slowing of reaction times in the manipulation conditions compared to the control condition) were observed after propranolol but not after atenolol. The propranolol effect was mainly observed in subjects with low emotional arousal (i.e. low state anxiety rating at baseline). Because both β-blockers induced a comparable decrease of blood pressure and pulse, the propranolol effect on the ‘working component’ of working memory is considered to be a central, presumably prefrontal one.

Mehta, Mitul A. ;Hinton, Elanor C. ;Montgomery, Andrew J. ;Bantick, R. Alexander ;Grasby, Paul M.

doi: 10.1177/0269881105048889pmid: 15671126

There is now substantial evidence from animal studies showing modulation of cognitive performance after administration of dopaminergic agents. Previous studies have focused on cognitive functions such as working memory (WM), with particular reference to spatial processing. However, to date, studies in normal human volunteers have proved inconsistent. We have therefore tested the effects of the dopamine D2 receptor antagonist sulpiride (400 mg) on WM and learning tasks, including those using auditory, spatial or non-spatial stimuli. A further aim was to explore a broader role of the dopaminergic system in mnemonic function by examining long-term and emotional memory. Eighteen healthy male participants were given a battery of cognitive tests after oral sulpiride or placebo, using the cross-over design. WM was assessed using a spatial searching task, and a task of auditory counting with distraction. Tasks that did not emphasize WM were spatial and non-spatial trial-and-error learning, long-term spatial memory and emotional memory. After dopamine D2 receptor blockade, performance was not impaired on the spatial WM (SWM) task, but was impaired on the auditory counting task with distraction. Sulpiride did not impair, but rather appeared to enhance trial-and-error learning overall. Thus, we were unable to support the notion that dopaminergic modulation preferentially influences spatial over non-spatial processing during learning. In addition, recognition was impaired in the emotional memory task after encoding on drug compared to placebo. These findings question the precise role of dopamine D2 receptor modulation on WM, and highlight the need for sensitive tests to study dopaminergic modulation of emotional processing.

Aasen, Ingrid ;Kolli, Lavanya ;Kumari, Veena

doi: 10.1177/0269881105048890pmid: 15671127

Prepulse inhibition (PPI) refers to the reduction in the response amplitude to a startling stimuli (pulse) if it is preceded (i.e. 30-500 ms) by a weak stimulus (prepulse). If the time interval between the prepulse and pulse is more than 500 ms, then an increase in this response amplitude can be seen, termed prepulse facilitation (PPF). PPI is thought to represent an operational index of sensorimotor function whereas PPF is thought to reflect, at least to some degree, sustained attention. Interestingly, PPI is found to be sexually dimorphic, with men exhibiting more PPI than women when subjects are tested without regard to where they are in the menstrual cycle, and to be impaired in several neuropsychiatric disorders known to exhibit sex differences in their clinical presentation. PPF has received relatively less attention in both normal and clinical studies. This study examined sex differences in both PPI and PPF in 62 healthy subjects (34 women, 28 men) using a range of prepulse-to-pulse intervals to elicit PPI (30, 60, 120, 240 and 480 ms) and PPF (1000 and 2000 ms). Men showed higher PPI than women but women showed higher PPF compared to men. These results suggest that reduced PPI in healthy women is not a simple reduction but rather a shift of the inhibition/facilitation curve in the direction of facilitation in women, relative to men. Future studies investigating pharmacological and treatment effects using a prepulse modification paradigm in normal and clinical populations of both sexes would benefit from an examination of sex effects and assessments of both PPI and PPF.

Tse, Wai S. ;Bond, Alyson J.

doi: 10.1177/0269881105048896pmid: 15671128

This study examined the cortisol response to reboxetine in a sample of healthy men and women. Forty healthy volunteers were randomly allocated to one of two treatment groups: placebo or 4 mg reboxetine under double-blind conditions. Saliva cortisol was measured pre, 1 and 1.5 h post-treatment. Mood and side-effects were also measured. A single oral dose of 4 mg reboxetine did not affect positive or negative mood but did produce some side-effects. It was also sufficient to increase cortisol release 1.5 h post-treatment compared to placebo. In addition, reboxetine lead to a significantly increased cortisol release in male compared to female volunteers. The results suggest that healthy male volunteers are more responsive to challenge with a noradrenergic compound than females.

Hovens, J. E. ;Dries, P. J. T. ;Melman, C. T. M. ;Wapenaar, R. J. C. ;Loonen, A. J. M.

doi: 10.1177/0269881105048897pmid: 15671129

Acutely psychotic patients presenting as psychiatric emergencies with aggression or agitation are often administered conventional antipsychotics intramuscularly. However, patients view intramuscular administration as coercive, and conventional antipsychotics are often associated with adverse events. In this open study, consecutive adult patients presenting with an acute exacerbation of schizophrenia or other psychotic disorder were assigned to oral risperidone 2-6 mg/day (n = 48) or oral zuclopenthixol 20-50 mg/day (n = 27) for 7-14 days. Lorazepam (either oral or intramuscular) was administered to both groups as needed. Patients were assessed regularly until day 14 or discharge. Mean Positive And Negative Syndrome Scale (PANSS) aggression scores (sum of item scores on excitement, poor impulse control, hostility and uncooperativeness) decreased steadily and similarly in both groups; the mean changes from baseline were statistically significant at days 10 and 14 and at study end-point. The mean decrease at study end-point in the PANSS component score for hostility was statistically significant in the risperidone group, but not in the zuclopenthixol group. Social Dysfunction and Aggression Scale aggression scores and Clinical Global Impression scores decreased significantly and similarly in both groups. Overall, 18.7% of patients showed minor extrapyramidal symptoms during the study, but only 16.7% of risperidone-treated patients, compared to 59.3% of zuclopenthixol-treated patients, received anti-parkinsonian medication (p< 0.001). Lorazepam was administered to all of the patients assigned to risperidone and to 89% of those assigned to zuclopenthixol. Oral risperidone plus lorazepam is a convenient, effective and well-tolerated alternative to conventional antipsychotics for the treatment of acute psychosis in emergency psychiatry.

Coppen, Alec ;Bolander-Gouaille, Christina

doi: 10.1177/0269881105048899pmid: 15671130

We review the findings in major depression of a low plasma and particularly red cell folate, but also of low vitamin B12 status. Both low folate and low vitamin B12 status have been found in studies of depressive patients, and an association between depression and low levels of the two vitamins is found in studies of the general population. Low plasma or serum folate has also been found in patients with recurrent mood disorders treated by lithium. A link between depression and low folate has similalrly been found in patients with alcoholism. It is interesting to note that Hong Kong and Taiwan populations with traditional Chinese diets (rich in folate), including patients with major depression, have high serum folate concentrations. However, these countries have very low life time rates of major depression. Low folate levels are furthermore linked to a poor response to antidepressants, and treatment with folic acid is shown to improve response to antidepressants. A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 µg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.

Cole, J. C. ;Sumnall, H. R. ;Smith, G. W. ;Rostami-Hodjegan, A.

doi: 10.1177/0269881105048898pmid: 15671131

Adverse reactions to polysubstance misuse are common in nightclubs, yet little is known of the physiological effects of polysubstance misuse in this environment. This study examined the heart rate, blood pressure and oral temperature of 50 participants recruited in a nightclub on four separate nights. In addition, the increase in environmental temperature was recorded throughout each night. There were no differences in oral temperature between polysubstance misusers (i.e. those who used Ecstasy, amphetamine, cocaine, alcohol and cannabis) and alcohol/cannabis misusers. On the other hand, there were significant differences in both heart rate and blood pressure between the two groups. These data suggest that polysubstance misusers may be at risk from cardio- and cerebrovascular toxicity. Further field/on-site work is clearly needed to investigate the effects of polysubstance misuse.