Bipolar Disorder: Novel Clinical Trials II

This is the second post reviewing recent novel trials for the treatment of bipolar disorder.

Again, for my sources I am using are clinicaltrials.gov and PubMed.

Clicking on the study title will take you to the clinicaltrials.gov site for more detailed protocol information.

Allopurinol Maintenance Study for Bipolar Disorder

This completed study examined the effect of 300 to 600 mg per day of allopurinol on mania prevention. Allopurinol is a drug used primarily for the treatment of gout or kidney stones. The drug lowers serum levels of uric acid. Uric acid in elevated in mania and potentially has a contribution role in mania. A small international randomized placebo-controlled study of allopurinol found significant improvements in acute mania. 

Quetiapine Alone Versus Quetiapine Plus Lithium for Mania

Physicians have a variety of drug choices in the treatment of the manic phase of bipolar disorder. In this study, manic subjects were randomized to 600 to 800 mg of quetiapine with or without lithium dosed from 500 mg to 2000 mg per day. The study was conducted in China and the results showed that quetiapine alone was as effective as quetiapine plus lithium in reducing symptoms of mania.

Internet-Based Interventions for Bipolar Disorder

This study is currently recruiting subjects between the ages of 21 to 65 years of age with a diagnosis of bipolar I, II or NOS. Subjects are randomized to one of three arms including: 1.) moderated discussion board, 2.) moderated discussion board plus psychoeducation or 3.) moderated discussion board, psychoeducation and interactive psychosocial tools. The study is sponsored by the VA Palo Alto System and primary outcome measures include assessment of depression and mania symptoms.

Bipolar Depression Treatment with Deep Brain Repetitive Transcranial Magnetic Stimulation

This study is currently recruiting subjects in Brazil and is sponsored by the University of Sao Paulo. The study uses a type of coil that is felt to be able to reach deeper areas of the brain felt to be important in mood regulation. Subjects must meet depression criteria at entry and the primary outcome measure is the Hamilton Rating Scale for Depression.

Citations below are provided for more information on the treatments in the above studies. Readers can access abstracts by clicking on the link in the citation.

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Jahangard, L., Soroush, S., Haghighi, M., Ghaleiha, A., Bajoghli, H., Holsboer-Trachsler, E., & Brand, S. (2013). In a double-blind, randomized and placebo-controlled trial, adjuvant allopurinol improved symptoms of mania in in-patients suffering from bipolar disorder Pharmacopsychiatry, 46 (06) DOI: 10.1055/s-0033-1353345

Lauder S, Chester A, Castle D, Dodd S, Gliddon E, Berk L, Chamberlain J, Klein B, Gilbert M, Austin DW, & Berk M (2015). A randomized head to head trial of MoodSwings.net.au: an Internet based self-help program for bipolar disorder. Journal of affective disorders, 171, 13-21 PMID: 25282145

Rapinesi C, Bersani FS, Kotzalidis GD, Imperatori C, Del Casale A, Di Pietro S, Ferri VR, Serata D, Raccah RN, Zangen A, Angeletti G, & Girardi P (2015). Maintenance Deep Transcranial Magnetic Stimulation Sessions are Associated with Reduced Depressive Relapses in Patients with Unipolar or Bipolar Depression. Frontiers in neurology, 6 PMID: 25709596

Bipolar Disorder: Novel Clinical Trials I

To finish out the bipolar disorder topic month I will review some of the novel clinical trials in this condition.

Clinicaltrials.gov is a valuable resource in searching for active and recently completed clinical trials.

Here are some of the rostered trials from this site related to bipolar disorder that caught my attention.

Sensoril for Bipolar Disorder
Sensoril is the trade name for the natural product ashwagandha an herbal extract from the herb Withania somnifera. This trial was sponsored through the University of Pittsburgh. It has been completed and the results were published in 2013. The study targeted some of the cognitive impairment associated with bipolar disorder. The results pointed to some evidence for improvement in working memory, reaction time and social cognition with the drug.

Mindfulness Therapy on Disrupted Sleep in Bipolar Disorder
This trial sponsored by Massachusetts General Hospital is listed as currently recruiting subjects. The study compares a form of mindfulness therapy compared to brief supportive therapy on total sleep time in a group of subjects with bipolar disorder and sleep complaints. Sleep problems including both insomnia and hypersomnia are common in bipolar and new innovative interventions are needed.

N-Acetyl Cysteine and Aspirin as Adjunctive Treatment for Bipolar Disorder
This trial is sponsored by the University of Texas Health Science Center, Houston and is also listed as currently recruiting subjects. Subjects receive aspirin, n-acetyl-cysteine or both in addition to their usual bipolar disorder drug treatment regimen. The study seeks to see if an anti-inflammatory drug or an antioxidant drug can reduce depression symptoms. 

Minocycline and Aspirin in the Treatment of Bipolar Depression
This study is sponsored by the Laureate Institute of Brain Research in Tulsa in collaboration with the Stanley Medical Research Institue and the University of Oklahoma.  Subjects are eligible for enrollment if they have bipolar disorder and are currently depressed. Subjects receive aspirin, minocycline or a combination compared to placebo and are monitored for change in depression scores as measured by the Montgomery-Asberg Depression Rating. Disclosure: I am a participating research psychiatrist in this protocol. 

Readers with more interest in these trials can find more information by going to clinicaltrials.gov and typing in bipolar disorder in the search box. Additionally, specific trial information can be access by clicking on the link in the headings for this post.

I have listed some of the relevant citations related to these trials below.

In the next post I will look at four more novel trials in bipolar disorder.

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Chengappa KN, Bowie CR, Schlicht PJ, Fleet D, Brar JS, & Jindal R (2013). Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. The Journal of clinical psychiatry, 74 (11), 1076-83 PMID: 24330893

Deckersbach T, Hölzel BK, Eisner LR, Stange JP, Peckham AD, Dougherty DD, Rauch SL, Lazar S, & Nierenberg AA (2012). Mindfulness-based cognitive therapy for nonremitted patients with bipolar disorder. CNS neuroscience & therapeutics, 18 (2), 133-41 PMID: 22070469

Savitz J, Preskorn S, Teague TK, Drevets D, Yates W, & Drevets W (2012). Minocycline and aspirin in the treatment of bipolar depression: a protocol for a proof-of-concept, randomised, double-blind, placebo-controlled, 2x2 clinical trial. BMJ open, 2 (1) PMID: 22357572

Bipolar Disorder Link to Rheumatoid Arthritis

Finding links between disorders felt to be distinct is a helpful tool in understanding genetics and pathophysiology. 

An example would be the discovery that individuals with genetically determined elevated cholesterol levels had higher rates of cardiovascular disease. This led to drug development of cholesterol lowering agents leading to reduced rates of cardiovascular disease and mortality.

A recent population-based study from a research team in Taiwan identified an increased risk of bipolar disorder in patients with rheumatoid arthritis.

In their study, 2,570 patients with a diagnosis of rheumatoid arthritis were identified from a national insurance database.

A comparison group of 2,570 patients without rheumatoid arthritis were identified as a control group.

The key finding from the study was an approximate doubling of the risk for a diagnosis of bipolar disorder in those with rheumatoid arthritis (odds ratio 2.13, 95% confidence interval 1.12-4.24). Rheumatoid arthritis patients had additional elevated bipolar riks if they also had asthma, cirrhosis of the liver or an alcohol use disorder. 

The research team noted a possible explanation for increased risk of bipolar disorder following rheumatoid arthritis is inflammatory immune dysfunction.

Peripheral markers of inflammation in rheumatoid arthritis have been linked to upregulation of central nervous system inflammation. The authors note peripheral markers of inflammation known as cytokines may reach the brain through blood brain barrier leaks, active transport, activation of endothelial cells or cytokine receptor binding.

The clinical implications of this finding are important. Early active treatment of rheumatoid arthritis may reduce risk for central nervous system complications including bipolar disorder. Clinicians treating patients with rheumatoid arthritis should actively monitor for emergence of mood disorders including bipolar disorder. 

One potential confounding issue in this study is the potential for rheumatoid arthritis medications to induce mood symptoms. Corticosteroid drugs such as prednisone are commonly used in rheumatoid arthritis. This class of drug is known to induce insomnia and hypomanic or manic states in some individuals.

Reader with more interest in this topic can access the free full-text manuscript by clicking on the PMID link below.

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Hsu CC, Chen SC, Liu CJ, Lu T, Shen CC, Hu YW, Yeh CM, Chen PM, Chen TJ, & Hu LY (2014). Rheumatoid arthritis and the risk of bipolar disorder: a nationwide population-based study. PloS one, 9 (9) PMID: 25229610

Bipolar Disorder Linked to Increased Dementia Risk

A variety of risk factors have been identified in Alzheimer's disease and other types of dementia.

The risk for dementia following major psychiatric syndromes in mid-life is an important research area.

Renate Zilkens and colleagues in Australia recently published an informative study of psychiatric disorders and later dementia risk. This study used a population-based case control methodology.

The key elements in the design of this study included the following:

• Subjects: General population in Western Australia
• Data sources: inpatient, outpatient and emergency medical records along with death records
• Cases: Incident cases of dementia between ages of 65 and 84 years of age
• Controls: Age and sex-matched individuals without incident dementia diagnosis
• Psychiatric diagnoses: medical record diagnoses that were required to be present at least ten years prior to dementia onset
• Statistical analysis: odds ratio using conditional logistic regression

The research group in this study used a variety of models to assess risk based on specific medical and psychiatric disorders.

For simplicity, I have used data from the study to put together the summary graph in this post.

This graph estimates later dementia odds ratios for specific disorders when that disorder is present during the 65-69 year age period.

There is evidence of a strong increase in risk for dementia following bipolar disorder diagnosis (odds ratio 4.71, 95% confidence interval 2.29 to 9.65). Bipolar disorder is the psychiatric disorder with the second highest odds ratio being topped only by schizophrenia with an estimated odds ratio of 12.1. The odds ratio with depression was only slight lower than that associated with a diabetes diagnosis (odds ratio 2.77 vs 3.47). Anxiety disorder had a small but statistically significant increased odds ration for later dementia (odds ratio 1.37, 95% confidence interval 1.14-1.65)

Alcoholism diagnosis by age 65 years of age is also associated with a marked increase in dementia risk (odds ratio 4.14, 95% confidence interval 2.25 to 7.61).

The authors note their findings support the role of psychiatric disorders in contributing to brain vascular abnormalities that can contribute to later cognitive decline. Additionally, they note there is increasing evidence that psychiatric disorders are associated with brain inflammation and immune system dysfunction, areas know to contribute to cognitive decline.

This study is important is suggests at lease five psychiatric disorders need to be considered as potential risk factors for dementia (bipolar disorder plus schizophrenia, depression, anxiety and alcoholism). Adding these risk factors may allow for improvement in detection and prevention efforts.

Additionally, the finding suggest dementia populations may have higher rates of psychiatric disorders. These psychiatric disorders can complicate dementia management and increase the need for psychiatric assessment and consultation in geriatric care settings.

Readers with more interest in this topic can access the free full-text manuscript by clicking on DOI link below.

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Zilkens, R., Bruce, D., Duke, J., Spilsbury, K., & Semmens, J. (2014). Severe Psychiatric Disorders in Mid-Life and Risk of Dementia in Late- Life (Age 65-84 Years): A Population Based Case-Control Study Current Alzheimer Research, 11 (7), 681-693 DOI: 10.2174/1567205011666140812115004

What to Expect at Your Annual Physical

Lori M. Noble, MD, a primary care physician at Spruce Internal Medicine, located at the new Penn Medicine Washington Square building, discusses what to expect at your annual physical.

Lori M. Noble, MD

Going to the doctor for your annual physical can be nerve-racking. You have questions and concerns, your doctor has a separate agenda full of blood tests, studies and vaccines, and all of this typically needs to be addressed in 30 minutes.

To help you avoid feeling overwhelmed, take a look below at tests your doctor may address at your next physical based on the latest United States Preventative Services Task Force recommendations.

For tips of staying healthy, check out Guidelines for Maintaining Good Health.

Cholesterol blood test:

WHO: Women over the age of 45 and men over the age of 35, every 5 years.
WHY: Cholesterol levels help predict risk of future heart attack and stroke. If, along with other risk factors, cholesterol levels point to an elevated risk, your doctor may suggest changing your diet, exercising more, and/or medication.
NOTE: Depending on conditions, such as diabetes or strong family history of cholesterol or heart disease, your doctor may start checking earlier and more frequently.

Also check out Guidelines for Maintaining Good Health

Colonoscopy:

WHO: All women and men age 50-75, every 10 years.
WHY: To detect and remove colon polyps, which could turn into colon cancer if left untreated.
NOTES: (1) If you have colon polyps, you will likely need to return for a repeat colonoscopy in 3-5 years. 2) The colonoscopy is the best test for colon cancer screening, but there are alternatives. Ask your doctor about this option if you are unable to complete a colonoscopy. 3) If you have a strong family history of colon cancer (i.e. a parent or sibling), your doctor may refer you for a colonoscopy earlier.

Abdominal Ultrasound

WHO: One time in men age 65-75 who smoke or who have previously smoked cigarettes.
WHY: To detect an aneurysm of the aorta (the largest blood vessel in the body), for which male smokers are at increased risk.
NOTE: If an aneurysm is detected, you will likely need periodic repeat ultrasounds. If the aneurism is large, surgery may be recommended.

Pap smear:

WHO: All women from the age of 21-65, every 3-5 years
WHY: To detect HPV (human papilloma virus), the virus that can cause changes to the cervix, which ultimately can turn into cervical cancer if not treated.
NOTE: You may need to be checked more often if the result comes back abnormal.

Mammogram:

WHO: All women from the age of 50-74, every 1-2 years; women aged 40-49 should have a discussion with their doctors to determine if they should be screened.
WHY: To detect breast cancer in its early stages.
NOTE: If a strong family history of breast cancer (i.e. your mother or sister) exists, you may be referred for mammography earlier.

Bone density testing (aka - DEXA scan)

WHO: All women over 65, every 2 years.
WHY: To detect low bone density, called osteoporosis, which increases the risk of fractures.
NOTES: 1) Women with risk factors for osteoporosis (such as a smoking history, a family history, low body weight, or history of fracture) are recommended to start screening at age 60. 2) There is no agreed upon age at which to stop screening at this time.

So now when it’s time to schedule your yearly physical, be prepared and armed with the knowledge about what to expect.

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What to Know About Testicular Cancer

There are certain tests and precautions men need to take to be proactive about their health. Jeffrey Millstein, MD, a primary care physician at Penn Internal Medicine Woodbury Heights, discusses why it’s important to check for testicular cancer.

Jeffrey Millstein, MD

Are you doing all you can to keep yourself healthy? If you aren’t performing a monthly testicular self-exam, you may not be.

It’s estimated that there are over 8,000 new cases of testicular cancer each year. Though it can occur in older men, it’s most common in men between ages 15 and 35.

Fortunately, testicular cancer is one of the most curable cancers. Men diagnosed and treated when the disease is in an early stage have a 97 to 100 percent chance of being cured. Therefore, early detection is critical – and relatively easy to do at home.

Who Is at Risk?

The risk factors associated with the development of testicular cancer are not well established. We’ve found that the disease is more prevalent in white men than in black, Asian, or other nonwhite ethnic groups.

Some factors that increase the risk of getting testicular cancer include:

• Having had an undescended testicle (also called cryptorchidism)
• A family history (having a close relative with testicular cancer)
• HIV infection
• Body size: Tall men may have a higher risk of testicular cancer.

What Are the Warning Signs?

Testicular cancer can have many symptoms or there may be no symptoms at all.

The most common sign of testicular cancer is a lump, swelling of a testicle or enlargement of a testicle. This may be accompanied by tenderness, pain or a feeling of heaviness. Other signs may include a dull ache in the lower abdomen, back or groin, or a sudden collection of fluid in the scrotum.

It’s also important to note that not every change or discomfort indicates cancer; however, if you notice any type of change in a testicle, seek a medical evaluation.

Monthly testicular self-examinations can help you become familiar with how your testicles normally feel and help you better recognize any changes.

How to Perform a Self-Exam

It’s best to perform a testicular self-examination once a month, during or soon after a warm shower or bath when the scrotal skin is most relaxed.

While standing, check for any swelling on the scrotum. You may need to do this in front of a mirror.

Examine one testicle at a time using both hands. Put your index and middle fingers under the testicle with thumbs on top. Roll the testicle gently between your fingers. It can be normal for one testicle to be slightly larger than the other.

What if You Find Something Different?

If you find something unusual or you’re not sure about, see a doctor right away.

The doctor will ask if you’ve been experiencing any pain, and if so, for how long. During a physical exam, he or she will examine your testicles for swelling or tenderness and for the size and location of any lumps.

The doctor may also examine your abdomen, groin area and other parts of your body, looking for any possible signs of cancer spread. If anything abnormal is found, additional tests may be performed.

Don’t put it off. Although it may be nothing, it’s important to check regularly and get any discomfort checked out. Better to catch it early than to ignore something that just doesn’t feel right.

Have additional questions or concerns?

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7 Tips to Eating Healthy on a Budget

Tina McGroarty, CRNP, a nurse practitioner at Penn Family and Internal Medicine Lincoln, offers tips on how you and your family can eat healthy - on a budget. 

Tina McGroarty, CRNP

We are all aware that eating healthy is an essential part of maintaining health and wellness, and we see and hear these phrases often:
“Eat more fruits and vegetables.”
“Go organic.”

“Avoid processed foods.”

“Incorporate whole grains, legumes and nuts.”

While most know what is recommended, many find it hard to make these dietary changes without significantly increasing the bottom line at the grocery checkout.

Although processed food is more accessible and less expensive, there are ways to incorporate healthier choices into your diet and stay within your budget. Here are just a few suggestions I have found helpful:

Plan ahead. Check out your supermarket’s weekly ads, or circulars, to be aware of any specials. By preparing your list beforehand, you can plan your meals around sale items.

Eat seasonal produce. Fruits and vegetables are fresher and less expensive when in season, so choose meals that incorporate those items. You can also stock up and freeze or can fruits and vegetables to use later. Berries, green beans, corn and tomatoes all freeze/can well and are sure to be enjoyed in the winter months.

Buy local. Most communities have local farmer’s markets or produce stands that offer seasonal fruits and vegetables at reasonable costs. The prices tend to be much cheaper than supermarkets and provide a wider variety of fresher produce.

Grow your own. There is nothing better than freshly picked vegetables from your backyard. Starting a family garden is a great way to add healthy foods at a low cost.

Eat less meat. Most of us eat more meat than necessary. Substituting beans, legumes and other herbivorous proteins in place of meat is much healthier and less expensive. If you are buying less meat, it may make it affordable to buy grass-fed and free-range options, which can be more nutritious.

Buy organic wisely. In an ideal world, we would all love to consume only organic foods, but that is not realistic for most of us. Knowing the most and least contaminated foods can help you decide where to invest your money when buying produce.

• 12 most contaminated foods: peaches, apples, bell peppers, celery, nectarines, strawberries, cherries, pears, imported grapes, spinach, lettuce, potatoes
• 12 least contaminated foods: onions, avocado, sweet corn (frozen), pineapple, mango, asparagus, peas (frozen), kiwi, bananas, cabbage, broccoli, papaya.

Prepare meals at home. Home-cooked meals tend to always be healthier and less expensive. Taking a few hours on the weekend to cook/prep a few meals for the week will go a long way. Soups and stews are a great option as they can be loaded with vegetables and proteins, they freeze well and are delicious! Packaging leftovers and individual salads for lunch is also a great way to ensure a healthy meal during your busy work week.

Eating healthy doesn’t have to be expensive. I hope these ideas help you incorporate some healthier meals into your diet.

Need help developing a plan to eat healthier?

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Brain Default Network in Psychotic Bipolar Disorder

In a previous post I reviewed a summary of research related to genetics and improved diagnosis in bipolar disorder.

One key point in this review was a highlight of the promise for integrating genetic with imaging research in bipolar disorder and other neuropsychiatric disorders.

An example of this type of integrated research has been recently published in PNAS by a group of Yale University, the University of New Mexico and the University of Texas Southwestern Medical Center.

This study used functional magnetic resonance imaging (fMRI) default mode network (DMN) across a group of subjects with psychotic bipolar disorder, schizophrenia and healthy controls. Additionally, study included imaging a group of unaffected relatives of the psychotic bipolar subjects and schizophrenia.

Subjects also had genetic analyses available for comparison with any imaging results that would emerge in the study.

The research team identified three circuit components in the DMN. The included the networks below (also identified by color as highlighted in group name):
Anterior DMN--Medial prefrontal cortex-anterior cingulate caudate DMN
Inferior posterior DMN--posterior cingulate caudate, inferior parietal lobule, middle temporal gyrus, cuneus/pre-cuneus
Superior posterior DMN--cuneus/pre-cuneus, inferior parietal lobule, cingulate

The key findings from the study include the following:

• Measures of hypoconnectivity in all three networks were identified in the psychotic bipolar and schizophrenia groups compared to controls.
• Unaffected psychotic bipolar disorder relatives had normal DMN measures in the three networks while the unaffected schizophrenic relatives showed hypoconnectivity in on one of the three networks.
• Genetic analysis revealed five genetic links to a brain connectivity sub-DMNs.
• Genes identified in this brain mapping linkage had previously been linked to psychosis and mood disorders

The five genetic clusters identified in this study were related to specific brain developmental and neuronal processes:

• NMDA long-term potentiation
• Protein kinase A regulation
• Immune response signaling
• Guidance of axonal development
• Synaptogenesis

The authors note an important advance in their study is the ability to

"dissect the underlying biological/molecular pathways and processes that might mediate genetic risk of psychosis via a valuable, noninvasive imaging marker."

Default mode network imaging and analysis is advancing as a promising research and clinical tool. It holds the promise of improving diagnostic accuracy and potentially improvement in targeting best treatment interventions for many brain disorders.

Readers with more interest in this topic can access the free full-text manuscript by clicking on the PMID link below.

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Meda SA, Ruaño G, Windemuth A, O'Neil K, Berwise C, Dunn SM, Boccaccio LE, Narayanan B, Kocherla M, Sprooten E, Keshavan MS, Tamminga CA, Sweeney JA, Clementz BA, Calhoun VD, & Pearlson GD (2014). Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 111 (19) PMID: 24778245

Genetics Leading to Better Bipolar Disorder Diagnosis

I wanted to alert Brain Posts readers to an important new review of genetics and diagnosis in brain disorders including bipolar disorder.

One hope for the emerging genetics research in mental disorders is a better diagnostic classification system.

The current psychiatric diagnostic system is hampered by use of a primary symptoms and signs approach leading to messy heterogeneous groups of clinical conditions.

Elliot Gerson has been a giant in neuroscience genetics for quite some time and recently published an important manuscript titled: "Genetic and genomic analyses as a basis for new diagnostic nosologies" in the journal Dialogues in Clinical Neuroscience.

Gershon notes current clinical diagnostic categories in psychiatry fail three of five tests for diagnostic validity described by Feigher in 1972:

• family study clustering
• course of illness 
• laboratory tests

There is promise for using genetic and genomic findings to improve diagnostic validity in psychiatric disorders. Gershon goes on to outline what is currently known in psychiatric genetics and how future genetic research can lead to "biologically coherent diagnostic entities".

Here is my summary on what I see as the key points in the review:

• The number of common gene single-neucleotide polymorphisms (SNPs) linked to brain disorders is growing (from 10 to over 100 for schizophrenia an example)
• Summing risk across known schizophrenia SNPs using risk profile scores accounts for 7% of genetic variance in schizophrenia (this increases to up to 23% of variance when broader phenotypic systems are used)
• A similar SNP risk profile approach separates bipolar disorder groups from controls
• Larger sample sizes may increase this SNP genetic variance understanding in schizophrenia and bipolar disorder
• Some SNPs contribute to risk for more than one disorder i.e. schizophrenia, bipolar disorder and major depression showing weakness of current classification system
• Common genome-wide SNP data may be a promising path to defining better diagnostic categories
• Rare variants such as copy number variations (CNVs) may also be promising for improved psychiatric diagnosis
• Chromosome 22q11 deletion (DiGeorge syndrome or velocardiofacial syndrome) occurs in 1/4000 births and has high penetrance for psychiatric diagnosis although nonspecific (23% autism sprectrum, 68% schizophrenia, 26% bipolar disorder)
• Brain molecular network modeling also holds promise as a basis for diagnosis
• Many known risk genes for psychiatric illness have been linked to key brain network nodes
• Genetic variants could be mapped to human molecular networks and this map may lead to predictable "therapeutic targets"
• Brain connectivity networks (fMRI) may be a promising alternate approach to psychiatric diagnosis

The validity criteria for psychiatric diagnosis described by Feighner in 1972 continue to be a gold standard. Emerging genetic, genomic and brain connectivity research may be part of the tool set that has been missing. Applying these tools to better diagnosis holds promise for new and better treatment and the reduction in pain and suffering for many brain disorders.

Interested readers can access the free full-text manuscript of the Gerson and Grennan review by clicking on the PMID link in the citation below.

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Gershon ES, & Grennan KS (2015). Genetic and genomic analyses as a basis for new diagnostic nosologies. Dialogues in clinical neuroscience, 17 (1), 69-78 PMID: 25987865

Bipolar Disorder Guidelines: NICE Update

Clinicians treating bipolar disorder and patients with a bipolar disorder diagnosis are aided by the availability of expert opinion guidelines.

In the last post, I reviewed a study that found decreased rates of suicidal behavior in bipolar patients treated with antidepressant drugs.

This review prompted me to look for a recent consensus update on assessment and treatment of bipolar. One recent update came from the UK National Institute for Health and Care Excellence or NICE. This guideline is freely available and I will post a link at the end of this blog post.

I will focus on psychopharmacology in my review but the reader is encouraged to take a look at these excellent guidelines for other details.

The recommendations from the guideline for general maintenance treatment of bipolar disorder in adults in specialty care:

• Do not use gabapentin or topiramate
• Antipsychotic drugs
• Lithium therapy
• Valproate therapy
• Lamotrigine therapy

Recommendations for treatment of mania in specialty care:

• If manic bipolar patient is taking antidepressant consider stopping it
• Electroconvulsive therapy is an intervention that should be considered in those with severe and prolonged mania
• The further treatment of mania follows the maintenance list as above: antipsychotics (haldol, olanzapine, quetiapine or risperidon), lithium, valproate and lamotrigine

Recommendations for treatment of bipolar depression in specialty care:

• Make sure full psychological services are used as a base in treatment
• Add fluoxetine plus olanzapine or quetiapine on it's own
• If no response to initial antidepressant treatment consider a trial with lamotrigine

As you can see from these depression guidelines, the use of standard antidepressants in bipolar depression is not recommended. The exception to this is the use of fluoxetine (covered with olanzapine).

The full pdf guideline from NICE is 59 pages and I would encourage interested reader to go to the website and download the full guide. You can do that by clicking HERE .

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Kendall T, Morriss R, Mayo-Wilson E, Marcus E, & Guideline Development Group of the National Institute for Health and Care Excellence (2014). Assessment and management of bipolar disorder: summary of updated NICE guidance. BMJ (Clinical research ed.), 349 PMID: 25258392

Antidepressants Linked to Lower Suicide in Bipolar Disorder

Bipolar disorder is known to have a marked increased lifetime risk for suicide.

There has been limited study of the effect of specific interventions in the risk of suicidal behavior and completed suicide.

A recent study has added to our understanding of this topic using data from the Collaborative Depression Study or CDS.

The CDS is a large longitudinal stud funded by the NIMH that enrolled a large sample of subjects with bipolar I disorder, bipolar II disorder and unipolar depression.

Subject were followed intensely after a research diagnostic assessment every six months. Follow up interviews including information about antidepressant treatment, mood state, suicidal ideation and suicidal behaviors.  

This was a significantly ill cohort. Twenty-four subjects committed suicide during the five year period of follow up.

Subjects receiving drug treatment with bipolar disorder had statistically lower suicidal behavior (but not in the unipolar group). The estimated level of reduction of suicidal behavior by diagnosis group was:

• Bipolar I disorder: 54% reduction (95% confidence interval 31% to 69
• %)
• Bipolar II disorder: 35% reduction (95% confidence interval 1% to 57%)
• Unipolar disorder: 12% reduction (95% confidence interval 36% reduction to 22% increase)

The authors note some clinicians are less likely to use antidepressants in bipolar depression due to concern about inducing mania or more rapid cycling. They note their study supports a link between antidepressant use and reduced suicidality in bipolar disorder.

Many clinicians recommend chronic use of mood stabilizers with intermittent antidepressant use in bipolar disorder during depressive episode only. This may reduce potential risk for the use of antidepressants in bipolar disorder. The authors note some previous studies support a specific role for the mood stabilizing drug lithium to reduce suicide risk in bipolar disorder.

The psychopharmacologic treatment of bipolar disorder is a complicated process that needs to be customized to individual patient comorbidity, tolerance, medical comorbidity and past treatment response. Patients with bipolar disorder are best managed in a setting of expert medical care, family support and longitudinal monitoring. Patients are best served when they make decisions about drug treatment options in this type of setting.

The CDS cohort study was done prior to the evolution of the use of the novel antidepressant drug treatment lamotrigine in bipolar disorder.  Lamotrigine is an antiepileptic drug that is increasing used in bipolar disorder and is an FDA approved drug for maintenance therapy. The FDA also has approved aripiprazole and the combination of olanzapine plus fluoxetine for the treatment of depression in bipolar disorder.

Readers with more interest in the above study can access the free full-text manuscript by clicking on the PMID link in the citation below.

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Leon AC, Fiedorowicz JG, Solomon DA, Li C, Coryell WH, Endicott J, Fawcett J, & Keller MB (2014). Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders. The Journal of clinical psychiatry, 75 (7), 720-7 PMID: 25093469

Neurobiology of Child Neglect/Abuse: Nemeroff Lecture Notes

I had the opportunity to attend the Warren Neuroscience Lecture presented by Dr. Charles Nemeroff in Tulsa, OK on June 2, 2015.

Dr. Nemeroff has been an international leader in research in mood and anxiety disorders. His recent focus has been on the effects of adverse childhood environments on risk for adult mood and anxiety disorders. 

Here are my notes that summarize some of the key points from his lecture.

Introduction:

• Stress is an important factor in understanding depression
• Early life stress is a risk factor for later adult depression
• Genes account for a significant portion of the variation in risk following stress exposure
• Brain systems that regulate emotions are disrupted during episodes of major depression

Psychiatry research slowed by complexity of brain, multiple cell types, complex heterogeneous disorders. But we are beginning to understand the key role genes play in a variety of key disorders. Genetic factors account for 65% of bipolar disorder variance, 50% of schizophrenia variance and around 35% of variance in major depression.

Early childhood abuse and neglect is common. Recent surveys estimate prevalence rates for each of the following:

• Physical abuse 15-28% of general population in U.S.
• Sexual abuse in 11-21% 
• Emotional abuse in 11-36%
• Parental divorce or separation in 25%

Early childhood abuse and neglect has multiple effects in neurobiology and later adult mood and anxiety disorder risk:

• Increased adult cerebral spinal marker of stress known as corticotrophin releasing factor (CRF)
• Increase serum ACTH and cortisol
• Increase inflammatory markers  such as interleukin-6
• Decreased cerebral spinal fluid oxytocin that may impair social function and bonding with children
• Reduced brain cortex thickness and hyperactivy amygdala response
• Increased adult PTSD and depression
• Increased adult rates of substance abuse
• Increased risk of suicidal behavior and completed suicide

There is a growing body of evidence that ten or more genes influence vulnerability to childhood abuse and neglect including genes regulating the HPA axis, serotonin function and a gene known as FKBP5. These genetic effects may interact with environmental stresses to reduce or amplify stress vulnerability. Stress may be viewed as a teratogen that influences genetic features through epigenetic and gene regulation effects.

For clinicians there are important treatment implications:

• Major depression in the context of moderate to severe childhood abuse is less responsive to medication or to psychotherapy intervention
• Childhood abuse and neglect in bipolar disorder is linked to early onset, greater severity and poor treatment response.

During the discussion following the lecture Dr. Nemeroff noted the importance of population-based efforts to reduce societal levels of exposure to child abuse and neglect including:

• Early education with teacher training to look for evidence of abuse/neglect
• Increased training for primary care physicians treating infants/children
• Increased training and funding for social services that evaluate and treat children referred for child abuse/neglect
• Increased detection and surveillance for sexual predators
• More research in the treatment of sexual disorders including pedophilia. There is almost no NIH funding in this area and little research interest and activity.

Below I have added citations featured in the presentation to allow readers with more interest to delve into some of the primary research studies.

Image is this post is "PBB Protein CRH image" from Wikipedia chapter on CRH. Image by ProteinBoxBot.  Licensed under Public Domain via Wikimedia Commons  

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Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, & Nemeroff CB (2000). Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA, 284 (5), 592-7 PMID: 10918705

Heim C, Mletzko T, Purselle D, Musselman DL, & Nemeroff CB (2008). The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biological psychiatry, 63 (4), 398-405 PMID: 17825799

Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, & Ressler KJ (2008). Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA, 299 (11), 1291-305 PMID: 18349090

Saveanu, R., & Nemeroff, C. (2012). Etiology of Depression: Genetic and Environmental Factors Psychiatric Clinics of North America, 35 (1), 51-71 DOI: 10.1016/j.psc.2011.12.001