Dhwani Shah, MD Associate Clinical Professor of Psychiatry, University of Pennsylvania School of Medicine
Lisa Rosenthal, MD Assistant Professor of Clinical Psychiatry, University of Pennsylvania School of Medicine
Dr. Shah and Dr. Rosenthal report no financial relationships with any commercial companies related to this article.
It’s easy to order labs—it’s the interpretation that’s difficult. In this article, we’ll review some of the more common labs you are likely to order as psychiatrists and give you some tips on interpreting them, as well as discussing what (if anything) you should do when a lab is abnormal.
We generally order thyroid levels in two situations. First, in order to rule out hypothyroidism or hyperthyroidism as a cause of psychiatric symptoms; and second, when we decide to use thyroid hormone as an augmentation strategy for depression. What with TSH, T3, and T4, dealing with the thyroid is confusing. Here is a quick primer of thyroid function.
Thyroid hormone is important for protein synthesis and metabolism for almost every organ, including the brain. Typical symptoms of hypothyroidism are cognitive and physical slowing, fatigue, cold intolerance and hair loss, while symptoms of hyperthyroidism include nervousness, tremor, sweating, diarrhea, and rapid or irregular heartbeat. The thyroid gland produces T3 (triiodothyronine, marketed as Cytomel) and T4 (thyrox¬ine, marketed as Synthroid). T4 is considered a “prohormone” with very little intrinsic activity: it is trans¬formed in the peripheral tissues into T3, which is the biologically active form of thyroid hormone. Both T3 and T4 are regulated by the release of thyroid stimulating hormone (TSH) from the pituitary gland, and TSH is in turn regulated by thyroid releasing hormone (TRH) from the hypothalamus. TSH levels increase when the serum T4 concentration falls below a person’s usual setpoint, and even subtle changes in T4 levels often lead to substantial increases in TSH, making it an ideal screening test for thyroid function.
Endocrinologists typically prescribe T4 (Synthroid) as thyroid supplementation for hypothyroidism, because this allows the patient’s own physiologic mechanisms to control the production of the active hormone. When monitoring levels of T4, it is important to order the “free T4 level” because virtually all of serum T4 is bound to a protein called TBG (thyroxine binding globulin). Serum total T4 levels include both “bound” and “free” T4, and the free T4 level gives a better estimate of the amount of thyroid that can be used by the tissues.
Psychiatrists use thyroid supplementation for a different purpose: as an augmentation strategy for antidepressants. T3 (Cytomel) augmentation has become a hot topic in psychiatric circles, in part due to research from STAR-D (Nierenberg et al., American Journal of Psychiatry 2006;163:1519-30) and a recently published randomized controlled trial demonstrating the benefit of T3 augmentation for depression (Cooper-Kazaz et al., Archives of General Psychiatry 2007;64:679-688). Why do psychiatrists use T3, while endocrinologists use T4? The reasons for this are unclear and may simply be due to the fact that historically we’ve used it and it has worked. There is some research showing that T3, being the active form of the hormone, may directly desensitize serotonin 5HT1A receptors leading to increased serotonin in the cortex (Gur E et al., J Pharmacol Exp Ther 1999;288: 81-7). There is also a small three week randomized trial (with no placebo) in which researchers com¬pared T3 and T4 as an augmentation strategy, and in which T3 was slightly more effective (Joffe RT et al., Psychiatry Res 1990;32: 241-51).
If you want to use T3 as augmentation to an antidepressant, most authorities recommend a starting dose of 25 micrograms a day, with the average dose range being 25-50 mcg daily. Check a baseline thyroid panel with a TSH and a free T4 and T3 before starting T3. You might discover a case of significant thyroid disease, in which case you should refer the patient to their primary care doctor for treatment. If the values are normal, go ahead and start T3, and once or twice a year thereafter check a thyroid panel to make sure that you are not overdosing your patient. Free T3 levels in the high normal range are usually well tolerated (John O’Reardon, MD, personal communication).
There are some potentially concerning side effects of T3. For exam¬ple, older patients (over 60) or patients with preexisting heart conditions can develop an arrhythmia from T3. In such patients, confirm that an EKG has been done within the past year and is normal before starting the hormone. Chronic use of thyroid hormones can cause bone loss leading to osteoporosis and fractures, so make sure to tell your patients at risk (especially post-menopausal women) to have their PCP monitor their bone density and to consider calcium and Vitamin D supplementation.
Sodium. SSRIs, carbamazepine, and oxcarbazepine can cause low sodium levels (hyponatremia). This is fairly rare, and it tends to develop within the first few weeks of starting the medication. It is more common in women and the elderly (Looper KJ et al., Psychosomatics 2007;48:1-9; Dong X et al., Neurology 2005;65: 1976-8). The hyponatremia is appar¬ently caused by SIADH (Syndrome of Inappropriate Anti-Diuretic Hormone secretion). To give you a quick physi¬ology refresher, SIADH is caused by an abnormal release of ADH (Anti-Diuretic Hormone) from the hypothalamus. This leads to retention of water in the kidney, causing dilution of serum sodium, and therefore, hyponatremia (defined as less than 135 mOsm/kg). Symptoms include malaise, nausea, headache, lethargy, confusion, and pedal edema. We recommend checking a baseline sodium in elderly patients over 65 or those at risk of developing hyponatremia (for example, patients taking thiazide diuretics or other medications that can potentially cause hyponatremia, or patients with congestive heart failure or cirrhosis); then recheck at least once after you’ve started treatment.
Chloride and bicarbonate. The anticonvulsant topiramate (Topamax) is a carbonic anhydrase inhibitor. Blocking carbonic anhydrase causes the kidney to excrete bicarbonate in the urine. Since bicarbonate is a base, having less of it can cause acidosis, and through a mechanism that no psychiatrist needs or wants to hear about, this can lead to hyperchloremic metabolic acidosis. You should know that some medical or psychiatric conditions can predispose someone to acidosis (such as laxative abuse, renal disease, severe respiratory disorders, status epilepticus, diarrhea) and therefore can add to the bicarbonate-lowering effects of topiramate. Symptoms of metabolic acidosis include hyperventilation, fatigue and anorexia. The metabolic acidosis caused by topiramate can also increase the risk of calcium kidney stones (Vega D et al., Expert Opinion Drug Safety 2007;6:547-57). The bottom line is that you should check serum bicarbonate levels once or twice a year in patients taking topiramate; if the level is low, either stop the drug or refer the patient to their PCP to make the decision.
Calcium and Vitamin D levels. Both calcium and vitamin D are necessary for bone density and prevention of osteoporosis. This is important information for psychiatrists because several recent studies have implied that SSRIs lower bone density in both men and women , which can potentially lead to osteoporosis and stress fractures (Haney EM et al., Arch Intern Med 2007; 167:1246-51, also see Diem SJ et al., Arch Intern Med 2007;167:1240-5). Any patient who takes an SSRI and who has other risk factors for osteoporosis (such as advanced age, chronic cigarette smoking, or anorexia nervosa) should go to their primary care physicians for screening which might include bone mineral density testing and calcium/Vitamin D levels.
White blood count. White blood cells, specifically neutrophils, are our body’s primary defense against infections. Neutropenia is defined as an absolute neutrophil count (ANC) of less than 1,500/microL.
Agranulocytosis refers to severe neutropenia (i.e., ANC less than 500/microL), and is a potentially fatal side effect of several psychiatric med¬ications, most notably clozapine and carbamazepine. This side effect, fortu¬nately, is rare. A 1996 study published in the New England Journal of Medicine analyzing data of 11,555 patients who received clozapine found that agranulocytosis developed in 73 patients (0.6%), resulting in death from infectious complications in two patients (Alvir JM et al., NEJM 1993;329:162-167). The FDA requires that you monitor any patient on Clozaril for WBC and ANC weekly for the first six months. If there have been no signs of neutropenia, monitoring can then decrease to every two weeks, and after one year of uneventful clozapine use, you can check the WBC/ANC monthly (for detailed pre¬scribing and monitoring information see http://www. clozaril.com /hcp/treating/wbc_anc.jsp).
Lithium, on the other hand, can cause a raised white blood cell count, referred to as a leukocytosis. This effect appears to be benign and unrelated to blood lithium levels (Carmen J et al., Natl Med Assoc 1993;85:301¬3). You should nevertheless check a CBC along with a lithium level and TSH every six to 12 months for patients on lithium.
Platelets. Depakote (valproate) and Tegretol (carbamazepine) can cause thrombocytopenia, defined as a reduction in platelet count to less than 150,000/microL. This is not a rare side effect: a recent study of 265 patients with epilepsy on Depakote found that 17.7% of patients experienced at least one episode of thrombocytopenia. Women were significantly more likely to develop the problem, and the probability of developing thrombocytopenia increased with Depakote levels above 100 mcg/ml in women and above 130 mcg/ml in men (Nasreddine W et al., Epilepsia 2008;49:438-45). While there are no clear guidelines for the most effective valproate levels for the treatment of mania, most authorities recommend 50-100 mcg/ml (for a good discus¬sion, see Leard-Hansson and Guttmacher, Clin Psych News 2004;32:26). For both Depakote and Tegretol, we recommend checking a baseline platelet count, then two weeks after starting the medication, then every six months or annually, with more vigilance in the elderly or patients with bleeding disorders (See TCPR, August 2007).
SSRIs do not cause thrombocytopenia, but they do affect platelet aggregation (possibly by decreasing the amount of serotonin reuptake in platelets), and this can lead to bleeding problems. For example, SSRIs have been associated with post-surgical bleeding complications (Movig et al., Arch Intern Med 2003;163:2354¬8), a risk of upper gastrointestinal bleeding, particularly in patients taking NSAIDs (De Abajo et al., Archives of Gen Psych 2008), and an increased risk of major nongastrointestinal bleeding in patients taking Coumadin (Schalekamp T et al., Arch Intern Med 2008;168:180-185). There are also case reports linking SSRI use to minor bleeding complications, such as easy bruising, hematomas and nose bleeds (Serebruany VL, Am J Med 2006;119:113-6).
Unfortunately, there is no good lab value to monitor the bleeding risk of SSRIs. You just have to keep this side effect in mind for patients on SSRIs who are also using NSAIDs, Coumadin or aspirin, and patients with upcoming surgical procedures. One study indicated that antidepressants with lower serotonin reuptake inhibition were less likely to cause bleeding. The least risky medications were Remeron, Wellbutrin, and trazodone; intermediate risk medications were Effexor, Celexa, and Luvox; while the highest risk medications were Prozac, Paxil, Zoloft, and clomipramine (Meijer WE et al., Arch Intern Med 2004 Nov 22;164(21): 2367-70).
Hematocrit. Anemia can cause fatigue, which can be misdiagnosed as a symptom of depression. If you have a patient with depression who has very prominent symptoms of fatigue that are not improving with treatment, check a hematocrit (included in the complete blood count).