Significant correlation between 14C-5-HT uptake by and 3H-paroxetine binding to platelets from healthy volunteers.

The lack of correlation between 5-HT uptake by platelets and the ability of platelet membrane to bind antidepressant drugs, particularly imipramine, has been reported. However, more recently it has been suggested that 3H-paroxetine could be a better drug with which to study the platelet 5-HT uptake mechanism in disease states. We have therefore compared the ability of platelet-rich plasma (PRP) from normal individuals to take up 5-HT with the ability of platelet membranes to bind paroxetine. A significant correlation was apparent between the Vmax of 14C-5-HT uptake by PRP and the Bmax of 3H-paroxetine binding to platelet membrane from 30 individuals (r = 0.6468, p = 0.0001). Furthermore, this correlation was highly significant in the 20 female (r = 0.7768, p = 0.00006) but not in the 10 male volunteers. There was also a significant association between Vmax and Bmax and the month of blood sampling but this did not totally account for the correlation between Vmax and Bmax. The simultaneous measurement of 5-HT uptake by PRP and paroxetine binding to platelet membranes from both depressed patients and matched controls should be carried out to confirm and extend these findings.

Cortisol suppression by dexamethasone in the healthy elderly: effects of age, dexamethasone levels, and cognitive function.

The effects of age, cognitive function (measured by Cambridge cognitive examination (CAM-COG) score); and dexamethasone (DEX) levels on the dexamethasone suppression test were studied in 33 healthy older subjects (age 51-96). Three subjects (9.1%) were nonsuppressors and were older and had lower CAMCOG scores than the 30 suppressors. Significant correlations were observed between natural log-transformed postdexamethasone cortisol (LNCOR) levels and age (r = 0.40) and CAMCOG score (r = -0.45). Multiple regression analysis was used to investigate the relationship between LNCOR, age, DEX levels, and CAMCOG score. Age and DEX combined explained 41% of the variance in LNCOR values, whereas CAMCOG score and DEX levels explained 44% variance. As age and CAMCOG were highly correlated (r = -0.72), both together did not significantly improve the fit of regression equation (47% variance explained). These findings suggest an association between advancing age, impaired glucocorticoid feedback, and cognitive dysfunction in healthy human subjects. Although any causal connection remains to be demonstrated, results would be consistent with the "glucocorticoid cascade" hypothesis of human aging.

Dexamethasone kinetics in depressed patients before and after clinical response.

Dexamethasone pharmacokinetics were measured in 19 depressed patients, 10 dexamethasone suppression test (DST) nonsuppressors and nine suppressors, following a 1 mg oral dose in tablet form at 2300 h. Median dexamethasone concentrations were significantly lower in the nonsuppressors from 3-16 hr post-administration. Nonsuppressors had a significantly lower area under the curve than suppressors, and plasma clearance was significantly faster in the nonsuppressors than in the suppressors. Eleven patients, six nonsuppressors and five suppressors, agreed to a repeat DST after clinical improvement when all six nonsuppressors had normal DST responses. There were no significant differences between the median dexamethasone concentrations, or any of the pharmacokinetic parameters measured, of the "normalising" nonsuppressors and the suppressors. Dexamethasone kinetics were altered in depressed nonsuppressors but became normal with remission of depressive symptoms and normalisation of the DST response.

Plasma cortisol and 11-deoxycortisol activity in depressed patients and normal volunteers.

Plasma cortisol and 11-deoxycortisol were measured in 30 depressed patients and 110 normal volunteers before and after a 1.0 mg dexamethasone suppression test (DST). Post-dexamethasone plasma cortisol, 11-deoxycortisol and the cortisol/11-deoxycortisol ratio were significantly higher in the depressives compared to the controls, even when age and sex were taken into account. Pre-dexamethasone plasma cortisol, post-dexamethasone cortisol, 11-deoxycortisol and their ratio were significantly higher in the cortisol nonsuppressors than in the suppressors. The measurement of post-dexamethasone 11-deoxycortisol and the ratio did not differentiate between endogenous and reactive depression. Using the normative data, we explored several methods for determining a criterion value to define abnormal post-dexamethasone plasma 11-deoxycortisol and the cortisol/11-deoxycortisol ratio in depressed patients. All showed poor sensitivity and a low positive predictive value for depression. The measurement of 11-deoxycortisol thus does not enhance the clinical utility of the DST.

Violence in schizophrenia: role of hallucinations and delusions.

The study examines the relationship between hallucinations/delusions and violent behaviour in a sample of long-stay inpatients with chronic schizophrenia. Thirty-one subjects defined as violent and meeting DSM-111-R criteria for schizophrenia were compared with 31 matched non-violent schizophrenia patients with respect to detailed phenomenologies of auditory hallucinations using the Mental Health Research Institute Unusual Perceptions Schedule (Carter and Copolov, 1993; Carter et al., 1995) and delusions using the Maudsley Assessment of Delusions Schedule (Taylor et al., 1994). Patients in the violent groups were significantly more likely to experience negative emotions, tone and content related to their voices than those in the non-violent group, whilst patients in the non-violent group were more likely to experience positive emotions, tone and content related to their voices. Patients in the non-violent group were significantly more likely to report success in coping with their voices. There was no association between command hallucinations and violent behaviour. Patients in the violent group were more likely to hold persecutory delusional beliefs than those in the non-violent group, while patients in the non-violent group were likely to hold grandiose delusions than those in the violent group. Patients in the violent group were also more likely to report that the delusion made them feel angry, while those in the non-violent group were more likely to report that the delusion made them feel elated. The results suggest specific aspects of the phenomenologies of hallucinations and delusions that should be clinically assessed to determine the likelihood of violence as a result of such psychotic symptoms.

Risk of adverse events with the use of augmentation therapy for the treatment of resistant depression.

Augmentation therapy is used for those situations where a patient's depression is either treatment-resistant, or partially and/or insufficiently responsive to treatment. It also may be used to attempt to induce a more rapid treatment response. Using drugs together may increase the risk of adverse effects, through potentiation of existing adverse effects or alterations in plasma concentrations of the drug. It is important that clinicians are aware of potential risks of augmentation therapy. Lithium augmentation of a tricyclic antidepressant is relatively well tolerated and the dangers are no greater than using these medications on their own. There are also no reports of serious adverse events when lithium is added to a monoamine oxidase inhibitor. With lithium augmentation of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) therapy there have been case reports of the development of a central serotonin syndrome, and thus caution must exercised. A serious concern when using a tricyclic antidepressant to augment an SSRI is the effect of the SSRI on the cytochrome P450 system and the resulting significant increase in tricyclic antidepressant blood concentrations. Augmentation with thyroid hormones appears to be well tolerated and effective. Case reports and open studies indicate that augmentation with buspirone and the psychostimulants, carbamazepine and valproic acid (valproate sodium) is effective and results in minimal adverse effects. However, there is no empirical evidence supporting these results. Recent work supports the tolerability and efficacy of pindolol augmentation. Considerable caution should be exercised when combining psychotropic drugs. The practitioner should only do so with a full knowledge of the compounds involved and their pharmacological properties.

Aggressive behaviour and extrapyramidal side effects of neuroleptics in schizophrenia.

The objective of this study was to determine whether extrapyramidal side effects of neuroleptics are associated with aggressive behaviour in schizophrenia. Thirty-one physically aggressive patients meeting DSM-III-R criteria for schizophrenia were compared with 31 matched non-aggressive patients in relation to their extrapyramidal side effects, including drug-induced parkinsonian (DIP) symptoms, akathisia and tardive dyskinesia. The aggressive group had significantly more severe DIP side effects than the non-aggressive group, but the association disappeared when level of psychopathology was controlled for. The aggressive group had more severe akathisia than the non-aggressive group, but the difference was not statistically significant. The two groups did not suffer in the severity of tardive dyskinesia. There was no significant, independent effect of extrapyramidal symptoms on aggressive behaviour in our sample of schizophrenic patients.

Aggressive behaviour in schizophrenia: role of state versus trait factors.

The objective of this article was to elucidate the relative importance of state vs. trait factors in determining aggressive behaviour in schizophrenia. Thirty-one aggressive schizophrenia patients in rehabilitation wards were compared with 31 matched non-aggressive patients with respect to their psychopathology, phenomenologies of hallucinations and delusions, neuroleptic motor side effects, history of aggression and personality traits. Significant differences between the two groups were found in relation to psychopathology, affective responses to hallucinations/delusions, history of aggression and personality traits, but there were no significant differences regarding neuroleptic motor side effects. The effects of history of aggression as well as personality traits were independent of and similar to the total level of psychopathology, but were much smaller when compared to those of negative affective responses to hallucinations/delusions.

Structural neuroimaging studies in late-life depression: a review.

Which patients presenting with depression in late life will progress to a dementia syndrome has been an important research question in recent times. In this paper we review selectively structural neuroimaging investigations of late-life depression (LLD) that have been performed over the past two decades. These studies indicate that there are neuroimaging changes commonly observed in LLD patients when compared to normal controls. Findings include ventricular enlargement and sulcal widening, and reduction in volume size of frontal lobes, hippocampus and caudate nucleus. White matter lesions are more common in depressed subjects and tend to be more severe. Some studies report these changes to be more pronounced in patients who present with late-onset depression (LOD) but this has been contradicted by other studies. Preliminary work suggests that these changes may be associated with a poor prognosis but there is a dearth of systematic, well-controlled longitudinal studies.

Personality pathology, depression and HPA axis functioning.

Hypothalamic pituitary adrenal (HPA) axis functioning, as measured by the dexamethasone suppression test (DST), has been extensively investigated in major depressive disorder (MDD). Evaluating DST response in MDD patients while simultaneously considering clinically relevant personality disorders may further clarify the contribution of both personality pathology and HPA axis function to depressive symptoms. The present study measured personality pathology by administering the revised version of the Millon Clinical Multiaxial Inventory (MCMI-II) in a sample of 25 patients diagnosed with MDD. Analyses revealed that suppressors (n = 19) scored significantly higher than non-suppressors (n = 6) on six of the 13 MCMI-II personality disorder scales: Avoidant, Schizoid, Self-Defeating, Passive-Aggressive, Schizotypal and Borderline. Increased personality pathology was associated with normal suppression of cortisol following the DST. This suggests that suppression of the DST may be associated with depressive states linked with personality pathology while the more biologically based depression is associated with abnormal HPA pathophysiology. Copyright 2001 John Wiley & Sons, Ltd.

A prospective study of assaults on staff by psychiatric in-patients.

This study determined the prevalence and features of assaults on staff, compared them with other aggressive incidents by psychiatric in-patients, and studied their relationship with the ward atmosphere. There were 181 physical assaults among 279 staff in two months, i.e. 389 assaults per 100 staff per year. A few patients were responsible for the majority of the assaults. Most assaults were triggered off by staff-patient interaction. About one-third of the staff were significantly psychologically shaken by the incidents. Patients were more likely to be provoked and used more severe means of aggression against staff than against other targets of aggression. There were no significant differences between the characteristics of patients who assaulted staff and those who had other targets of aggression.

Studies of aggressive behaviour in schizophrenia: is there a response bias?

Of 73 patients who met selection criteria to enter into a study on aggressive behaviour in schizophrenia, 11 patients (15.1%) did not participate. The participants and non-participants were similar in age, gender ratio and proportion who had aggressive behaviour. The participants, however, had a longer duration of illness, a longer duration of current admission, were more likely to suffer from residual schizophrenia, but less likely to suffer from disorganized schizophrenia and were less severely ill than the non-participants. These results indicate the need, in studies of aggressive behaviour in schizophrenia, to consider non-response bias as a confounding variable.

Psychiatric disorders among elderly patients in a general hospital.

OBJECTIVES: To determine the approximate point prevalence of psychiatric disorders among elderly patients in a general hospital and to ascertain the frequency of mental state examination on admission, psychotropic drug use and documentation of psychiatric disorder in discharge summaries. METHOD: Weekly enrollment of 10 beds until the entire hospital was screened. Patients aged over 65 years were interviewed with the Geriatric Mental State schedule and psychiatric diagnoses were made using the AGECAT computer program. PATIENTS AND SETTING: Inpatients aged 65 years and over in all wards of a metropolitan teaching hospital over 16 months in 1990-1991. RESULTS: Of 495 enrolled patients, 204 were aged over 65 years and 167 of these could be interviewed. Eighteen per cent showed evidence of organic mental impairment, 27% were depressed and 2% had other psychiatric disorders. Some mental state findings were recorded on admission for 25% of patients, 52% of patients were prescribed hypnotic or psychotropic drugs and 30% of the psychiatric disorders identified by the survey were mentioned in the discharge summary. CONCLUSIONS: Screening for psychiatric disorders in this setting is not routine. The frequency of such disorders makes it desirable to conduct prospective evaluation of the use of brief cognitive and depression screening instruments on admission to hospital.

A review of the use of augmentation therapy for the treatment of resistant depression: implications for the clinician.

OBJECTIVE: To critically review the literature on augmentation therapy in resistant depression in order to assist the clinician to make a reasoned choice. Augmentation therapy is defined as the addition of a second agent to an existing antidepressant regimen with the aim of achieving improved clinical response. METHOD: The available literature which related specifically to currently popular augmentation strategies in treatment resistant depression for the past 20 years was examined. The scientific evidence supporting the efficacy of these regimens and their safety was reviewed. RESULTS: Considerable research on lithium augmentation has been undertaken, and on triiodothyronine augmentation to a lesser degree. A number of other drugs have been trialed as augmentation agents with claims of success; however, most of the evidence supporting these agents is anecdotal and in the form of case reports. There are very few well-performed double-blind placebo-controlled studies of augmentation therapy. CONCLUSIONS: Because of possible complex pharmacodynamic and pharmacokinetic interactions, augmentation therapy is not without its potential complications. Lithium augmentation of tricyclic antidepressants can be recommended as a safe and effective strategy and there is a body of scientific evidence supporting the addition of T3 as an effective augmentation agent. Recent research with pindolol augmentation of selective serotonin re-uptake inhibitors (SSRIs) is encouraging, but these findings require replication. There is no empirical evidence supporting buspirone, carbamazepine, sodium valproate, methylphenidate or amphetamine as effective augmentation agents, or that adding a tricyclic to a SSRI has usefulness in relieving depressive symptoms. There is a need for considerable research in this area, with more prospective well-controlled placebo studies.

Antiglaucoma medication and clinical depression.

OBJECTIVE: The aim of this paper is to alert the medical community to the potential risk of clinical depression following the use of antiglaucoma medication. METHOD: The available literature concerning systemic side-effects of topical antiglaucoma medication and the association of these agents with clinical depression were reviewed. In addition, two cases are reported of the occurrence of clinical depression following use of topical betaxolol which only resolved completely after switching glaucoma medication. RESULTS/CONCLUSIONS: The case reports presented here add to the increasing body of literature linking topical ophthalmic beta-adrenoceptor antagonists with depression. While these cases are uncommon, this phenomenon continues to be poorly recognized by the medical profession, psychiatrists, ophthalmologists and general practitioners alike.

Aggressive behaviour in schizophrenia: the role of psychopathology.

OBJECTIVE: The aim of this study was to determine the psychopathological correlates of aggressive behaviour in schizophrenia. METHOD: Thirty-one aggressive patients in rehabilitation wards meeting DSM-III-R criteria for schizophrenia were compared with 31 matched non-aggressive patients in relation to their psychopathology using the Clinical Global Index (CGI), Positive and Negative Symptoms scale (PANSS) and the Montgomery-Asberg Depression Rating Scale. RESULTS: The aggressive group had significantly higher CGI, positive symptom, negative symptom, general psychopathology and total PANSS scores than the non-aggressive group. The two groups could be distinguished by three sets of symptoms: symptoms with verbal or/and physical aggression as part of their definition; symptoms suggesting frontal lobe impairment; and excitement. The two groups did not differ in their level of depressive symptomatology. CONCLUSIONS: The aggressive group were overall more ill than the non-aggressive group, and the former could be distinguished from the latter by certain aspects of their psychopathology.

A prospective study of aggression among psychiatric patients in rehabilitation wards.

OBJECTIVE: The aim of the study was to determine, among patients in rehabilitation wards, the prevalence and nature of aggressive behaviour and the relationship between aggressive behaviour and patient characteristics and ward factors. METHOD: The aggressive behaviour of all 220 inpatients within the rehabilitation program of a large psychiatric hospital in Victoria was assessed using the Staff Observation Aggression Scale. RESULTS: Physical assaults occurred at a rate of 97.6 per 100 patients per year. About 40% of all incidents appeared to be unprovoked. Most physical incidents involved use of body parts and use of a weapon was uncommon. Aggression was most often directed at a staff member. Serious injury was rare. Aggressive behaviour was correlated with gender and duration of admission for the whole sample; however, there were different correlates of aggressive behaviour for different ward populations and different types of aggression. As for ward variables, time of day but not patient/staffing level was associated with aggressive behaviour. CONCLUSIONS: There was a high rate of aggressive behaviour among patients in rehabilitation wards; this should be taken into consideration in the planning of their community placement. The findings also caution against aggregating different ward populations and types of aggressive behaviour for research.

A brief sensitive screening instrument for depression in late life.

Data collected with the depression scale (DEP) of the Brief Assessment Scale (BAS) at interviews with 811 elderly subjects were analysed to determine which of its 21 individual items could be selected to produce a short screening scale for depression which would have less than 10 items and a Cronbach's alpha above 0.8. Eight items which fulfilled these requirements were selected to form the Even Briefer Assessment Scale for Depression (EBAS DEP). The validity of the scale was assessed against psychiatric diagnoses made on a subset of 211 subjects. The EBAS DEP had a sensitivity and specificity for a diagnosis of a DSM-III-R mood disorder (depressed) of 0.91 and 0.72, respectively. The EBAS DEP could be useful as a brief screen for depression in busy hospital and primary care settings where a full assessment of mood for every patient is impractical. The EBAS DEP is presented, together with instructions for its use, to enable independent study of its reliability and validity in other populations.

The differentiation of depression from dementia by temporal lobe magnetic resonance imaging.

Temporal lobe Magnetic Resonance Imaging (MRI) was performed in 43 patients with NINCDS/ADRDA Alzheimer's disease (AD) (33 probable, 7 possible, 3 definite) and 32 subjects with DSM-III-R Major Depression (DEP) matched for age, sex and level of education. Hippocampus (anterior and posterior, right and left), amygdala, entorhinal cortex, parahippocampal gyrus and cerebral cortex were rated for atrophy on a 4-point scale. Good discrimination between groups could be achieved using a cut-off of 2 or more on anterior hippocampal atrophy rating (sensitivity 93%; specificity 84%; 89% cases correctly grouped overall). Even among a subgroup of 9 mild AD subjects and 10 cognitively impaired DEP subjects (matched on mini-mental state score), the same cut-off correctly grouped 84% (16/19) cases. Hippocampal atrophy increased with age in both AD and DEP subjects leading to a reduction in specificity (but not sensitivity) for those aged over 75. Within the AD group a significant correlation was observed between length of history and atrophy of the entorhinal cortex (r = 0.39, P = 0.009). We conclude that temporal lobe atrophy on MRI can provide good discrimination between AD and DEP subjects, including those DEP patients with cognitive impairment apparent on screening tests of cognitive function.