Search PubMed⌕ Search

Biomedical subjects

J J Mann

Publications and source records attributed to J J Mann.

At least 19 recordsLinked to original sources
PubMed2006

Prospective studies of suicidal behavior in major depressive and bipolar disorders: what is the evidence for predictive risk factors?

OBJECTIVE: Prospective studies over the past 30 years have identified an array of predictive indicators for suicidal acts in mood disorders. However, prediction of suicidal behavior remains an elusive goal. This paper reviewed evidence from prospective studies for clinical factors that elevate risk of suicidal acts in that group. METHOD: English language prospective studies of suicidal behavior in major depressive and bipolar disorders were examined. RESULTS: The predictors with the best support were a past history of suicidal behavior and the presence of refractory or recurrent depressions. For other risk factors, there was either not enough data to consider them robust or findings were contradictory. CONCLUSION: Future studies must not only be comprehensive in their inclusion of potentially contributing factors, but must also address their relative importance towards the goal of developing predictive models and enhance suicide prevention efforts.

Bipolar Disorder↗
PubMed2005

Zinc pyrithione induces apoptosis and increases expression of Bim.

We demonstrate herein that zinc pyrithione can induce apoptosis at nanomolar concentrations. Zinc pyrithione was a potent inducer of cell death causing greater than 40-60% apoptosis among murine thymocytes, murine splenic lymphocytes and human Ramos B and human Jurkat T cells. Conversely, the addition of a zinc chelator protected thymocytes against zinc pyrithione induced apoptosis indicating these responses were specific for zinc. Zinc-induced apoptosis was dependent on transcription and translation which suggested possible regulation by a proapoptotic protein. Indeed, zinc induced a 1.9 and 3.4 fold increase respectively in expression of the BimEL and BimL isoforms and also stimulated production of the most potent isoform, BimS. This increase in Bim isoform expression was dependent on transcription being blocked by treatment with actinomycin D. Overexpression of Bcl-2 or Bcl-xL provided substantial protection of Ramos B and Jurkat T cells against zinc-induced apoptosis. Zinc also activated the caspase cascade demonstrated by cleavage of caspase 9. Addition of specific inhibitors for caspase 9 and caspase 3 also blocked zinc-induced apoptosis. The data herein adds to the growing evidence that free or unbound zinc could be harmful to cells of the immune system.

Animals↗
PubMed2005

Clinical features of depressed patients with or without a family history of alcoholism.

OBJECTIVE: To compare clinical features of depressed subjects without alcoholism but with a family history of alcoholism to a depressed group without alcoholism and without a family history of alcoholism. METHOD: Clinical and demographic data of 209 depressed subjects without a history of alcoholism in first-degree relatives and 73 depressed individuals with a history of alcoholism in first-degree relatives were compared. Subjects with a personal history of alcoholism were excluded. RESULTS: Depressed subjects with a family history of alcoholism have a significantly higher prevalence of reported childhood physical and sexual abuse and post-traumatic stress disorder (PTSD), make more suicide attempts, and have greater intent to die at the time of their most lethal suicide attempt, compared to depressed subjects without a family history of alcoholism. CONCLUSION: Depressed patients with a family history of alcoholism are at greater risk for suicidal behavior and PTSD and may require more careful management.

Adult↗
PubMed2005

Risk factors for suicide completion in major depression: a case-control study of impulsive and aggressive behaviors in men.

OBJECTIVE: Major depression is a major risk factor for suicide. However, not all individuals with major depression commit suicide. Impulsive and aggressive behaviors have been proposed as risk factors for suicide, but it remains unclear whether their effect on the risk of suicide is at least partly explained by axis I disorders commonly associated with suicide, such as major depression. With a case-control design, a comparison of the level of impulsive and aggressive behaviors and the prevalence of associated psychopathology was carried out with control for the presence of primary psychopathology. METHOD: One hundred and four male suicide completers who died during an episode of major depression and 74 living depressed male comparison subjects were investigated with proxy-based interviews by using structured diagnostic instruments and personality trait assessments. RESULTS: The authors found that current (6-month prevalence) alcohol abuse/dependence, current drug abuse/dependence, and cluster B personality disorders increased the risk of suicide in individuals with major depression. Also, higher levels of impulsivity and aggression were associated with suicide. An analysis by age showed that these risk factors were more specific to younger suicide victims (ages 18-40). A multivariate analysis indicated that current alcohol abuse/dependence and cluster B personality disorder were two independent predictors of suicide. CONCLUSIONS: Impulsive-aggressive personality disorders and alcohol abuse/dependence were two independent predictors of suicide in major depression, and impulsive and aggressive behaviors seem to underlie these risk factors. A developmental hypothesis of suicidal behavior, with impulsive and aggressive behaviors as the starting point, is discussed.

Adult↗
PubMed2004

Postmortem mu-opioid receptor binding in suicide victims and controls.

BACKGROUND: Endogenous opiates may reinforce self-injurious behavior in animal and human subjects. Higher postmortem mu-opioid receptor binding is reported in some brain regions in young compared with older suicide victims. The present study compared opioid receptor binding kinetics in postmortem brains of young suicide victims and matched controls in two brain areas. METHODS: The density (Bmax) and affinity (K(D)) of the mu-opioid receptors were assayed postmortem using [3H] DAGO in prefrontal cortex (PFC) and pre-post central gyri (PPCG) in 9 suicide victims and 10 controls, matched for age and gender ratio. RESULTS: Binding indices did not differ between suicide victims and controls in either brain area and did not correlate with age. PFC Bmax was higher than PPCG Bmax (F=8.030; df=1,16; p=.012) for the combined sample. There was no brain region difference in K(D) between PFC and PPCG, but the interaction between K(D) and group was significant (F = 5.890; df = 1,16; p = .027). The K(D) in the suicide victims was lower than controls in the PFC and higher than controls in the PPCG. CONCLUSION: Our study demonstrated more mu-opioid receptors in PFC compared with PPCG binding regardless of suicide status. The region-dependent differences in binding affinity in suicide victims may reflect regionally different opiate transmission.

Adult↗
PubMed2004

Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims.

Endogenous and exogenous cannabinoids (CBs) acting through the CB(1) receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB(1) receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS). [(3)H]CP-55,940 and CB(1) receptor-stimulated [(35)S]GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB(1) receptor density (B(max)) was observed in DS (644.6+/-48.8 fmol/mg protein) compared with matched controls (493.3+/-52.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.14+/-0.08 vs control; 1.12+/-0.10 nM). Higher density of CB(1) receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB(1) receptor-stimulated [(35)S]GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB(1) receptors with concomitant increase in the CB(1) receptor-mediated [(35)S]GTPgammaS binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior.

Adolescent↗
PubMed2004

Rates of lifetime suicide attempt and rates of lifetime major depression in different ethnic groups in the United States.

OBJECTIVE: Rates of major depression and suicide vary across ethnic groups within the US. This also may be true of suicide attempts. METHOD: Data on lifetime suicidal behavior and major depression among Mexican American, Cuban American, and Puerto Rican adults who participated in the Hispanic Health and Nutrition Epidemiologic Survey were pooled with Epidemiological Catchment Area Study data for Blacks, Whites and Hispanics. RESULTS: Rates of major depression ranged from 9.3 (Puerto Ricans) to 3.24% (Cuban Americans). Puerto Ricans and whites had the highest rates of depression. Similarly, suicide attempt rates ranged from 9.1% for Puerto Ricans to 1.9% for Cuban Americans. Puerto Ricans had higher suicide attempt rates compared with other groups. CONCLUSION: This study underscores that there are differences between Hispanic ethnic groups. The impact of the migration process, socioeconomic status, and acculturation may underlie differences in major depression and suicide attempt rates across ethnic groups.

Adult↗
PubMed2003

Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins.

Schizophrenia unfolds during the late period of brain maturation, while myelination is still continuing. In the present study, we used MRI and T2 relaxation analysis to measure the myelin water fraction in schizophrenia. In schizophrenia (n=30) compared with healthy subjects (n=27), overall white matter showed 12% lower myelin water fraction (P=0.031), with the most prominent effects on the left genu of the corpus callosum (36% lower, P=0.002). The left anterior genu was affected in both first-episode (P=0.035) and chronic patients (P=0.011). In healthy subjects, myelin water fraction in total white matter and in frontal white matter increased with age, and with years of education, indicating ongoing maturation. In patients with schizophrenia, neither relation was statistically significant. Post-mortem studies of anterior frontal cortex demonstrated less immunoreactivity of two oligodendrocyte-associated proteins in schizophrenia (2',3'-cyclic nucleotide 3'-phosphodiesterase by 33%, P=0.05; myelin-associated glycoprotein by 27%, P=0.14). Impaired myelination in schizophrenia could contribute to abnormalities of neural connectivity and persistent functional impairment in the illness.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2002

Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness.

Recent imaging and postmortem studies suggest that impaired connectivity is involved in the pathophysiology of schizophrenia and major affective disorders. We investigated the presynaptic proteins complexin (Cx) I and Cx II in postmortem prefrontal cortex in schizophrenia (n = 13; six suicide, seven nonsuicide), major depression (n= 11, all suicide) and controls (n = 11) with an enzyme-linked immunoadsorbent assay (ELISA). Overall analysis indicated a significant difference between groups (F = 3.93, P = 0.007). Cx I (enriched in inhibitory terminals) was decreased 33% in schizophrenia (26% in schizophrenia/nonsuicide, 42% in schizophrenia/suicide) and 27% in major depression. Cx II (enriched in excitatory terminals) was not significantly different. Analysis of the ratio of Cx II/Cx I was carried out as an indication of the balance of excitatory to inhibitory terminals. A significant difference between groups (ANOVA, F = 6.42, P = 0.005) was observed. The mean value of Cx II/Cx I was significantly increased by 34% in schizophrenia (26% in schizophrenia/nonsuicide and 43% in schizophrenia/suicide) and by 32% in depression compared with control (Student-Newman-Keuls test, P = 0.05). Immunoreactivities of the two complexins were highly correlated in all groups. However, compared with controls and depression, samples from cases with schizophrenia appeared to have relatively less Cx I for similar amounts of Cx II. Immunocytochemical studies of rat frontal cortex after 3 weeks treatment with chlorpromazine, trifluoperazine or haloperidol revealed no differences in complexins, synaptophysin, SNAP-25, syntaxin or VAMP in comparison with animals treated with vehicle. Alterations of complexins may contribute to the molecular substrate for abnormalities of neural connectivity in severe mental disorders.

Adaptor Proteins, Vesicular Transport↗
PubMed2001

Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels.

BACKGROUND: We have proposed a stress-diathesis model for suicidal behavior, in which major depression is a stressor and the diathesis is shared with aggression. Neurotransmitter correlates of the stress or diathesis have not been adequately evaluated by previous studies, because they did not simultaneously examine the relationship of multiple neurotransmitters to all three psychopathologies in the same population. In the present study we investigated the relationship of monoamine metabolites to aggressivity, suicidal behavior, and depression in patients with mood disorders. METHODS: Ninety-three drug-free subjects with a major depressive episode underwent lumbar puncture and psychiatric evaluation. Cerebrospinal fluid CSF levels of 5hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA) and methoxy-hydroxy-phenylglycol (MHPG) were assayed. The relationships between monoamine metabolites and clinical variables were statistically evaluated. RESULTS: Higher lifetime aggressivity correlated significantly with lower CSF 5-HIAA. Lower CSF 5-HIAA and greater suicidal intent were found in high-lethality suicide attempters compared with low-lethality suicide attempters. Low-lethality attempters did not differ biologically from nonattempters. No correlation between CSF HVA and any of the psychopathological variables was found. Only aggression showed a trend statistically in correlating positively with CSF MHPG levels. CONCLUSIONS: Lower CSF 5-HIAA concentration was independently associated with severity of lifetime aggressivity and a history of a higher lethality suicide attempt and may be part of the diathesis for these behaviors. The dopamine and norepinephrine systems do not appear to be as significantly involved in suicidal acts, aggression, or depression. The biological correlates of suicide intent warrant further study.

Adult↗
PubMed2001

Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression.

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. METHODS: The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. RESULTS: No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)". CONCLUSIONS: This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.

Adolescent↗
PubMed2001

Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial.

CONTEXT: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT. OBJECTIVE: To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode. SETTING: Two university-based hospitals and 1 private psychiatric hospital. PATIENTS: Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study. INTERVENTIONS: Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28). MAIN OUTCOME MEASURE: Relapse of major depressive episode, compared among the 3 continuation groups. RESULTS: Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse. CONCLUSIONS: Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.

Antidepressive Agents↗
PubMed2001

Understanding the neurobiology of suicidal behavior.

Our current knowledge about the neurobiology of suicide is still limited. Technical limitations and the complexity of the CNS are major obstacles. However, there is evidence for a hereditary disposition to suicide, which appears to be independent of diagnosis. Clinical, postmortem, genetic, and animal studies suggest that serotonin has a central role. The main regions of interest in the CNS have been the dorsal and median raphe nuclei in the midbrain that host the main serotonergic cell bodies and the prefrontal cortex, particularly the ventral PFC, innervated by the serotonergic system. In vivo and postmortem studies indicate serotonergic hypofunction in suicide and serious suicide attempts. This deficiency in turn can lead to a predisposition to impulsive and aggressive behavior, probably due to a breakdown in the inhibitory function of the ventral prefrontal cortex as a result of less serotonin input. In the context of this predisposition and the development of mental illness or other life stressors, the individual is at risk of acting on suicidal thoughts. Such deficient serotonin input into the PFC may arise as a result of genetic, parenting, head injury, and other effects. Identifying psychiatric, social, and environmental predictors of suicide are studied to improve prediction and prevention of suicide. A better understanding of the neurobiology of suicide can help detect at risk populations and help develop better treatment interventions.

Adolescent↗
PubMed2001

Differential occupancy of somatodendritic and postsynaptic 5HT(1A) receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans.

Augmentation of selective serotonin reuptake inhibitors (SSRIs) therapy by the 5-HT(1A) receptor agent pindolol may reduce the delay between initiation of antidepressant treatment and clinical response. This hypothesis is based on the ability of pindolol to block 5-HT(1A) autoreceptors in the dorsal raphe nuclei (DRN) and to potentiate the increase in 5-HT transmission induced by SSRIs. However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT(1A) receptors during treatment with pindolol controlled release (CR) in nine healthy volunteers with Positron Emission Tomography and [11C]WAY 100635. Subjects were studied four times: at baseline, following one week of pindolol CR 7.5 mg/day (4 and 10 hrs post dose), and following one dose of pindolol CR 30 mg(4 hrs post dose). Occupancy of the DRN was 40 +/- 29% on scan 2, 38 +/- 26% on scan 3, and 64 +/- 15% on scan 4. The average occupancy in all other regions was significantly lower at each doses (18 +/- 5% on scan 2, 12 +/- 3% on scan 3, and 42 +/- 4% on scan 4). These results suggest that the blockade in the DRN reached in clinical studies (7.5 mg/day) might be too low and variable to consistently augment the therapeutic effect of SSRIs. However, these data indicate that pindolol exhibits in vivo selectivity for the DRN 5-HT(1A) autoreceptors. As DRN selectivity is desirable for potentiation of 5-HT function, this observation represents an important proof of concept for the development of 5-HT(1A) agents in this application.

Adult↗
PubMed2001

The neurobiology and genetics of suicide and attempted suicide: a focus on the serotonergic system.

Numerous abnormalities have been found in the serotonergic system in suicide attempters and completers. There is considerable evidence that the serotonergic system is partly under genetic control and that as yet unknown genetic factors mediate the risk for suicidal behavior independently of the genetic factors responsible for the heritability of major psychiatric conditions associated with suicide. An argument is made that there is a relationship of genetic variants to intermediate phenotypes, such as impulsivity, psychomotor change, pathological aggression and biological abnormalities including specific gene products. A variety of biological indices have been generated by new approaches using postmortem tissue and in vivo imaging that will provide a rich substrate for further genetic studies.

Animals↗
PubMed2001

Prolactin response to dl-fenfluramine challenge before and after treatment with paroxetine.

The prolactin response to dl-fenfluramine (an indirect central serotonin agonist) challenge has been used to assess serotonergic function and appears to be blunted in depressed patients. We used this method to determine whether the serotonergic deficit in depressed patients is corrected by treatment with paroxetine. Prior to treatment with paroxetine sixteen depressed patients received a placebo challenge followed by a dl-fenfluramine challenge the next day. The same two challenges were repeated after treatment. Prolactin baseline levels were measured before pill administration, and then hourly for 5 hours. Fenfluramine/norfenfluramine levels were assayed at each time point after drug administration. Treatment with paroxetine significantly increased the baseline prolactin level independently of treatment response but positively correlated with paroxetine dose. We found that pre-treatment prolactin response to dl-fenfluramine challenge did not predict clinical response to paroxetine, nor did the prolactin response change significantly after treatment. There was no significant difference in the post-treatment prolactin response between treatment responders and treatment non-responders. We found evidence of increased prolactin levels that may reflect effects of paroxetine in enhancing serotonin levels. Acute release of serotonin as measured by the prolactin response to fenfluramine is not altered by paroxetine treatment.

Aged↗
PubMed2001

Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims.

Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT(1A) receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT(1A) autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT(1A) binding was not different between controls and suicides (p >.05). In the DRN of suicides, the volume of tissue defined by 5-HT(1A) binding was 40% smaller than controls. An index of the total number of 5-HT(1A) receptors (receptor binding x volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT(1A) and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT(1A) autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides.

8-Hydroxy-2-(di-n-propylamino)tetralin↗