Addison's disease may cause psychosis, say researchers

Research suggests that chronic adrenal insufficiency, more commonly known as Addison's disease, may be responsible for psychiatric symptoms in those who suffer with it. Unfortunately, these symptoms are poorly understood and inadequately studied. In one case, a 41-year-old construction worker was admitted to a psychiatric clinic complaining of depression. He had trouble sleeping and concentrating and had lost 6 pounds due to a loss of appetite. He was placed on 20mg of fluoxetine but returned 2 weeks later complaining that the therapy did not work, and even reported hallucinating his ex-wife, who had recently died in a car accident. He returned again later 4 months later and was found to have a weak pulse, major hypotension, and hyponatremia and hyperkalemia. It was at this point that he was diagnosed with Addison's disease.

The disease was first described by Thomas Addison in the mddle of the 19th century. It involves inadequate secretion from the adrenal glands, leading to lower secretion of glucocorticoids. Its usual symptom pigmentation involves fatigue, weight loss, nausea, vomiting, weakness and abdominal pain. Among its psychiatric symptoms are psychosis and delirium.

"An array of neuropsychiatric symptoms is associated with AD. Addison is quoted as saying in 1855 that AD patients might present with “attacks of giddiness, anxiety in the face, and delirium.”1 Anglin et al1 also noted four case series published in the 1940s and 1950s that found the prevalence of neuropsychiatric symptoms in AD to be between 64 and 84 percent. Iwata et al6 reported that in some cases, the neuropsychiatric symptoms were the initial and sole presentation of AD, even though such symptoms are more common in the late course of the disease; this might lead to a patient initially being misdiagnosed, as it did in our case, and in turn, incorrectly treated. Neuropsychiatric symptoms of AD include, but are not limited to, depression, lack of energy, and sleep disturbances. During an Addisonian crisis, agitation, delirium, and, in some cases, visual and auditory hallucinations are reported.1 According to Smart,7 neuropsychiatric symptoms might also be the first presentation of an Addisonian crisis, especially in a patient who was previously symptom free while under therapy."

It is not clear exactly why these neuropsychiatric symptoms appear. It is possible that electrolytic and metabolic disturbances could produce these symptoms, and hyponatremia, which is its central expression, can result in brain damage. Other researchers believe that the neuropsychiatric symptoms are the effects of glucocorticoid abnormalities on the brain. Some researchers believe that unusually low amounts of the substance could produce hallucinations. In one report, Addison's disease presented as a psychotic break:

"A Caucasian 63-year-old man presented a five-month history of progressive depressive symptoms with sadness, anhedonia, asthenia, hyporexia, insomnia, limb weakness, and psychotic symptoms. He was a former heavy smoker and had been diagnosed with chronic occupational lung disease (silicosis). After a specialized psychiatric consultation, the patient started taking fluoxetine, risperidone, and nitrazepam. After a short period of time, the patient withdrew his medication by his own because of worsening of the limb weakness. The patient became severely paranoid with persecutory beliefs, delusions, an infantile speech, progressive social isolation, fear of leaving his home, periods of mental confusion and disorientation, and sporadic nausea and vomits. A few days before hospital admission, the patient almost stopped fluid intake and evolved with syncope."

From http://www.examiner.com/article/addison-s-disease-may-cause-psychosis-say-researchers

Evaluation of depression, quality of life and body image in patients with Cushing’s disease

Nilufer Alcalar, Sedat Ozkan, Pinar Kadioglu, Ozlem Celik, Penbe Cagatay, Baris Kucukyuruk and Nurperi Gazioglu

 

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Abstract

The aim of this study was to evaluate patients with Cushing’s disease (CD) who had undergone transsphenoidal surgery in terms of depression, quality of life (QoL), and perception of body image in comparison to healthy controls.

Forty patients with CD and 40 healthy controls matched for demographic characteristics were included in the study. The subjects were evaluated with the Beck depression inventory (BDI), the health survey-short form (SF-36) and the multidimensional body-self relations questionnaire (MBSRQ). Subgroups of the patients with CD were formed on the basis of remission status and BDI scores. In this study, QoL in the general health category and body image were lower in the patients with CD than in the healthy subjects. However, no differences in depression scores were found between the two groups.

When the CD group was evaluated according to remission rate, the mean BDI score was significantly higher in the CD patients without remission than in both the CD patients with remission and the healthy subjects (p = 0.04). However, the physical functioning, bodily pain and general health scores of the CD patients without remission on the SF-36 questionnaire were lower than in the CD patients in remission and the healthy subjects (p = 0.002, p = 0.04, p = 0.002, respectively). Fitness evaluation, health evaluation and body areas satisfaction scores of the MBSRQ were significantly different in the three groups (p = 0.003, p = 0.009 and p = 0.001, respectively). In this study, patients with CD were found to have lower QoL, lower body image perception and higher levels of depression compared to healthy controls, particularly if the disease is persistant despite surgery.

Keywords  Cushing’s disease – Pituitary surgery – Depression – Quality of life – Body image

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A New Link in the Stress Response Could Mean Better Treatment Soon

Hoping to pave the way for improved treatment options, researchers have found that they can significantly reduce our response to stress.

 

A team at Tufts University appears to have found an important step in the body's stress reaction, and blocking this step from occurring can significantly reduce the response. The finding may pave the way for improved treatments for depression and anxiety.

The stress cascade is governed by the brain's hypothalamus, which communicates with the pituitary and adrenal glands, which in turn secrete stress hormones like cortisol. Disruptions in this pathway are also connected with problems like postpartum depression, obesity, Cushing's syndrome (hypercortisolism), premenstrual syndrome (PMS), epilepsy, and osteoporosis, according to the study's press release.

Using mice as their subjects, the researchers set out to fill in some of the blanks in the cascade of events that leads to the secretion of the stress hormone coriticosterone (the mouse equivalent to our cortisol). They used brain samples from mice, and tracked the activity of the brain cells that release corticotrophin-releasing hormone (CRH), which ultimately stimulates the secretion of stress hormones.

They discovered that specific "neurosteroids" are needed to bind to receptors on the CRH neurons to activate them, serving as an important early step in the stress response. The team reasoned that disrupting the synthesis of the neurosteroids should significantly reduce the stress response by stopping it almost before it begins.

This is just what they found. When they blocked the neurosteroids' synthesis in live mice, their coriticosterone levels were reduced after stressful situations compared to normal mice. Additionally, if neurosteroid synthesis was halted, the mice did not show anxiety-like behaviors after they had been stressed.

One of the authors, Jamie Maguire, said that the data "suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors."

The study is published in The Journal of Neuroscience.

From http://www.theatlantic.com/health/archive/2012/01/a-new-link-in-the-stress-response-could-mean-better-treatment-soon/250570/

Corlux: Corcept Therapeutics Announces Third Quarter Results and Corporate and Development Update

MENLO PARK, CA, Nov 07, 2011 (MARKETWIRE via COMTEX) -- Corcept Therapeutics IncorporatedCORT -1.58% , a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders, today reported financial results for the quarter ended September 30, 2011, and updated its corporate progress.

"Following the acceptance by the U.S. Food and Drug Administration (FDA) of our New Drug Application (NDA) for the use of our lead product candidate, Korlym(TM), in Cushing's Syndrome," said Joseph Belanoff, M.D., Chief Executive Officer of Corcept, "we continue to focus our efforts on building our commercial capabilities to support the launch of Korlym, if Korlym is approved by the FDA, in order to allow us to provide an important treatment option to patients suffering from Cushing's Syndrome."

Corporate and Development Highlights

--  Received notification in October 2011 that the FDA had accepted our proposed brand name, Korlym (formerly referred to as CORLUX(R)), for our lead product candidate in the treatment of endogenous Cushing's Syndrome.   --  Advanced our commercial launch preparations related to Korlym for the treatment of Cushing's Syndrome, including developing our internal infrastructure and engaging third-party vendors to provide market analytics and to support distribution and other logistical needs in the event Korlym is approved by the FDA.   --  Received notification in October 2011 that the European Commission had granted Korlym Orphan Designation for the treatment of endogenous Cushing's Syndrome (hypercortisolism) in the European Union (EU). Benefits of Orphan Drug Designation in the EU are similar to those in the U.S., but include ten years of marketing exclusivity in all 27 member states, free scientific advice during drug development, access to a centralized review process and a reduction or complete waiver of fees levied by the European Medicines Agency.   --  Enrolled additional patients in our double-blind placebo controlled Phase 3 trial of Korlym for the treatment of the psychotic features of psychotic depression.   --  Continued the clinical portion of our Phase 1b/2a multi-dose safety and proof of concept studies of CORT 108297, one of our selective GR-II antagonists.   --  Identified additional compounds from among our proprietary series of selective GR-II antagonists to advance toward an Investigational New Drug submission.

Third Quarter Financial Results

For the third quarter of 2011, Corcept reported a net loss of $6.4 million, or $0.08 per share, compared to a net loss of $7.1 million, or $0.10 per share, for the third quarter of 2010.

In the third quarter of 2011, research and development expenses decreased to $3.2 million from $5.2 million in the third quarter of 2010. This decrease in research and development expenses was due primarily to decreases in clinical trial costs related to drug-drug interaction and other NDA-supportive studies with Korlym, which were substantially completed in late 2010, and decreases in the clinical trial costs related to the Phase 1b/2a studies with CORT 108297. These decreases were partially offset by increased costs associated with the prosecution of our NDA for Korlym for the treatment of Cushing's Syndrome. General and administrative expenses increased to $3.2 million for the third quarter of 2011 from $1.9 million for the same period in 2010 due primarily to additional expenditures on commercialization activities for the potential launch of Korlym for Cushing's Syndrome.

Our cash balance as of September 30, 2011 was $45.9 million, up from $24.6 million at December 31, 2010. "We anticipate that our current cash balance is sufficient to fund the company through the end of 2012," said Charles Robb, the company's Chief Financial Officer.

Anticipated Activities for the Remainder of 2011

We continue to concentrate our efforts on advancing Korlym toward approval and commercialization for the treatment of Cushing's Syndrome. We also continue our efforts to be prepared to respond in a timely fashion to any questions posed by the FDA during the course of their review of our NDA.

"We are focused intently on developing the commercial and logistical capabilities we will need to make Korlym available to patients suffering from Cushing's Syndrome, should the FDA approve our drug for this indication," added Dr. Belanoff. "Korlym is the first step in unlocking the value of our scientific platform. The regulation of cortisol is a critical biological function; its dysregulation is equally critical in many important disease states. Our own research and research from increasing numbers of academic investigators point to the potential importance of cortisol antagonism in a wide variety of diseases. We believe our expanding library of selective cortisol antagonists may help address these unmet medical needs."

About Cushing's Syndrome

Endogenous Cushing's Syndrome is caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing's Syndrome is an orphan indication which most commonly affects adults aged 20 to 50. An estimated 10 to 15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients in the United States. An estimated 20,000 patients in the United States have Cushing's Syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing's Syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Psychotic Depression

Psychotic depression is a serious psychiatric disorder that affects approximately three million people annually in the United States. It is more prevalent than either schizophrenia or bipolar I disorder. The disorder is characterized by severe depression accompanied by delusions, hallucinations or both. People with psychotic depression are approximately 70 times more likely to commit suicide than the general population and often require lengthy and expensive hospital stays. There is no FDA-approved treatment for psychotic depression.

About Weight Gain Caused by Antipsychotic Medications

The group of medications known as second-generation antipsychotics, including olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel) and clozapine (Clozaril), are widely used to treat schizophrenia and bipolar disorder. All medications in this group are associated with treatment emergent weight gain of varying degrees and also carry warning labels relating to treatment emergent hyperglycemia and diabetes mellitus. There is no FDA-approved treatment for the weight gain associated with the use of antipsychotic medications.

About Korlym

Corcept's first-generation compound, Korlym, also known as mifepristone, directly blocks the cortisol (GR-II) receptor and the progesterone (PR) receptor. Intellectual property protection is in place to protect important methods of use for Korlym. Corcept retains worldwide rights to its intellectual property related to Korlym.

About CORT 108297

CORT 108297 is a potent, selective antagonist of the cortisol (GR-II) receptor that we have discovered and for which Corcept owns worldwide intellectual property rights. In in vitro binding affinity and functional assays this compound has no affinity for the progesterone (PR), estrogen (ER), androgen (AR) or mineralocorticoid (GR-I) receptors.

About Corcept Therapeutics Incorporated

Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs for the treatment of severe metabolic and psychiatric disorders. The company has completed its Phase 3 study of Korlym for the treatment of Cushing's Syndrome, and has an ongoing Phase 3 study of Korlym for the treatment of the psychotic features of psychotic depression. Corcept also has a Phase 2 program for CORT 108297, a selective GR-II antagonist that blocks the effects of cortisol but not progesterone. Corcept has developed an extensive intellectual property portfolio that covers the use of GR-II antagonists in the treatment of a wide variety of psychiatric and metabolic disorders, including the prevention of weight gain caused by the use of antipsychotic medication, as well as composition of matter patents for our selective GR-II antagonists.

Statements made in this news release, other than statements of historical fact, are forward-looking statements, including, for example, statements relating to the potential benefit of Korlym for patients diagnosed with Cushing's Syndrome, Corcept's clinical development and research programs, the outcome of the FDA's review of our NDA filing, our estimates for our capital requirements and needs for additional financing, the introduction of Korlym and future product candidates, including CORT 108297, the ability to create value from Korlym or other future product candidates or our scientific platform and our commercialization plans. Forward-looking statements are subject to a number of known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements. For example, there can be no assurances with respect to the cost, rate of spending, completion or success of clinical trials; financial projections may not be accurate; there can be no assurances that Corcept will pursue further activities with respect to the development of Korlym, CORT 108297, or any of its other selective GR-II antagonists. These and other risk factors are set forth in the Company's SEC filings, all of which are available from our website ( www.corcept.com ) or from the SEC's website ( www.sec.gov ). We disclaim any intention or duty to update any forward-looking statement made in this news release.

CORCEPT THERAPEUTICS INCORPORATED CONDENSED BALANCE SHEETS (in thousands)  September 30,  December 31, 2011           2010 -------------- -------------- (Unaudited)      (Note) ASSETS: Current assets: Cash and cash equivalents                    $       45,909 $       24,578 Other current assets                                    427            418 -------------- -------------- Total current assets                               46,336         24,996  Other assets                                               43            108 -------------- -------------- Total assets                               $       46,379 $       25,104 ============== ==============  LIABILITIES AND STOCKHOLDERS' EQUITY: Current liabilities: Accounts payable                             $        1,066 $          817 Other current liabilities                             1,647          3,043 -------------- -------------- Total current liabilities                           2,713          3,860  Total stockholders' equity                             43,666         21,244 -------------- --------------  Total liabilities and stockholders' equity $       46,379 $       25,104 ============== ==============  Note: Derived from audited financial statements at that date.  CORCEPT THERAPEUTICS INCORPORATED CONDENSED STATEMENTS OF OPERATIONS (in thousands, except per share amounts)  (Unaudited)  For the Three Months Ended   For the Nine Months Ended September 30,               September 30, --------------------------  -------------------------- 2011          2010          2011          2010 ------------  ------------  ------------  ------------  Operating expenses: Research and development*      $      3,228  $      5,224  $     14,355  $     14,286 General and administrative*          3,209         1,881         8,049         5,327 ------------  ------------  ------------  ------------ Total operating expenses               6,437         7,105        22,404        19,613 ------------  ------------  ------------  ------------  Loss from operations       (6,437)       (7,105)      (22,404)      (19,613)  Interest and other income, net                    3             4             3           758 Other expense                  (1)           (3)          (17)          (18) ------------  ------------  ------------  ------------ Net loss         $     (6,435) $     (7,104) $    (22,418) $    (18,873) ============  ============  ============  ============   Basic and diluted net loss per share  $      (0.08) $      (0.10) $      (0.27) $      (0.28) ============  ============  ============  ============ Shares used in computing basic and diluted net loss per share                 84,188        72,045        83,000        66,982 ============  ============  ============  ============  *Includes non-cash stock-based compensation of the following: Research and development     $        110  $         45  $        432  $        170 General and administrative           844           500         1,971         1,361 ------------  ------------  ------------  ------------ Total non-cash stock-based compensation  $        954  $        545  $      2,403  $      1,531 ============  ============  ============  ============

CONTACT: Charles Robb Chief Financial Officer Corcept Therapeutics 650-688-8783 Email Contact  www.corcept.com

SOURCE: Corcept Therapeutics

http://www2.marketwire.com/mw/emailprcntct?id=150008C85C40D638      http://www.corcept.com/