PubMed Health⌕ Search

Biomedical subjects

Michael Berk

Publications and source records attributed to Michael Berk.

At least 19 recordsLinked to original sources
PubMed2024

Convergence on CaMK4: A Key Modulator of Autism-Associated Signaling Pathways in Neurons.

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For many people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the CaMK4 (calcium/calmodulin-dependent protein kinase 4) enzyme. CaMK4 is a key component of a Ca2+-activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss 3 genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on 4 other genetic variations in CAMK4 that show associations with autism spectrum disorder, as well as 12 examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight 3 environmental risk factors that impact CaMK4 signaling based on studies of preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest that defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and we propose CaMK4 as a potential therapeutic target.

Humans↗
PubMed2006

The effects of physical activity in the acute treatment of bipolar disorder: a pilot study.

BACKGROUND: Physical activity has demonstrated efficacy in depression and anxiety, but its potential in the management of bipolar disorder is yet unexplored. This study is a pilot investigation into the effectiveness of an adjunctive walking program in the acute treatment of bipolar disorder. METHODS: This is a retrospective cohort study of all patients admitted over a 24-month period to a private psychiatric unit with a primary diagnosis of bipolar disorder (ICD-10). All patients were invited to participate voluntarily in a walking group during their admissions. Those who reliably attended the walking group (participants) were compared against those who did not attend (non-participants), using the clinician-rated Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) scales and the self-reported 21-item Depression Anxiety Stress Scales (DASS) as primary outcome measures. RESULTS: There were 24 admissions for participants and 74 admissions for non-participants. The two groups did not differ significantly in patient demographics or admission CGI and DASS measures, except for a lower DASS Stress subscore for participants (p=0.049). At discharge, the inter-group differences in CGI measures remained non-significant, but participants had significantly lower scores than non-participants for DASS (p=0.005) and all its subscales (Depression p=0.048, Anxiety p=0.002, Stress p=0.01). LIMITATIONS: Methodological limitations include a retrospective design, small sample size, lack of randomisation or control, and indirect measure of manic symptoms. CONCLUSIONS: The results of this trial provide preliminary support for a therapeutic role of physical activity in bipolar disorder, and warrant further investigation with randomised controlled trials.

Acute Disease↗
PubMed2006

Hypoxia enhances lysophosphatidic acid responsiveness in ovarian cancer cells and lysophosphatidic acid induces ovarian tumor metastasis in vivo.

Lysophosphatidic acid (LPA) is elevated in ascites of ovarian cancer patients and stimulates growth and other activities of ovarian cancer cells in vitro. Tissue hypoxia is a critical factor for tumor aggressiveness and metastasis in cancers. We tested whether the ascites of ovarian cancer is hypoxic and whether hypoxia influences the effects of LPA on ovarian cancer cells. We found that ovarian ascitic fluids were hypoxic in vivo. Enhanced cellular responsiveness to LPA, including migration and/or invasion of ovarian cancer cells, was observed under hypoxic conditions. This enhancement could be completely blocked by geldanamycin or a small interfering RNA targeting hypoxia-inducible factor 1 alpha (HIF1 alpha). LPA-induced cell migration required cytosolic phospholipase A(2) (cPLA(2)) and LPA stimulates cPLA(2) phosphorylation in a HIF1 alpha-dependent manner under hypoxia conditions. Furthermore, we show for the first time that exogenous LPA enhances tumor metastasis in an orthotopic ovarian cancer model and HIF alpha expression in tumors. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (an inhibitor of the heat shock protein 90) effectively blocked LPA-induced tumor metastasis in vivo. Together, our data indicate that hypoxic conditions are likely to be pathologically important for ovarian cancer development. HIF1 alpha plays a critical role in enhancing and/or sensitizing the role of LPA on cell migration and invasion under hypoxic conditions, where cPLA(2) is required for LPA-induced cell migration.

Cell Hypoxia↗
PubMed2006

Diagnosing bipolar disorder: how can we do it better?

Accurate diagnosis of bipolar disorder is essential for effective treatment. The diagnosis of bipolar disorder is particularly complex, resulting in lengthy delays between first presentation and initiation of appropriate therapy. Inappropriate therapy destabilises the course and outcome of the disease. Although the defining features of bipolar disorder are manic or hypomanic episodes, patients typically present for treatment of depression and commonly deny symptoms of mood elevation. A correct diagnosis can easily be masked by comorbidities, personality issues and complex phenomenology. A diagnosis of bipolar disorder can be assisted by: asking about symptoms of mania or hypomania in every patient presenting with symptoms of depression. recognising mixed states in which manic and depressive symptoms occur simultaneously. identifying the features of bipolar depression that distinguish it from unipolar depression. There is a risk of over-diagnosis of bipolar disorder among patients who are histrionic, show abnormal illness behaviour and/or have issues of secondary gain.

Age of Onset↗
PubMed2006

Do ambient electromagnetic fields affect behaviour? A demonstration of the relationship between geomagnetic storm activity and suicide.

The relationship between ambient electromagnetic fields and human mood and behaviour is of great public health interest. The relationship between Ap indices of geomagnetic storm activity and national suicide statistics for Australia from 1968 to 2002 was studied. Ap index data was normalised so as to be globally uniform and gave a measure of storm activity for each day. A geomagnetic storm event was defined as a day in which the Ap index was equal to or exceeded 100 nT. Suicide data was a national tally of daily male and female death figures where suicide had been documented as the cause of death. A total of 51 845 males and 16 327 females were included. The average number of suicides was greatest in spring for males and females, and lowest in autumn for males and summer for females. Suicide amongst females increased significantly in autumn during concurrent periods of geomagnetic storm activity (P = .01). This pattern was not observed in males (P = .16). This suggests that perturbations in ambient electromagnetic field activity impact behaviour in a clinically meaningful manner. The study furthermore raises issues regarding other sources of stray electromagnetic fields and their effect on mental health.

Age Distribution↗
PubMed2006

Pharmacological treatment in the early phase of bipolar disorders: what stage are we at?

OBJECTIVE: To review available guidelines, explore treatment strategies currently applied, identify critical issues and propose direction for new developments. METHOD: Literature review based on Medline search and hand search of relevant literature. RESULTS: Pharmacological treatment of the early phase of bipolar disorders lacks specific guidelines. Mood stabilizers are often prescribed after many years of illness, antipsychotic medications are frequently prescribed and often for extensive periods of time, and adherence to medication is relatively poor. In addition, mania is frequently misdiagnosed, and there is limited knowledge on which to base identification of bipolar depression and identification of the initial prodrome to bipolar disorders. CONCLUSIONS: There is an urgent need for more research in the early phases of bipolar disorders to develop means to identify patients earlier and to develop approaches that would address the specific needs of this population in a more adequate manner.

Anticonvulsants↗
PubMed2006

A clinical monitoring system for clozapine.

OBJECTIVE: To describe a framework for the initiation and ongoing monitoring of patients on clozapine, and detail support materials that can be used in clinical settings, including general practice, to support this process. CONCLUSIONS: A framework is described. Clozapine has a special place in the management of treatment-resistant schizophrenia. However, it has certain side-effects that require its use to be carefully evaluated on an individual patient basis, and encompass excellent documentation and discussion with all relevant parties. Comprehensive longitudinal monitoring is required.

Antipsychotic Agents↗
PubMed2006

Symptomatic and functional outcome 12 months after a first episode of psychotic mania: barriers to recovery in a catchment area sample.

OBJECTIVE: Recent studies have shown that outcome in mania is worse than previously thought. Such studies have been conducted in selected samples with restrictive measures of outcome. We aimed to explore outcome and its predictors in a catchment area sample of first-episode psychotic mania of DSM-III-R bipolar I disorder. METHODS: Prospective 6 and 12 months follow-up was conducted with 87 DSM-III-R first-episode psychotic mania patients admitted to Early Psychosis Prevention and Intervention Centre between 1989 and 1997. Syndromic and symptomatic outcome were determined with the Brief Psychiatric Rating Scale; functional outcome with the Quality of Life Scale and Premorbid Adjustment Scale subitems. RESULTS: Symptomatic outcome was assessed in 67 patients at 6 months and 61 patients at 12 months, and functional outcome in 56 patients at 6 months and 49 patients at 12 months. Logistic regressions were conducted on 46 and 43 patients, respectively, to explore predictors of outcome. While 90% of patients achieved syndromic recovery at 6 and 12 months, 40% had not recovered symptomatically at 6 and 12 months, still presenting with anxiety or depression. A total of 66% of patients at 6 months and 61% of patients at 12 months failed to return to previous level of functioning. Age at intake, family history of affective disorder, illicit drug use and functional recovery at 6 months predicted functional outcome at 12 months. CONCLUSIONS: This study confirms poor symptomatic and functional outcome after first-episode psychotic mania. It suggests possible usefulness of early intervention strategies in bipolar disorders and need for developing specific interventions addressing anxiety, depression and substance abuse comorbidity.

Adolescent↗
PubMed2006

Combination pharmacotherapy in unipolar depression.

It is estimated that between 60 and 80% of those with major depressive disorder do not achieve full symptomatic remission from first-line antidepressant monotherapy. Residual depressive symptoms substantially impair quality of life and add to the risk of recurrence. It is now clear that depression would benefit from more vigorous treatment, in order to ameliorate its disease burden. While there are established algorithms in situations of treatment resistance, the use of combination pharmacotherapy in unipolar depression is a relatively under-investigated area of treatment and may be an effective and tolerable strategy that maximizes the available resources. This paper reviews the current evidence for combination pharmacotherapy in unipolar depression and discusses its clinical applications.

Antidepressive Agents↗
PubMed2005

The effect of macroeconomic variables on suicide.

BACKGROUND: There are a large number of factors mediating suicide. Many studies have searched for a direct causal relationship between economic hardship and suicide, however, findings have been varied. METHOD: Suicide data was obtained from the Australian Bureau of Statistics for the period between January 1968 and August 2002. These were correlated with a suite of macroeconomic data including housing loan interest rates, unemployment rates, days lost to industrial disputes, Consumer Price Index, gross domestic product, and the Consumer Sentiment Index. RESULTS: A total of 51845 males and 16327 females committed suicide between these dates. There were significant associations between suicide rates and eleven macroeconomic indicators for both genders in at least one age range. Data was divided into male and female and five age ranges and pooled ages. Analyses were conducted on these 132 datasets resulting in 80 significant findings. The data was generally stronger for indices measuring economic performance than indices measuring consumers' perceptions of the state of the economy. A striking difference between male and female trends was seen. Generally, male suicide rates increased with markers of economic adversity, while the opposite pattern was seen in females. There were significantly different patterns in age-stratified data, with for example higher housing loan interest rates having a positive association with suicide in younger people and a negative association in older age groups. CONCLUSION: Macroeconomic trends are significantly associated with suicide. The patterns in males and females are very different, and there are further substantial age-related differences.

Adolescent↗
PubMed2005

To combine or not to combine? A literature review of antidepressant combination therapy.

OBJECTIVE: Treatment resistant depression is a common clinical problem and a major public health concern. The use of antidepressant combinations to overcome treatment resistance, while somewhat controversial, is a popular strategy in practice. This paper reviews published trials on combination antidepressants with a view to inform clinical practice. METHOD: A systematic but selective review of the published literature was conducted using EMBASE, PSYCHLIT and MEDLINE with relevant search terms. RESULTS: A number of trials suggesting efficacy of combination antidepressants were found. These are incorporated into a number of treatment guidelines for the management of treatment refractory depression. Clinicians should be cautious regarding pharmacokinetic and pharmacodynamic interactions, including the serotonin syndrome, however combination strategies are an effective option. CONCLUSIONS: Many antidepressants can be usefully combined especially if they engage separate mechanisms of action. Clinically, antidepressant combinations provide a useful resort in otherwise treatment resistant individuals. However, much further research is needed to determine relative efficacy and determine long term outcome.

Antidepressive Agents↗
PubMed2005

KiSS1 suppresses metastasis in human ovarian cancer via inhibition of protein kinase C alpha.

Metastasis is a vital target for cancer treatment, since the majority of cancer patients die from metastatic, rather than the primary disease. KiSS1 has been identified as a metastasis suppressor gene in melanoma and breast carcinomas. We show here that KiSS1 is also a metastasis suppressor in human ovarian cancer. Overexpression of KiSS1 in ovarian cancer cells inhibits cell migration induced by serum or lysophosphatidic acid (LPA), and colonization in soft agar, but not cell proliferation, representing the characteristics of a metastasis suppressor gene. Furthermore, using an experimental metastatic mouse model, we show that expression of KiSS1 in SKOV3 ovarian cancer cells suppresses >50% metastatic colonization in mice (P < 0.0001). We find that activating protein kinase C (PKC) reverses about 80% of the inhibited cell migration induced by KiSS1, while down-regulation of PKCalpha with shRNA restores KiSS1 effect, providing evidence that inhibiting PKCalpha may be an important mechanism of the effect of KiSS1. These results suggest that KiSS1 is a metastasis suppressor of ovarian cancer and may be a potential molecular target for the treatment.

Animals↗
PubMed2005

Are treatment emergent suicidality and decreased response to antidepressants in younger patients due to bipolar disorder being misdiagnosed as unipolar depression?

While antidepressants have been demonstrated to be a safe and effective treatment for unipolar major depressive disorder (MDD) in adults, the use of antidepressants to treat children and adolescents is controversial. There is a paucity of evidence to suggest that antidepressants are effective when used to treat children and adolescents and some recent placebo-controlled evidence has suggested that antidepressant treatment increases suicidality in this population. MDD is a very broad construct, and includes many clinical subtypes. Bipolar Disorder (BD) has an earlier age of onset than MDD. The initial polarity of illness in bipolar disorder is frequently depression. Patients are more likely to first present for treatment during the depressive phase of the illness than during manic or hypomanic phases. It is probable that a substantial portion of depressed children and adolescents may not suffer from unipolar MDD but may have a bipolar spectrum disorder. There are few trials supporting the efficacy of antidepressants in bipolar disorder, and some evidence that they may induce rapid cycling, switching and mania. Antidepressant induced mania is often mixed, with admixtures of manic and depressive features. An increased suicide risk is a particular feature of mixed states, potentially explaining why suicidal ideation can emerge with antidepressant treatment. Antidepressants are unlikely to somehow act differently in children than they do in adults. A more plausible explanation is that incipient bipolar disorder is often not diagnosed early in children and adolescents and the differential effects of antidepressants in this group is a result of differing diagnostic casemixes.

Adolescent↗
PubMed2005

'Bipolar missed states': the diagnosis and clinical salience of bipolar mixed states.

OBJECTIVE: To explore diagnostic and treatment issues concerning bipolar mixed states. METHOD: Bipolar mixed states are described and concerns about diagnostic and treatment difficulties are summarized and discussed. RESULT: Mixed states can present with equal admixtures of depressive or manic symptoms, or more commonly one component predominates. There is fair consensus, although little data, regarding the management of manic mixed states. However depressive mixed states are far more complex both in terms of recognition and management. People suffering from mixed states characteristically present with complaints of depression. CONCLUSIONS: The boundaries between depressive mixed states and agitated depression are vague, yet carry substantial therapeutic implications. Bipolar mixed states are often difficult to treat, and tend to take much longer to settle than either pure mania or depression. Furthermore there is data that treatment with antidepressants can worsen the course of mixed states. Hence missed diagnoses can potentially have negative clinical implications. Therefore in this paper the clinical presentation, diagnosis and therapy of mixed states is reviewed with a view to improving management.

Affect↗