Gaba-a receptors and the positive allosteric modulation of the bZs

GABA-A receptors become activated once endogenous GABA molecules bind to them

This allows a conformational change in an adjacent chloride channel, opening an ion pore, allowing negatively charged chloride ions to enter the neuron and hyperpolarize it, and inhibit it from firing

Studies with the BZ diazepam (Valium) in animal models suggest

• – GABA must be bound at the GABA-A receptor for the drug to work

• – Diazepam, when bound simultaneously, actually increases the affinity of the GABA-A receptor for endogenous GABA in the synapse

• – This facilitates increased GABA/GABA-A receptor binding rates and ultimately allows more chloride channels to open, or open more frequently

• – This effect, when a drug binds a receptor and facilitates its usual activity, is called PAM

• – In the case at hand, this action may lower anxiety or improve sleep translationally

• – Facilitating GABA-A receptor activity in the sleep-inducing centers of the brain (VLPO) will increase sleepiness. Enhancing GABA tone in the limbic system may lower anxiety. Depending on the neuroanatomic preference of these drugs (their affinity for certain receptor subtypes in specific brain areas), clinicians may see a difference in anxiolytic versus hypnotic propensity

Gaba-a receptors: desensitization, tachyphylaxis, and tolerance

• After repeated use of alcohol, barbiturates, or BZs, which all bind at the GABA-A receptor, it is often noted that clinical effectiveness may diminish over time or that increasing doses of these agents are required to obtain the same clinical effect found upon initial dosing

• This is called tachyphylaxis or tolerance from a pharmacological point of view

  • – The term tolerance is more often used clinically

• The present case may demonstrate this effect, as the patient was taking chronic, moderate-dose clonazepam (Klonopin), which appeared to require greater doses over time to maintain clinical anxiolytic effectiveness

• Additionally, a cross-tolerance may have developed as he was a non-responder to the GABA-A receptor PAM sleeping agent, zolpidem (Ambien), even at double the approved dose

• It was as if the patient’s GABA-A receptors in his sleep centers did not respond to the zolpidem hypnotic agent, likely as his GABA-A receptors were desensitized

• Or in this case, as GABA-A PAM did not improve sleep, the histaminergic system was next manipulated to improve sleep

Why does this happen?

The subunits shown in the Figure 23.1 include six different alpha isoforms, three different beta isoforms, three different gamma isoforms, delta, epsilon, pi, theta, and three different rho isoforms

The ultimate type and function of each GABA-A receptor subtype will depend on which subunits it contains (Figure 23.1C)

• – BZ-sensitive GABA-A receptors (middle two) contain gamma- and alpha- (1 through 3) subunits and preferentially respond when a patient takes a BZ

• – BZ-sensitive GABA-A receptors containing alpha-1 subunits are involved in sleep induction (second from left), while those that contain alpha-2 and/or alpha-3 subunits are involved more in reducing anxiety (second from right)

• – GABA-A receptors containing alpha-4, alpha-6, gamma-1, or delta subunits (far right) are BZ insensitive

Tolerance to BZ after chronic, repeated exposure may occur when BZ-sensitive gamma subunits are replaced by the individual neuron with more insensitive subunits, i.e., alpha-4 or -6 subunits

Likely, neurons interpret excessive GABA-A PAM as a novel and toxic situation

• – As the brain strives to maintain homeostasis in the face of BZ use, neurons expressing GABA-A receptors likely react when transcription factors become active in neuronal nuclei, turning certain genes off (those that produce gamma subunits) and turning certain genes on (those that make alpha subunits)

• – The net effect over time is that more alpha subunit-based GABA-A receptors are made instead of gamma subunit-based receptors, and sent to the neuronal surface

• – These newer GABA-A receptors are now more often insensitive to BZs that are ingested, and patients may either require higher doses of BZ, or frankly, will stop responding to them

Figure 23.1. Gamma-aminobutyric acid-A (GABA-A) receptors.

A: Shown here are the four transmembrane regions that make up one subunit of a GABA-A receptor. B: There are five copies of these subunits in a fully constituted GABA-A receptor, at the center of which is the chloride channel, or pore. C: Different types of subunits can combine to form a GABA-A receptor.

Posttest self-assessment question and answer

Which of the following antidepressants is also formally approved for treating insomnia?

A. Quetiapine

B. Diphenhydramine

C. Hydroxyzine

D. Trazodone

E. Amitriptyline

F. Doxepin

G. All of the above

H. None of the above

Answer: F

Doxepin (Sinequan) is an antidepressant and also approved at much lower doses as a hypnotic (Silenor). At these low doses, the cardiotoxic and anticholinergic side effects and risks are generally avoided. EKG and plasma level monitoring is not required. Trazodone and amitriptyline are approved antidepressants often used off-label to induce sleep. Hydroxyzine is an antihistamine anxiolytic that may be used off-label as a hypnotic. Quetiapine is an atypical antipsychotic that may induce sleep but is not formally approved as a hypnotic.

References

1.Stahl SM. Stahl’s Essential Psychopharmacology, 4th edn. New York, NY: Cambridge University Press, 2013.

2.Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

3.Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract 2011; 65:189–210.

4.Miller DD. Atypical antipsychotics: sleep, sedation, and efficacy. Primary care companion. J Clin Psychiatry 2004; 6:3–7.

5.Chemerinski E, Ho BC, Flaum M, et al. Insomnia as a predictor for symptom worsening following antipsychotic withdrawal in schizophrenia. Compr Psychiatry 2002; 43:393–6.

6.Masand PS, Schwartz TL, Wang X, et al. Prescribing conventional antipsychotics in the era of novel antipsychotics: informed consent issues. Am J Ther 2002; 9:484–7.

7.Sadock BJ, Sadock VA. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th edn. Philadelphia, PA: Lippincott Williams & Wilkins, 2007.

8.Lavoie AM, Twyman RE. Direct evidence for diazepam modulation of GABA-A receptor microscopic affinity. Neuropharmacology 1996; 35:1383–92.

Patient file

The Case:

The man with greasy hands needs fine tuning

The Question:

What to do with a bizarre side effect

The Dilemma:

Fine tuning polypharmacy treatment

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

Which of the following evidence-based antidepressant augmentations likely has the least side-effect burden?

A. SAMe

B. Lithium carbonate

C. Aripiprazole

D. Thyroid hormone