Lithium induced subclinical hypothyroidism

Lithium induced subclinical hypothyroidism

Definition: elevated TSH (thyroid stimulating hormone) in a lithium treated patient, with normal T4 and T3

Prevalence: 6-52% in 11 reports (UptoDate Lithium and the Thyroid, accessed 3.8.2015), average 20-30%

Odds ratio for hypothyroidism on lithium: 5.78

TSH should be tested for every 6-12 months

When does it occur? “usually within the first 6-18 months of treatment” (Managing the Side Effects of Psychotropic Medications, Joseph Goldberg, MD, Carrie Ernst, MD, APP, 2012, page 185)

May be more common in patients with circulating thyroid antibodies (ie, underlying chronic autoimmune thyroiditis; measure antiperoxidase and antithyroglobulin
More common in women

When should supplemental thyroid hormone be added?
Opinions differ
1. One option is to monitor TSH more often (every 3 months) but not treat unless TSH levels “exceed 10 mU/L or clinical manifestations emerge”
2. Typical manifestations are “fatigue, anergia, weight gain, poor concentration, depression, cold intolerance, and brittle hair.” (Clinician’s Guide to Bipolar Disorder, David Miklowitz, PhD and Michael Gitlin, MD, Guilford Press, 2014, p. 123)
3. Another option: add thyroid hormone whenever TSH is high (eg, 4-10), especially if there are mood symptoms, or complaints of lethargy and fatigue

How to add:
1. Start with T4 (eg Synthroid, levothyroxine) 0.025 mg/day .
2. Recheck TSH in 6 weeks.
3. If still low, continue to increase by 25 micrograms every 6 weeks, rechecking TSH, until levels have normalized.

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lithium induced hyperparathyroidism

Lithium, hypercalcemia (increased serum calcium), and hyperparathyroidism
or
What to do when you’re stable on lithium and your calcium level is high?

Lithium therapy increases the prevalence of hypercalcemia and hyperparathyroidism (http://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2013.13081057):
1. 10% absolute risk in 730 lithium-treated patients compared with 730 unexposed
2. Recent case-control study of 112 patients with bipolar disorder found 8.6% prevalence hyperparathyroidism and 24.1% hypercalcemia
3. General population rate: from 0.1-0.7%

Mechanisms:
1. Lithium stimulates calcium reabsorption form renal tubules and bowel
2. Lithium stimulates parathyroid hormone release
3. lithium may affect the set point at which the parathyroid gland slows parathyroid hormone release in response to increasing serum calcium levels
4. Increase in parathyroid gland mass correlates with the duration of lithium therapy, and may lead to “lithium-induced ‘primary’ hyperparathyroidism”, which becomes independent of lithium.

How does parathyroid hormone work? :
1. It regulates the concentration of serum ionized calcium
2. It stimulates the kidneys to reabsorb calcium.
3. It stimulates the gut to reabsorb calcium
4. parathyroid hormone secretion is regulated by a very sensitive calcium sensing receptor on the parathyroid cell surface.
5. Increasing serum ionized calcium inhibits parathyroid hormone secretion.

Classic hypercalcemia/primary hyperparathyroidism presents with “stones, bones, thrones, abdominal groans and psychiatric moans”
1. stones represents kidney stones, diabetes insipidus (polyuria and polydipsia)
2. bones represents bone problems: bone pain, pathological fractures, osteoporosis.
3. abdominal groans represents nausea, vomiting, constipation, peptic ulcers, acute pancreatitis
4. Thrones refers to constipation and polyuria
5. psychiatric moans refers to lethargy, fatigue, and depression

Good news is that “up to 80% of cases (of hypercalcemia and primary hyperparathyroidism have no symptomatic manifestations” (Am J Psychiatry 172: 1, January 2015 p. 13) and go by the name of “asymptomatic primary hyperparathyroidism”.

Female/male prevalence is 2.5/1
Three times more common in patients over age 80 vs patients 20-29

Lithium-associated hypercalcemia/ hyperparathyroidism is different from primary hyperparathyroidism:
1. serum calcium levels are less elevated
2. phosphate levels are normal rather than low.
3. magnesium levels are increased, rather than normal .
4. calcium in the urine is decreased rather than increased (hypocalciuria), so there are lower rates of kidney stones
5. parathyroid hormone levels are lower
6. lithium protects bone
The evidence to date (albeit uncontrolled) suggests that lithium induced calcium elevations cause less risk of damage to the kidney and the bones. However, there are “numerous case reports” of “classical symptomatic hypercalcemic states in lithium treated patients” (AJP page 14)

What are the options?
1. Surgical referral (the standard of care for primary hyperparathyroidism is parathyroidectomy)
2. discontinue lithium (the condition is often reversible)
3. continue lithium and monitor it (“Monitored lithium continuation in asymptomatic cases may be a prudent option for many patients, modeled on commonly practiced asymptomatic primary hyperparathyroidism surveillance. ..Monitored surveillance should proceed cautiously and with an appreciation for nuance. Subtle signs of hypercalcemia/ hyperparathyroidism may mimic underlying psychiatric disorders, with disturbances in mood, energy, and cognition in patients who are otherwise classified as asymptomatic.” )
4. calcimimetic therapy (Cinacalcet, FDA approved has “reversed lithium-associated hypercalcemia/ hyperparathyroidism in…five cases to date”
“In consultation with an endocrinologist, cinacalcet represents an important additional treatment option in symptomatic patients for whom lithium discontinuation poses substantial psychiatric risks, for whom surgical intervention has failed, or for whom surgery is contraindicated.”)
5. cinacalcet problems: high rates of gastrointestinal side effects, high cost
6. Get baseline calcium testing in all patients and follow-up testing at 6 months and annually thereafter

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In Praise of ADHD, by James J McGough, MD (Oxford American Psychiatric Library), 2014, Oxford University Press

This superb summary of ADHD is likely to be of interest to several different types of reader. First, the physician who wants a brief (the entire book, including index, is 125 pages) overview; second, the therapist whose patients have ADHD and wants to learn more about it; third, the parent who wonders if their child has ADHD, and whether they should treat it, and how; fourth, the curious layperson.

Dr. McGough, a professor of psychiatry at UCLA, and one of the top researchers in the ADHD field, is a forceful lecturer, and his book is also pithy and powerful. Every sentence counts; there is not a wasted word. The person who likes to highlight the text will often be confronted with entire pages of yellow.

His book, the first in a new series, the “Oxford American Psychiatric Library”, by Oxford University Press (other volumes are bipolar disorder by Stephen Strawkowski, MD and Schizophrenia, by Stephen Marder, MD) captures the state of the art of ADHD knowledge and treatment in 2014.

Let’s take a brief tour through this book.

In the Introduction, Dr. McGough notes that ADHD “is a frequently occurring, brain-based, neurodevelopmental disorder with substantial negative consequences for individual and public health. Once viewed as a childhood condition, , it is now recognized that a majority of cases persist throughout adolescence and adulthood.”

“The high community prevalence of ADHD suggests that there are affected patients in virtually every clinical practice in every medical specialty. Nevertheless, comprehensive education about ADHD is largely limited to specialized programs in child and adolescent psychiatry and behavioral pediatrics.”

“MIsinformation about ADHD abounds. Some assert that ADHD is not real….that childhood inattention and hyperactivity are normal, the diagnosis is subjective….older student fake symptoms to obtain academic advantages….adults are similarly drug seeking….or that the condition represents a conspiracy by pharmaceutical companies and organized psychiatry to increase medication sales.”

“ADHD…is among the most scientifically validated psychiatric disorders”, with diagnostic reliability “on par with many conditions in general medicine”,and well demonstrated biological underpinnings….”the accumulated evidence base for its clinical management is of the strongest in mental health. Medications for ADHD have been used for over 70 years in millions of patients annually, creating an indisputable record of real-world safety and positive benefit….Treatment effect sizes are double those typically seen with more widely prescribed medications for depression and schizophrenia.”

Chapter 2, Historical Perspectives, reviews the history of ADHD (first mentioned in an 18th century medical text) and follows it through the various iterations of the DSM, including the DSM-5.

Chapter 3, Epidemiology and Burden, notes how common the condition is, with an estimated 5.3% worldwide mean. Male/female ratios, 9/1 in school age clinic samples, are 1/1 in adult clinic samples. This implies that boys are treated as children because they are more likely to disrupt the classroom, while quietly inattentive girls are ignored. The late Dennis Cantwell, MD, one of my best teachers, used to describe boys as having “garlic symptoms” (which bother the environment), while girls have “onion symptoms”, and suffer internally.

Chapter 3 also notes the extensive co-morbidity of ADHD, Mood disorders and anxiety disorders are quite common, and often the underlying ADHD is missed. Chapter 4 reviews etiology and neurobiology. Chapter 5 reviews diagnostic criteria, especially the different forms the criteria take in children and adults.

Chapter 6 reviews the various aspects of a thorough assessment. “ADHD is a clinical syndrome….ADHD is not diagnosed on the basis of any distinct neuropsychological profile. There is no scientific justification for claiming to diagnose ADHD on the basis of other laboratory studies, computerized tests of attention, electroencephalography (EEG), or other brain imaging methods.” A careful reading of this chapter could save a parent thousands of dollars, and spare a child needless radiation exposure.

Chapter 7 and 8 review Treatment Planning in Children and Adolescents, and in Adults.

Chapter 9 reviews basic pharmacology.Here are a few of the pearls strewn though its pages. “It is commonly stated that 70% of patients respond favorably to stimulants. In fact, approximately 70% respond favorably to the first stimulant prescribed, whether a methylphenidate or amphetamine. Of those who fail, an additional 70% respond favorably to the alternative class. As such, more that 90% of patient have satisfactory clinical improvement with stimulants, at least during acute treatment.”

Is my child/spouse/partner being overmedicated by their physician? Tables 9-2, 9-3, and 9-4 and the associated text show the reader how the meds are commonly used, ie what are the usual standards of care.

OK, so should I start my ADHD patients on amphetamine or methyphenidate? “Some patients respond preferentially to one or another stimulant class, but there is no method other than clinical trial and error to predict whether MPH or AMPH is the optimal choice.”

OK, so what is the difference between how methyphenidate and amphetamine work at the cellular level? “Both AMPH and MPH inhibit catecholamine reuptake into presynaptic neurons by blocking norepinephrine and dopamine transporters. AMPH further directly displaces norepinephrine and dopamine from presynaptic storage vesicles, and it inhibits monoamine oxidase and subsequent neurotransmitter breakdown.”

OK, so how do these drugs work at the level of brain circuits? This is fascinating, and a little complicated, and still being worked out, but here goes (pages 74-75): “Recent research suggests that ADHD treatment response is not a direct effect of increased catecholamine release, but that increased levels of norepinephrine and dopamine have indirect modulating effects on glutaminergic signaling in the the prefrontal cortex (PFC).”

PFC circuits regulate lots of stuff (attention, executive functioning, etc, etc). “One subset .. mediates active attention to “preferred” inputs or “signals”, while another subset mediates attention to “nonpreferred” inputs or noise.”

so “ADHD treatment can be viewed as a rebalancing of “signal” to “noise” ratios….Ideally, individuals should appropriately focus on important tasks (signal), while retaining some awareness of background activity (noise) and the ability to shift attention flexibly when required. Optimal balancing of signal to noise ratios in the PFC is dependent on a narrow range of catecholaminergic activity. If catecholamine levels are excessively elevated, perhaps from too high medication doses or stress, PFC networks collapse with concomitant deteriorations in cognitive or motor control. Dopamine increases that might be useful for tasks requiring highly focused attention could also cause problems with overfocus, cognitive rigidity, and a loss of personality and spontaneity.”

This is, in my opinion, a brilliant and succinct summary of a very complicated area, and it suggests what a delicate touch is required in adjusting a patient’s medication.

Chapter 10 is clinical medication management. Dr McGough has developed a method (which in my notes I label the McGough titration) to quickly (within 2 weeks) and efficiently (with one prescription) answer 2 questions: is this medication helpful or harmful to my patient, and what is the optimal dosage ? (pages 81-83, and table 10-1). When to use combination pharmacotherapy, and how to handle various common side effects are also discussed.

My psychiatrist wants to see me every month to give me refills. Is this really necessary? (see page 82)

Patients are often dealt more than one diagnostic card, and chapter 11 shows how to deal when a patient has comorbid diagnoses.

Chapter 12 reviews medication controversies Do ADHD meds stunt growth or cause sudden death? Should one get an EKG before starting a stimulant? What if the patient is using alcohol or marijuana? Do ADHD meds cause birth defects? Do patients fake symptoms to get stimulants? Do ADHD meds stop working?

Chapter 13, Complementary and Alternative Medicine Therapies, covers the evidence base, and the quality of the research, for restriction/elimination diets, dietary supplements, neuropsychological treatments, and mind-body therapies. Careful reading of this chapter could help parents avoid wasting a lot of money on treatments with scant evidence to support their efficacy. The treatments with the strongest evidence base are the addition of essential fatty acids, and the removal of artificial colors.

This is a book that the practicing psychiatrist will want to read from cover to cover, and then read again. It may be of even more benefit to the parent or the adult patient.

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James D Watson on anti-oxidants and cancer

I’ve been impressed by James D. Watson, the co-discoverer of DNA, ever since I read his  account of the discovery of the structure of DNA,  The Double Helix  and used his Molecular Biology of the Gene to study biology as an undergraduate  (first published 1965; 7th edition, 2014). I like the quality of his writing and the clarity and simplicity  of his thought.

Dr Watson, now 86, gave an interesting and provocative lecture at UCLA in January, 2013 on  “Oxidants, anti-oxidants and the curing of cancer”

http://www.imedseminar.com/seminars/oxidants-antioxidants-and-the-curing-of/video

and published an article on the same subject  “Oxidants, antioxidants and the current incurability of metastatic cancers”  http://rsob.royalsocietypublishing.org/content/3/1/120144.

In his lecture and his article, he makes 3 assertions that are worth considering.

First, anti-inflammatory agents such as aspirin (low dose, eg 81 mg, used daily) “lead to much less cancer in those human beings who regularly take them”, probably because aspirin inhibits the “pushing by cytokines of otherwise quiescent mesenchymal cancer cells to grow and divide.” (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61720-0/fulltext )

Second, metformin is a relatively non-toxic, well-tested drug that preferentially kills mesenchymal stem cells. “This most widely used anti-diabetic drug’s heightened ability to kill late-stage mesenchymal cancer cells probably explains why those humans who use it regularly have reduced incidences of many cancers”. (http://www.pnas.org/content/110/3/972, and other papers by Kevin Struhl of Harvard, who discovered this “in a still much unappreciated article published three years ago in Cancer Research” in 2009).

Thirdly, free-radical-destroying antioxidative nutritional supplements may cause more cancers than they prevent. Humans kill cancer cells largely by  oxidizing them. Late stage cancer cells are hard to kill, in part, because they can make too many anti-oxidants. There have been numerous trials using anti-oxidants to prevent cancer which not only have failed to demonstrate benefit, but have led to an increased risk of cancer in those taking them. (http://www.ctu.dk/media/8831/Bjelakovic-Nikolova-and-Gluud-JAMA-2013.pdf ) “In light of the recent data strongly hinting that much of late-stage cancer’s untreatability may arise from its possession of too many antioxidants, the time has come to seriously ask whether antioxidant use much more likely causes than prevents cancer.”

So, bottom line:

  1. Daily aspirin, low dose, 81 mg
  2. metformin works synergistically with cancer chemotherapy to kill the most dangerous cells
  3. anti-oxidants in food, not as pills
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Exercise

I’ve had too many discussions with patients about exercise that go like this:

Doctor: How much are you exercising?

Patient: I’m not. Too busy.

To avoid this stalemate, I think it’s helpful to think about what we mean by exercise.

Patients often equate exercise with intense physical activity: running, spinning, weight lifting, tennis. This sort of exercise makes you sweat and requires a change of clothes and a shower. It’s often hard to fit into a workday.

I think it is helpful to consider exercise in terms of the Met, or metabolic equivalent, which shows the energy cost of activities, in kcalories/kilograms/hour. Sleeping uses 0.9 Mets, sitting 1.0 Mets.

 

So for a 70 kg person (154 lbs), one hour of sitting would use 70 kcalories. 24 hours of sitting would use 70 x 24=1680 calories.

 

The Compendium of Physical Activities lists the Mets for numerous activities:

http://prevention.sph.sc.edu/tools/docs/documents_compendium.pdf

Considered this way, whenever you’re not sitting or lying down, you’re exercising, since you are burning more calories than you use at rest. Whenever you get up out of your chair, you are exercising.

The question then becomes not whether you exercise, (since unless you’re on bed rest, you exercise every day), but how much you exercise.

This can be measured in two ways: by how many minutes/day one spends in moderate  intensity activities (walking is the classic example), or by how many steps/day one takes.

This is easily measured by movement sensors such as pedometers, or exercise monitors (the Fitbit One is my personal favorite), phone apps, etc.

The CDC currently recommends that all adults spend a minimum of 150 minutes/week in moderate intensity exercise, or 75 minutes/week in vigorous intensity exercise. Moderate intensity exercise is done at 3.0-5.9 times the intensity of rest, or 3.0-5.9 Mets.  Vigorous intensity exercise is > 6.0 times the intensity of rest, or greater than 6.0 Mets.

http://www.cdc.gov/physicalactivity/everyone/guidelines/

More benefit comes from doubling those numbers: 300 minutes/week of moderate, or 150 minutes of vigorous, or some mix of the two.

Two days/week of muscle strengthening exercises to prevent muscle atrophy are also recommended.

Vigorous exercise is more time efficient in the short run (one gets one’s exercise done in half the time),  but it carries a higher risk of injury, hence may be less sustainable in the long run.

But is vigorous exercise “better” for you than moderate exercise? Or is moderate exercise sufficient to get all the benefits of exercise? I’m not sure what is the correct answer, or if data exists that can answer this.

An interesting line of research has suggested that time sitting is not good for your health: increased rates of death, both all cause and specific (colon cancer) correlate with the number of hours one sits in a day. This suggests the benefits of simple activities that interrupt sitting, such as getting up and taking a walk around the office or the block, or going to the kitchen to make a cup of (green) tea.

 

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The California Prescription Monitoring Program (CURES)

I first became aware of the CURES program a few years ago, after a  psychiatrist left a voicemail warning  me that patient X, to whom I had been prescribing a controlled substance,   was receiving the same drug not only from him, but, he had recently learned, from a pharmacist using a state database,  also from a third physician.

Thinking that it would be extremely helpful to have the almost magical capacity to learn which patients are not telling the truth about their medications, I enrolled in the CURES program. CURES gives the physician the capacity to review the details of every controlled substance prescription the patient has received within the last 12 months:  name of drug,  strength, number of pills,  date of prescription,  name of the prescribing physician, and  dispensing pharmacy.

The following signs suggest the need for consultation with the patient’s previous physician:

  1. The patient is taking high doses of controlled substances.
  2. The patient is using  greater than the maximum dosage of a medication
  3. The patient has seen several different physicians, sequentially, for their prescriptions.

The worst-case scenario, and precisely what the CURES is designed to prevent,  is the patient seeing multiple physicians at the same time, receiving prescriptions for  identical medications, and   filling them at different pharmacies. For example, a patient I was asked to see had received prescriptions from 16 physicians in the last 12 months, had them filled at 16 different pharmacies, and  had  a 60 day prescription for the maximum dose of a schedule II controlled substance filled, then one week later another 60 day prescription for the same drug filled, then 4 days later  a 120 day prescription for the same drug filled by a different physician, and then a 60 day prescription filled 18 days later, receiving 9 months supply of the drug, at its  maximum dosage,  in less than 30 days.

I routinely screen all patients who receive controlled substance prescriptions, and 98-99% of the time  I find nothing of concern.

Until recently, I screened all new patients a few minutes before interviewing them. But for the 1-2% where there is a problem, this is inefficient.  When I tell patients that I have concerns about  their prescription drug use, and that I want to consult their previous physicians before prescribing for them, they invariably leave my practice.  Occasionally they take the time to  post critical  reviews on Yelp.  Perhaps a  better way of proceeding  would be to screen the patient after  scheduling their appointment, but well before their actual visit, so that if their profile raises  concerns, there is time to ask them to please send me their previous physicians’ records to review before their appointment. This would give them the option of cancelling their appointment, saving them money, time, and aggravation.

 

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