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27 August 2015

Assessing the effects of cardiovascular drugs on cognition

It is becoming increasingly accepted that side-effects of medication for both central nervous system (CNS) and non-CNS diseases could include cognitive impairment but why should we assess the effects of cognition specifically in cardiovascular drugs?

Key points:

  • Medication for CNS and non-CNS disease could have an effect on cognition
  • The extent of side effects of medication on cognition has not been thoroughly examined previously
  • RCTs with objective cognitive endpoints are needed
  • Objective cognitive assessment is now possible with Cantab Connect

It is becoming increasingly accepted that side-effects of medication for both central nervous system (CNS) and non-CNS diseases could include cognitive impairment such as memory loss and confusion, and self-reports of perceived cognitive problems by patients is becoming more and more frequent. There are several studies that associate medications developed specifically for cardiovascular disease with cognitive or neuropsychiatric consequences1, however the extent of these consequences have not been thoroughly examined. There are several reasons for this, including:

  • A lack of sensitive and standardized cognitive assessment tools that can be implemented during the drug development process to determine a drug’s impact to cognition early on. Few randomized control trials (RCT) are designed to examine these associations, resulting in a tendency to rely on case reports and self-reported adverse events (AE) to record cases of cognitive impairment, meaning that prevalence of impairments associated with medication may be seriously underestimated.
  • Cognitive or neuropsychiatric syndromes can often form part of a patient’s underlying cardiac illness (for example, depression, anxiety, delirium), therefore self-reported AEs and post-marketing studies may simply be picking up symptoms of disease progression. Until the cognitive impairments associated with non-central nervous system diseases are determined, it is difficult to differentiate whether reported cognitive impairments are associated with medication or underlying disease.
  • To improve our knowledge about the relationship between diseases and their treatments, and their effects on cognitive function, more RCTs with objective cognitive endpoints are needed. This would enable characterization of a drug’s cognitive profile before it is brought to market and appropriate label claims can be made to inform the public of the potential cognitive effects. For example beta blockers are often associated with depression by physicians1. This is because, particularly small lipophilic molecules such as Propranolol, can easily permeate the blood brain barrier and affect cognition. However, recent randomized control trials and large meta-analyses that included objective cognitive assessments have failed to support these long-held associations, causing controversy in this area. These more recent trials have shown that beta-blockers are in fact often associated with positive cognitive benefits and are used to treat anxiety2, aggression3 and even reduce the risk of post-traumatic stress disorder4.

A recent example of post-marketing AE reports directly resulting in safety label changes is that of a class of cholesterol-lowering drugs, known as statins. Rare reports of cognitive impairments associated with statins caused the U.S. Food and Drug Administration (FDA) to approve important safety label changes in 2012 informing the public of the possible cognitive adverse effects of statins, also stating that “symptoms are generally not serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks)”5. This rather vague statement supports the need for more targeted RCTs to accurately determine the extent of the adverse effects.

In 2014 a paper in the Journal of Pharmacovigilance conducted a review to investigate effects of statin types in association with reports of cognitive dysfunction using the FDA’s Adverse Event Reporting System (AERS), and gauge the generalizability of the FDA mandated statins warning6. Incidences of cognitive dysfunction (including amnesia, memory impairment, confusion and delusion) were recorded in 1.7% of the AE reports. Interestingly, a Cochrane review of four available RCTs examining the potential beneficial effects of statins in subjects in patients with Alzheimer’s disease found no effect of these medications (positive or negative) on cognition, behavior or activities of daily living7. In order to address these disparate finds on the modulation of cholesterol metabolism in different patient populations, clinical trials that are evaluating new cholesterol lowering drugs will likely be required to include objective cognitive assessments in order to determine what, if any, effects on cognition they may have.These trials would benefit from cognitive safety and efficacy assessments throughout all stages of clinical development. CANTAB cognitive assessments have been used for over 30 years in over 150 clinical trials and use cloud technology on an iPad making testing quicker, easier and more reliable.

Find out more about using CANTAB in drug development.


1Huffman, J.C. & Stern, T.A., (2007), Neuropsychiatric consequences of cardiovascular medications, Dialogues in Clinical Neuroscience, 9(1), 29-45

2Hirschmann, S., Dannon, P.N., Iancu, I., Dolberg, O.T., Zohar, J. & Grunhaus, L., (2000), Pindolol augmentation in patients with treatment-resistant panic disorder: A double-blind, placebo-controlled trial. Journal of Clinical Psychopharmacology, 20, 556- 559.

3Haspel, T., (1995), Beta-blockers and the treatment of aggression. Harvard Review of Psychiatry, 2, 274-281.

4Vaiva, G., Ducrocq, F., Jezequel, K., et al., (2003), Immediate treatment with pro- pranolol decreases posttraumatic stress disorder two months after trauma, Biological Psychiatry, 54, 947-949. Erratum in: Biological Psychiatry, 2003, 54:1471.


6Sahebzamani, F.M., Munro, C.L., Marroquin, O.C., Keller, E. & Kip, K.E., (2012), Examination of the FDA Warning for Statins and Cognitive Dysfunction, Journal of Pharmacovigilance, 2:4

7McGuinness, B., Craig, D., Bullock, R., Malouf, R. & Passmore, P., (2014) Statins for the treatment of dementia, Cochrane Database Systematic Review, 7:CD007514. 

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