Pharmacodynamic moment

Atypical antipsychotics and anti-H1 receptor antagonism-induced sedation

There are now many atypical antipsychotics available for use

They may be divided into those with higher or lower EPS rates

They may be divided into those with higher or lower rates of weight gain, hyperlipidemia, or hyperglycemia

Blocking H1 receptors has been well known to cause sedating side effects since psychotropics, such as the TCAs and phenothiazine-based typical antispychotics, were first approved in the 1950s

• – Therefore, the atypical antipsychotics may also be divided into those with more or less sedation, higher or lower antihistamine activity, respectively

The atypical antipsychotics are not immune to this pharmacodynamic property either

Based on affinity for each atypical antipsychotic for antagonizing the H1 receptor, clinicians may be able to predict sedation rates from this class of psychotropics

This table shows the least antihistaminergic atypical antipsychotic at the top and increased anti-H1 receptor antagonism activity at the bottom

Therefore, sedating side effects should increase in theory as you progress down the table

If a patient is sedated on an agent lower in the table, then the clinician could switch to an atypical antipsychotic higher up in the table that is less sedating

This is complicated

• – Antihistaminergic activity is associated with sedation. Some atypical antipsychotics possess increased noradrenergic activity (quetiapine, ziprasidone), which can promote wakefulness

• – Other atypical antipsychotics antagonize NE alpha-1 receptors (iloperidone), which may cause fatigue in addition to the antihistamine effects

• – Tables can help guide clinicians but clinicians must be aware that they do not exist in a vacuum and many of our psychotropics possess multiple pharmacodynamic properties

Table 20.1. Atypical antipsychotics and antihistamine receptor antagonism

Atypical	Affinity for H1
(Ki-value provided by manufacturer where higher values equal lower affinities)
Lurasidone (Latuda)	1000+
Iloperidone (Fanapt)	473
Aripiprazole (Abilify)	61
Ziprasidone (Geodon)	47
Olanzapine (Zyprexa)	7
Risperidone (Risperdal)	5.2
Paliperidone (Invega)	3.4
Quetiapine/norquetiapine (Seroquel)	4.41/1.15
Asenapine (Saphris)	1

*Table reproduced with permission of K. Bedynerman MD, SUNY Upstate Medical University

Pretest self-assessment question and answer

Regarding Lyme disease as a neuropsychiatric illness, which is most accurate?

A. Almost all patients bitten by infected Lyme disease-carrying ticks will develop an easily diagnosable rash

B. Once bitten, most patients will develop clinical Lyme disease

C. Depression as a result of Lyme disease is a common clinical presentation

D. Blood antibody testing is often a definitive diagnosis and should be followed by antibiotic treatment

Answer: D

A sizeable minority of patients do not recognize they have been bitten and a majority of patients will not develop clinical Lyme disease. Depression is a controversial complication of Lyme disease and great variability among infected patients is common. The combination of living in a highly tick-infested geographic area, exhibiting clinical signs and symptoms, and use of blood testing is fairly accurate (albeit not perfect) in diagnosing Lyme disease.

References

1.http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0025348/. Accessed July 15, 2011.

2.Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006; 43:1089–134.

3.Feder HM Jr., Johnson BJ, O’Connell S, et al. A critical appraisal of “chronic Lyme disease.” N Engl J Med 2007; 357:1422–30.

4.Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2007; 69:91–102.

5.http://www.ilads.org/lyme/treatment-guideline.php. Accessed July 15, 2011.

6.Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163:1905–17.

7.Schwartz TL, Siddiqui UA, Raza S, Costello A. Acamprosate calcium as augmentation therapy for anxiety disorders. Ann Pharmacother 2010; 44:1930–2.

8.Bedynerman K, Schwartz TL. Utilizing pharmacodynamic properties of second generation antipsychotics to guide treatment. Drugs of Today 2012; 48:283–92.

Patient file

The Case:

Hindsight is always 20/20, or attention deficit hyperactivity disorder

The Question:

What to do when a primary anxiety disorder is fully treated and inattention remains

The Dilemma:

Residual inattention may be difficult to treat

Pretest self-assessment question (answer at the end of the case)

How does an alpha-2a receptor agonist really improve attention?

A. It lowers brainstem NE output similar to its antihypertensive effects

B. It promotes DA activity in the DLPFC secondarily

C. It lowers GABA activity, which allows greater glutamate activity in the thalamus

D. It allows fine tuning of cortical pyramidal glutamate neurons to improve signal to noise ratios in frontocortical information processing