Mary V. Seeman

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study

Abstract. Rationale: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). Objective: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. Methods: The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. Results: There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. Conclusion: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.

Cognitive therapy for schizophrenia: a preliminary randomized controlled trial

BACKGROUNDnThe aim of the current study was to assess whether patients with a DSM-IV diagnosis of schizophrenia and experiencing persistent positive and negative symptoms improve with the addition of cognitive-behavioural therapy to enriched standard treatment.nnnMETHODSnA controlled study was completed with 42 patients randomized to either cognitive-behavioural therapy plus enriched treatment-as-usual (CBT-ETAU) (n = 24) or enriched treatment-as-usual only (ETAU) (n = 18). Enriched treatment-as-usual comprised comprehensive treatment within specialised schizophrenia treatment services. Cognitive-behavioural therapy was conducted on an individual basis for 6 months (20 sessions). Clinical assessments were done at pretreatment, posttreatment and at 6-month follow-up by raters blind to group allocation.nnnRESULTSnSignificant clinical effects were observed for positive, negative and overall symptom severity for patients treated in CBT-ETAU, although there were no statistically significant differences between the treatment groups at posttreatment. The most pronounced effect of CBT-ETAU in comparison to ETAU in this study was in the reduction of negative symptoms at follow-up.nnnCONCLUSIONnThese results show promise for the impact of CBT on negative symptoms when explicitly targeted in treatment.

The role of estrogen in schizophrenia: implications for schizophrenia practice guidelines for women.

Objective: The objective of this paper is to integrate what is known about estrogen effects on symptoms and treatment response into a global understanding of schizophrenia. The aim is to expand Canadian schizophrenia guidelines to include the specific needs of women. Method: We searched the Medline database; keywords included estrogen, estrogen replacement therapy, schizophrenia, psychosis, treatment, tardive dyskinesia (TD), and women. We examined reference lists from relevant articles to ensure that our review was complete. We review the evidence for the effects of estrogen in schizophrenia and we make recommendations for the next revision of official practice guidelines. Results: The epidemiologic evidence suggests that, relative to men, women show an initial delay in onset age of schizophrenia, with a second onset peak after age 44 years. This points to a protective effect of estrogen, confirming animal research that has documented both neurotrophic and neuromodulatory effects. Clinical research results indicate that symptoms in women frequently vary with the menstrual cycle, worsening during low estrogen phases. Pregnancy is often, though not always, a less symptomatic time for women, but relapses are frequent postpartum. Some work suggests that in the younger age groups women require lower antipsychotic dosages than men but that following menopause they require higher dosages. Estrogen has been used effectively as an adjunctive treatment in women with schizophrenia. Estrogen may also play a preventive role in TD. Conclusions: Symptom evaluation and diagnosis in women needs to take hormonal status into account. Consideration should be given to cycle-modulated neuroleptic dosing and to careful titration during pregnancy, postpartum, and at menopause. We recommend that discretionary use of newer neuroleptic medication and adjuvant estrogen therapy be considered.

Reduced vasodilatory response to methylnicotinate in schizophrenia as assessed by laser Doppler flowmetry.

The normal vasodilatory response to topically applied methylnicotinate has been reported to be absent or reduced in patients with schizophrenia, a finding thought to be related to aberrant phospholipid metabolism. Previous studies have however failed to measure vasodilation using a direct and objective method. In addition, it is unknown whether methylnicotinate insensitivity is specific to schizophrenia. To address these issues we compared the magnitude of methylnicotinate-induced vasodilation in chronically ill patients with schizophrenia (SCZ) (n=27) or bipolar disorder (BP) (n=26) to that in healthy controls (n=32). Blood flow was monitored using laser Doppler flowmetry. Vasodilatory response to 1 and 10 mM methyl nicotinate was markedly and significantly reduced in patients with schizophrenia compared to that in subjects with bipolar disorder and healthy controls. In conclusion, reduced methyl nicotinate response in schizophrenia has been demonstrated using an objective measure of vasodilation. Our data further support the potential utility of this measure as a diagnostic marker for schizophrenia.

Cyclooxygenase inhibitor modulation of dopamine-related behaviours

The sequential action of phospholipase A(2) and cyclooxygenase leads to the production of prostaglandins in the brain, an event hypothesised to cause dopaminergic stimulation. To investigate this further, we examined the effect of the nonselective cyclooxygenase inhibitors indomethacin and piroxicam on several indices of dopaminergic function in adult male rats. Both drugs inhibited catalepsy induced by the dopamine D1-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390), the dopamine D2-like receptor antagonist raclopride and by haloperidol, findings in agreement with a dopaminergic effect of cyclooxygenase inhibitors. However, neither cyclooxygenase inhibitor had an effect upon disruption of prepulse inhibition of the auditory startle reflex by amphetamine or on the rate of amphetamine self-administration. Both drugs reduced amphetamine-stimulated locomotor activity. Our data indicate that the mechanism by which cyclooxygenase inhibitors alter motor behaviour is unlikely to be due to a simple direct action at the dopaminergic synapse. Their apparent ability to antagonise hypoactivity without generalised dopaminergic stimulation suggests that other, possibly multiple, neurotransmitter systems may be involved.

Schizophrenia: Women Bear a Disproportionate Toll of Antipsychotic Side Effects

BACKGROUND: Men and women with schizophrenia suffer not only from their illness but also from the side effects of their medications. OBJECTIVE: To review the toll of antipsychotic side effects specifically on women. STUDY DESIGN: A review of the literature in the PubMed database since 1990 using search terms: sex difference, antipsychotics, schizophrenia, pharmacokinetics, pharmacodynamics, and pharmacogenomics and retrieving additional publications from the reference lists of the original articles. RESULTS: Findings suggest that, because of differing pharmacokinetics, women are more vulnerable than men to weight gain secondary to antipsychotics and to the consequences (metabolic, cardiovascular, reproductive) of weight gain. They are also more vulnerable to hyperprolactinemia and QTc prolongation. CONCLUSIONS: Dosing guidelines need to be critically appraised. The greater toll of side effects in women may undermine adherence to prescribed treatments, add to the stigma that attaches to mental illness, and diminish the quality of women’s lives. Side effects increase the cost of mental illness and heighten the burden experienced by caregivers. They exacerbate morbidity and raise mortality rates. They affect the children of women treated with antipsychotic medication.

Duration of pretreatment phases in schizophrenia: women and men.

Objective: To determine the relative duration of the prepsychotic prodrome and the period of untreated psychosis in women and men with schizophrenia. Method From a larger study population, we selected 27 women and 34 men treated at 1 facility. To determine the time of first behavioural change and the time of first psychotic symptoms, we administered the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS). Subjects mothers were interviewed using the same instrument. Time of first treatment was determined by hospital record. Results The first sign of behavioural disturbance occurred at approximately the same age in women and men. The prepsychotic prodrome was almost twice as long for women as for men. The duration of untreated psychosis did not differ between the 2 sexes. Substance abuse did not influence the observed difference between men and women in the duration of the prepsychotic phase. The interval between first behavioural sign and first treatment was, on average, 6 years for men and 9 years for women. Conclusion As-yet-unknown factors speed up the progression from nonspecific symptoms to psychosis in men or delay it in women.

Treating schizophrenia at the time of menopause

The purpose of this review is to optimize treatment for women with schizophrenia during the menopause. Recommendations are based on a relatively sparse literature derived from searching PubMed, PsychINFO, SOCINDEX with appropriate search terms for all years subsequent to 2000. Attention needs to be paid to menopausal symptoms in women with schizophrenia and to the possibility that psychotic symptoms may worsen at this time and that general health may deteriorate. Antipsychotic treatment may need to be modified and cardiac and metabolic health indices closely monitored.

Canada: Psychosis in the Immigrant Caribbean Population

Background: Many reports from European countries suggest that acute episodes of psychosis are more frequent among immigrants from the Caribbean than among their non-immigrant peers. Aim: The aim of this selective review is to examine how the social correlates of migration to Canada interact with biological mechanisms to contribute to psychosis in the Caribbean population. Method: PubMed and JSTOR social science databases (between 1966 and 2010) were searched using the following search terms: psychiatric genetics; dopamine pathways; Caribbean family structure and child rearing; cannabis and psychosis; obstetric complications and schizophrenia; social defeat; social capital; racial discrimination; urbanicity; immigration; assimilation; and immigration. This was followed by the cross-checking of references pertinent to Canada. Results: There was no information about the prevalence of psychosis in Afro-Caribbean immigrant groups to Canada. There was a suggestion that the form the acute episode takes may differ, depending perhaps on the island of origin. Conclusion: Ethnicity and migration influence susceptibility and response to psychotic illness in a number of distinct and interacting ways depending both on the host country and the country of origin. Understanding the pathways can help to protect the health of immigrants.

A graduate student oath.

The Hippocratic Oath, recited by medical school graduates worldwide, is arguably the best-known professional honor code. This centuries-old oath instills a commitment to altruism, professionalism, honesty, skill, knowledge, duty, loyalty, and fraternity among medical doctors. The positive impact of