Brexanolone Treatment in a Real-World Patient Population: A Case Series and Pilot Feasibility Study of Precision Neuroimaging.

PURPOSE/BACKGROUND: Brexanolone is approved for postpartum depression (PPD) by the United States Food and Drug Administration. Brexanolone has outperformed placebo in clinical trials, but less is known about the efficacy in real-world patients with complex social and medical histories. Furthermore, the impact of brexanolone on large-scale brain systems such as changes in functional connectivity (FC) is unknown. METHODS/PROCEDURES: We tracked changes in depressive symptoms across a diverse group of patients who received brexanolone at a large medical center. Edinburgh Postnatal Depression Scale (EPDS) scores were collected through chart review for 17 patients immediately prior to infusion through approximately 1 year postinfusion. In 2 participants, we performed precision functional neuroimaging (pfMRI), including before and after treatment in 1 patient. pfMRI collects many hours of data in individuals for precision medicine applications and was performed to assess the feasibility of investigating changes in FC with brexanolone. FINDINGS/RESULTS: The mean EPDS score immediately postinfusion was significantly lower than the mean preinfusion score (mean change [95% CI]: 10.76 [7.11-14.40], t (15) = 6.29, P < 0.0001). The mean EPDS score stayed significantly lower at 1 week (mean difference [95% CI]: 9.50 [5.23-13.76], t (11) = 4.90, P = 0.0005) and 3 months (mean difference [95% CI]: 9.99 [4.71-15.27], t (6) = 4.63, P = 0.0036) postinfusion. Widespread changes in FC followed infusion, which correlated with EPDS scores. IMPLICATIONS/CONCLUSIONS: Brexanolone is a successful treatment for PPD in the clinical setting. In conjunction with routine clinical care, brexanolone was linked to a reduction in symptoms lasting at least 3 months. pfMRI is feasible in postpartum patients receiving brexanolone and has the potential to elucidate individual-specific mechanisms of action.

Risk of Breast Cancer With Prolactin Elevating Antipsychotic Drugs: An Observational Study of US Women (Ages 18-64 Years).

PURPOSE/BACKGROUND: Antipsychotic drugs are well established to alter circulating prolactin levels by blocking dopamine D2 receptors in the pituitary. Prolactin activates many genes important in the development of breast cancer. Prior studies have found an association with antipsychotic use and risk of breast cancer. METHODS/PROCEDURES: The IBM MarketScan Commercial and Medicaid Databases were used to establish a large, observational cohort of women taking antipsychotics drugs compared with anticonvulsants or lithium. A new user design was used that required 12 months of insurance enrollment before the first antipsychotic or anticonvulsant/lithium prescription. Invasive breast cancer was identified using diagnostic codes. Multivariable Cox proportional hazards models were used to evaluate the risk of breast cancer with antipsychotic drug exposure controlling for age and other risk factors. FINDINGS/RESULTS: A total of 914 cases (0.16%) of invasive breast cancer were identified among 540,737 women. Exposure to all antipsychotics was independently associated with a 35% increased risk of breast cancer (aHR [adjusted hazard ratio], 1.35; 95% confidence interval, 1.14-1.61). Category 1 drugs (high prolactin) were associated with a 62% increased risk (aHR, 1.62; 95% CI, 1.30-2.03), category 2 drugs a 54% increased risk (aHR, 1.54; 95% CI, 1.19-1.99), and category 3 drugs were not associated with breast cancer risk. IMPLICATIONS/CONCLUSIONS: In the largest study of antipsychotics taken by US women, a higher risk between antipsychotic drug use and increased risk for breast cancer was observed, with a differential higher association with antipsychotic categories that elevate prolactin. Our study confirms other recent observational studies of increased breast cancer risk with antipsychotics that elevate prolactin.

Prolactin and Estrogen Levels in Postmenopausal Women Receiving Aripiprazole Augmentation Treatment for Depression.

BACKGROUND: Antipsychotic drugs are well established to alter serum prolactin levels, often resulting in adverse effects including amenorrhea, galactorrhea, osteoporosis, and loss of libido. There is growing preclinical evidence that prolactin-elevating drugs can instigate the progression of precancerous lesions to breast cancer and that genes activated by prolactin are associated with the development and proliferation of breast cancer. Current guides advise a cautious approach (weighing risks and benefits) to the administration of prolactin-elevating antipsychotic drugs in women with a previously detected breast cancer. Aripiprazole is known to be a prolactin-sparing antipsychotic; however, data regarding its effects on prolactin and estrogens in postmenopausal women are lacking. METHODS: We examined serum hormone levels in n = 66 women who participated in a randomized, double-blind, placebo-controlled, multicenter trial of aripiprazole (high and low doses) added to an antidepressant in adults older than 60 years. Aripiprazole or placebo tablets were administered for 12 weeks as an augmentation strategy in venlafaxine-treated women. The primary outcomes were the difference in prolactin and estrogen levels. RESULTS: There was no significant effect of aripiprazole treatment on prolactin or estrogen levels, including in models that divided groups into low and high doses: prolactin (P = 0.075), estrone (P = 0.67), and estradiol (P = 0.96). CONCLUSIONS: Aripiprazole addition to an antidepressant did not alter serum estrogens or prolactin. These findings may be relevant in the treatment of some postmenopausal women with depression.

Cognitive-affective drivers of fixation in threat assessment.

Pathological fixation - preoccupation with a person or a cause that is accompanied by deterioration in social and occupational functioning - has been found to precede most cases of targeted violence. It is clinically observed and theorized to have three different cognitive-affective drivers: delusion, obsession, or extreme overvalued belief. Each driver is explained, and case examples are provided in the context of threat assessment. Extreme overvalued belief as a new concept is discussed in detail, both its historical provenance and its demarcation from delusions and obsessions. Threat management for each separate cognitive-affective driver is briefly summarized, based upon current clinical findings and research. Emphasis is placed upon understanding both the categorical and dimensional nature (intensity) of these cognitive-affective drivers, and suggested guidelines are offered for the assessment of such in a clinical examination by a forensic psychiatrist or psychologist.

Extreme Overvalued Beliefs.

An extreme overvalued belief is shared by others in a person's cultural, religious, or subcultural group. The belief is often relished, amplified, and defended by the possessor of the belief and should be differentiated from a delusion or obsession. Over time, the belief grows more dominant, more refined, and more resistant to challenge. The individual has an intense emotional commitment to the belief and may carry out violent behavior in its service. Study participants (n = 109 forensic psychiatrists) were asked to select among three definitions (i.e., obsession, delusion, and extreme overvalued belief) as the motive for the criminal behavior seen in 12 randomized fictional vignettes. Strong interrater agreement (kappa = 0.91 [95% CI 0.83-0.98]) was seen for vignettes representing extreme overvalued belief. Vignettes representing delusion and obsession also had strong reliability (kappa = 0.99 for delusion and 0.98 for obsession). This preliminary report suggests that forensic psychiatrists, given proper definitions, possess a substantial ability to identify delusion, obsession, and extreme overvalued belief. The rich historical foundation of extreme overvalued belief and this small survey study highlight the benefit of inclusion of "extreme overvalued belief" in future glossaries of the Diagnostic and Statistical Manual.

Should Trackable Pill Technologies Be Used to Facilitate Adherence Among Patients Without Insight?

Aripiprazole tablets with sensor offer a new wireless trackable form of aripiprazole that represents a clear departure from existing drug delivery systems, routes, or formulations. This tracking technology raises concerns about the ethical treatment of patients with psychosis when it could introduce unintended treatment challenges. The use of "trackable" pills and other "smart" drugs or nanodrugs assumes renewed importance given that physicians are responsible for determining patients' decision-making capacity. Psychiatrists are uniquely positioned in society to advocate on behalf of vulnerable patients with mental health disorders. The case presented here focuses on guidance for capacity determination and informed consent for such nanodrugs.

Extreme Overvalued Belief and the Legacy of Carl Wernicke.

Individuals with extreme overvalued beliefs often carry out abhorrent and inexplicable acts of violence. They hold odd and bizarre beliefs that are shared by others in their culture or subculture. This creates a dilemma for the forensic psychiatrist because the definition of delusion may not be adequate. We discuss the evolution of the term "overvalued idea" first described in a forensic context by neuropsychiatrist Carl Wernicke in 1892. The overvalued idea is invoked in British scholarship as a definition for beliefs seen in anorexia nervosa, morbid jealousy, paranoid litigious states, and other disorders. This is sometimes referred to as delusional disorder by psychiatrists in the United States. The concept of an extreme overvalued belief has recently been validated and is separate from an obsession or delusion. It plays an important role in identifying fixation as a warning sign in threat assessment. We use this definition in three well-known cases (i.e., Anders Breivik, John Hinckley, Jr., and Ted Kaczynski) to emphasize how form and content of beliefs are critical to understanding the mens rea in violent criminal acts. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, would be enhanced by the addition of extreme overvalued belief as a definition to differentiate it from idiosyncratic, fixed, false beliefs seen in delusion.

Extreme Overvalued Beliefs: How Violent Extremist Beliefs Become "Normalized".

Extreme overvalued beliefs (EOB) are rigidly held, non-deusional beliefs that are the motive behind most acts of terrorism and mass shootings. EOBs are differentiated from delusions and obsessions. The concept of an overvalued idea was first described by Wernicke and later applied to terrorism by McHugh. Our group of forensic psychiatrists (Rahman, Resnick, Harry) refined the definition as an aid in the differential diagnosis seen in acts of violence. The form and content of EOBs is discussed as well as group effects, conformity, and obedience to authority. Religious cults such as The People's Temple, Heaven's Gate, Aum Shinrikyo, and Islamic State (ISIS) and conspiracy beliefs such as assassinations, moon-hoax, and vaccine-induced autism beliefs are discussed using this construct. Finally, some concluding thoughts on countering violent extremism, including its online presence is discussed utilizing information learned from online eating disorders and consumer experience.

Schizophrenia: An Overview.

Few changes were made to the diagnostic criteria for schizophrenia in DSM-5. Schizophrenia is a chronic mental illness with positive symptoms (delusions, hallucinations, disorganized speech and behavior), negative symptoms, and cognitive impairment. Discoveries in genetics, neuroimaging, and immune function continue to advance understanding of the etiologies for this elusive disease. The authors reviewed the current literature to give an overview. The topics include historical foundations, epidemiology, suicide risk, genomewide association studies, twin studies, neuroimaging, ventricular size, complement component 4 mediated synapse elimination, major histocompatibility complex markers, and associations seen in obstetrical complications, nutritional issues, prodromal and attenuated states, cannabis use, childhood trauma, immigration, and traumatic brain injury. Also reviewed are expressed emotions of caregivers and recidivism, conditions comorbid with obsessive-compulsive disorder, mood disorders, substance use, and finally some legal and ethical issues. These important developments in elucidating the disease mechanism will likely allow for the development of future novel treatment strategies.

Anders Breivik: Extreme Beliefs Mistaken for Psychosis.

The case of Anders Breivik, who committed mass murder in Norway in 2011, stirred controversy among forensic mental health experts. His bizarrely composed compendium and references to himself as the "Knights Templar" raised concerns that he had a psychotic mental illness. Beliefs such as Mr. Breivik's that precede odd, unusual, or extremely violent behavior present a unique challenge to the forensic evaluator, who sometimes struggles to understand those beliefs. Psychotic disorder frequently is invoked to characterize odd, unusual, or extreme beliefs, with a classification that has evolved over time. However, the important concept of overvalued idea, largely ignored in American psychiatry, may better characterize these beliefs in some cases. We discuss the definitions of delusion and overvalued ideas in the context of Anders Breivik's rigidly held extreme beliefs. We also review the British definition of overvalued idea and discuss McHugh's construct, to introduce the term "extreme overvalued belief" as an aid in sharpening the forensic evaluator's conceptualization of these and similar beliefs.

Carbamazepine in bipolar disorder with pain: reviewing treatment guidelines.

OBJECTIVE: To determine if any monotherapy drug treatment has robust efficacy to treat comorbid bipolar disorder and chronic pain. DATA SOURCES: The American Psychiatric Association (APA) treatment guidelines for bipolar mood disorder and the 2012 Cochrane database for pain disorders. STUDY SELECTION: We relied on the treatment guides to determine if the drugs that are APA guideline-supported to treat bipolar disorder have supporting data from the Cochrane database for chronic pain. DATA SYNTHESIS: No single drug was mentioned by either guideline to treat this comorbidity. However, carbamazepine was the only drug that has guideline-supported robust efficacy in the management of each condition separately. CONCLUSIONS: Carbamazepine was found to have strong preclinical data for the treatment of comorbid bipolar mood disorder and chronic pain disorders. While requiring more studies in this population, we propose that this treatment modality may benefit patients.

Antipsychotic treatment in breast cancer patients.

Special consideration is required when prescribing antipsychotic drugs for patients with an existing diagnosis of breast cancer. The package inserts of all approved antipsychotics contain precautions regarding their administration in this patient group. These drugs are well known to elevate serum prolactin levels to varying degrees. Overexpression of the prolactin receptor is seen in more than 95% of human breast cancers. Many genes that are activated by the prolactin receptor are associated with tumorigenesis and cancer cell proliferation. The authors discuss the pathophysiology, clinical implications, and pertinent preclinical data and make specific recommendations regarding the use of antipsychotics in patients with breast cancer.