by Grace Jackson, M.D., Diplomate , American Board of Psychiatry and Neurology

I read with interest the February 18th Washington Post article (“Mental illness and heart disease are often found in the same patients”) by Dr. Nathaniel P. Morris, a physician in training at Stanford University’s psychiatry residency program. The article was correct about the bidirectional relationship between cardiac conditions and the phenomenological entity known as “clinical depression.” However, with the exception of one sentence (“older psychiatric drugs, such as tricyclic antidepressants, came with high-risk side effects on the heart”), the article overlooked the potential for most classes of psychiatric medication to cause or enhance cardiac problems. Equally striking, the article suggested that “newer generations of psychiatric drugs – such as selective serotonin reuptake inhibitors, may protect cardiovascular health.” Such a claim remains contestable, and a fact check is in order.

A thorough review of the medical literature (see sample abstracts, below) suggests that psychiatric drugs – particularly, antipsychotics and antidepressants -- remain a significant and controllable risk factor for coronary artery disease, sudden cardiac death, myocarditis, cardiomyopathy, arrhythmias (including pulseless electrical association), thromboembolic disease, stroke, transient ischemic attacks, and small vessel ischemia in the brain. Before any psychiatrist can act constructively as a consultant to other specialists, he or she must master the “target organ toxicities” associated with psychiatric and non-psychiatric pharmaceuticals.

While it was reassuring to read the empathic remarks of Dr. Morris, whose writings reflected a commendable sensitivity to the physical and emotional impact of the medical procedures which his patients had endured, I found myself frightened by possible inadequacies and omissions in his current training. I hope his empathy will be bolstered by unbiased instruction which must include the mortality and morbidity associated with all psychiatric drugs.

Sample abstracts:
-Epidemiol Psychiatr Sci. 2017 Feb;26(1):18-21. doi: 10.1017/S204579601600086X. Epub 2016 Nov 22. Antipsychotic drug exposure and risk of myocardial infarction. Barbui C1, Gastaldon C1, Papola D1, Ostuzzi G1.

It found nine studies and calculated that the odds (risk) for developing MI were 1.88-fold higher in antipsychotic users compared with individuals who had not taken antipsychotic drugs.

-Circulation. 2014 Jul 15;130(3):235-43. doi: 10.1161/CIRCULATIONAHA.114.008779. Epub 2014 May 16. Association between antipsychotic use and risk of acute myocardial infarction: a nationwide case-crossover study. Lin ST1, Chen CC2, Tsang HY2, Lee CS2, Yang P2, Cheng KD2, Li DJ2, Wang CJ2, Hsieh YC2, Yang WC2.

The adjusted odds ratio of AMI risk was 2.52 (95% confidence interval, 2.37-2.68) for any antipsychotics, 2.32 (95% confidence interval, 2.17-2.47) for first-generation antipsychotics, and 2.74 (95% confidence interval, 2.49-3.02) for second-generation antipsychotics.

-Arch Intern Med. 2004 Jun 28;164(12):1293-7. Antipsychotics and the risk of sudden cardiac death. Straus SM1, Bleumink GS, Dieleman JP, van der Lei J, 't Jong GW, Kingma JH, Sturkenboom MC, Stricker BH.

Current use of antipsychotics was associated with a 3-fold increase in risk of sudden cardiac death. Current use of antipsychotics in a general population is associated with an increased risk of sudden cardiac death, even at a low dose and for indications other than schizophrenia.

-Eur J Clin Pharmacol. 2017 Jan 9. doi: 10.1007/s00228-016-2187-x. [Epub ahead of print] Use of antidepressants and the risk of cardiovascular and cerebrovascular disease: a meta-analysis of observational studies. Biffi A1, Scotti L2, Corrao G2.

Use of SSRIs was associated with an increased risk of cerebrovascular disease (RRs, 1.24; 95% CI, 1.15 to 1.34), while the use of TCA was associated with an increased risk of acute heart disease (RRs, 1.29; 95% CI, 1.09 to 1.54).

-Neuropsychopharmacology. 2015 Dec;40(13):3027-35. doi: 10.1038/npp.2015.158. Epub 2015 Jun 10. White Matter Hyperintensity Accumulation During Treatment of Late-Life Depression. Khalaf A1, Edelman K1, Tudorascu D1, Andreescu C1, Reynolds CF1, Aizenstein H1.

Among all patients, there was as a significant increase in WMHs over 12 weeks (t(46)=2.36, P=0.02).

-Int J Cardiol. 2016 Jan 15;203:867-73. doi: 10.1016/j.ijcard.2015.11.032. Epub 2015 Nov 6. Antidepressant use and risk for mortality in 121,252 heart failure patients with or without a diagnosis of clinical depression. Brouwers C1, Christensen SB2, Damen NL1, Denollet J1, Torp-Pedersen C2, Gislason GH3, Pedersen SS4.

Patients with HF taking antidepressants had an increased risk for all-cause and CV-mortality, irrespectively of having clinical depression.

-Biomed Sci Instrum. 2015;51:400-6. The Effect Of Selective Serotonin Reuptake Inhibitors and Antidiabetic Drugs on Cardiomyocytes. Nelson SA1, Wilson GA, Tucci M, Benghuzzi H.

Cardiomyocytes were grown in a tissue culture environment and challenged with therapeutic concentrations of SSRIs alone or a combination of SSRIs and antidiabetic drugs. Intracellular markers for stress and cytomorphometric analysis indicated SSRIs and SSRIs in combination with antidiabetic drugs negatively impact the health of the cardiomyocytes with time in culture.

-Int J Cardiol. 2011 Jan 7;146(1):64-7. doi: 10.1016/j.ijcard.2010.01.006. Epub 2010 Feb 26. High mortality among heart failure patients treated with antidepressants. Veien KT1, Videbæk L, Schou M, Gustafsson F, Hald-Steffensen F, Hildebrandt PR; Danish Heart Failure Clinics Network.

In a Cox Proportional Hazard Model, pharmacologically treated depression was associated with a 49% increased mortality risk (Hazard ratio: 1.49, 95% confidence interval: 1.03-2.16) after adjustment for traditional confounders.

-Circ Heart Fail. 2009 Nov;2(6):582-90. doi: 10.1161/CIRCHEARTFAILURE.109.851246. Epub 2009 Sep 22. Prognosis in heart failure and the value of {beta}-blockers are altered by the use of antidepressants and depend on the type of antidepressants used. Fosbøl EL1, Gislason GH, Poulsen HE, Hansen ML, Folke F, Schramm TK, Olesen JB, Bretler DM, Abildstrøm SZ, Sørensen R, Hvelplund A, Køber L, Torp-Pedersen C.

Antidepressants were prescribed to 19,411 patients, and both TCA and SSRI were associated with increased risk of overall and cardiovascular death (TCA: HR, 1.33; CI, 1.26 to 1.40; and HR, 1.25; CI, 1.17 to 1.32; SSRI: HR, 1.37; CI, 1.34 to 1.40; and HR, 1.34; CI, 1.30 to 1.38, respectively). Coadministration of SSRI and beta-blockers was associated with a higher risk of overall and cardiovascular death compared with coadministration of beta-blockers and TCA (P for interaction <0.01). Coadministration of SSRIs and beta-blockers was associated with increased risk of overall death and cardiovascular death compared with coadministration of TCAs and beta-blockers.

-J Biochem Mol Toxicol. 2016 Sep 2. doi: 10.1002/jbt.21836. [Epub ahead of print]. Toxicity of lithium on isolated heart mitochondria and cardiomyocyte: A justification for its cardiotoxic adverse effect. Salimi A1,2,3, Gholamifar E1, Naserzadeh P1,3, Hosseini MJ4,5, Pourahmad J6.

Results revealed that Li+ induced a concentration- and time-dependent rise in mitochondrial ROS formation, inhibition of respiratory complexes (II), mitochondrial membrane potential (MMP) collapse, mitochondrial swelling, and cytochrome c release in rat heart mitochondria and also induced Caspase 3 activation through mitochondrial pathway, decline of ATP and lipid peroxidation in rat cardiomyocytes. These results indicate that the cardiotoxic effects of Li+ were initiated from mitochondrial dysfunction and oxidative stress, which finally ends in cytochrome c release and cell death signaling heart cardiomyocytes.

-Am J Emerg Med. 2015 Sep;33(9):1330.e1-5. doi: 10.1016/j.ajem.2015.03.023. Epub 2015 May 18. Acute cardiomyopathy precipitated by lithium: is there a direct toxic effect on cardiac myocytes? Anantha Narayanan M1, Mahfood Haddad T2, Bansal O3, Baskaran J4, Azzouz MS3, Akinapelli A3, Esterbrooks DJ3.

A patient with typical features of lithium toxicity including sinus bradycardia and junctional rhythm, who, in addition, presented atypical features with diffuse T-wave inversions, QT prolongation, and acute left ventricular systolic dysfunction with serum cardiac marker elevation.

-Drug Saf Case Rep. 2016 Dec;3(1):10. STEMI Secondary to Coronary Vasospasm: Possible Adverse Event of Methylphenidate in a 21-Year-Old Man with ADHD. Baumeister TB1, Wickenbrock I2, Perings CA2.

The case of a 21-year-old man diagnosed with ADHD who recently started therapy with Ritalin® Adult 20 mg for at least 3 days. Afterwards he presented with chest pain, elevated troponin and creatine kinase, and posterolateral ST elevations. A myocarditis was initially supposed. In the coronary angiography, signs of coronary artery spasm could be found. The echocardiography showed mild left ventricular dysfunction; no acute myocarditis could be found in the cardiac MRI and myocardial biopsy. The medication with methylphenidate was stopped, and after 12 days the asymptomatic patient was discharged from hospital.

-Case Rep Pediatr. 2015;2015:905097. doi: 10.1155/2015/905097. Epub 2015 Jun 28. Cardiac Arrest following a Myocardial Infarction in a Child Treated with Methylphenidate. Munk K1, Gormsen L2, Kim WY1, Andersen NH1.

A case with an 11-year-old child, treated with methylphenidate, who suffered cardiac arrest and was diagnosed with a remote myocardial infarction. This demonstrates that myocardial infarction can happen due to methylphenidate exposure in a cardiac healthy child, without cardiovascular risk factors.

But see:

-Atherosclerosis. 2014 Aug;235(2):496-502. doi: 10.1016/j.atherosclerosis.2014.05.918. Epub 2014 Jun 5. Anti-anxiety drugs use and cardiovascular outcomes in patients with myocardial infarction: a national wide assessment. Wu CK1, Huang YT2, Lee JK3, Jimmy Juang JM4, Tsai CT4, Lai LP4, Hwang JJ4, Chiang FT4, Lin JL4, Chen PC5, Lin LY6.

Anti-anxiety medications are independent associated with a decreased risk of cardiac mortality and heart failure hospitalization in patients after a new MI.

-J Cardiovasc Pharmacol. 1994 Jul;24(1):55-8. Antiischemic effects of intravenous diazepam in patients with coronary artery disease. Rossetti E1, Fragasso G, Xuereb RG, Xuereb M, Margonato A, Chierchia SL.

DZP significantly delays onset of exercise-induced myocardial ischemia in patients with coronary artery disease.