Skip to main content
SpringerLink
Log in

Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance

  • Original Paper
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Objective

There is evidence of more widespread use and abuse of benzodiazepines (BZPs) among elderly women. However, factors underlying this observation are poorly understood but could be related to more intense withdrawal reactions, which are a major risk factor for continued BZP use. We previously reported elevations in interdose morning plasma cortisol levels in healthy elderly individuals after chronic treatment with alprazolam, possibly consistent with increased hypothalamic–pituitary–adrenal (HPA) axis activity and drug withdrawal. In this study, we examined sex-related differences in this population.

Method

Twenty-five cognitively intact healthy elderly (13 women and 12 men) participated in a parallel, double-blind, placebo-controlled study that included a group that received acute and chronic (3 weeks) treatment with alprazolam (0.5 mg b.i.d.).

Results

Elderly women, but not men, experienced significant elevations in interdose morning plasma cortisol levels over 3 weeks of chronic treatment with alprazolam (0.5 mg b.i.d.) compared to placebo. In addition, higher morning plasma cortisol levels were significantly associated with better cognitive performance but not with higher plasma drug levels or greater degree of tolerance development to an acute alprazolam challenge.

Conclusion

Elderly females experienced a greater interdose activation of the HPA axis during treatment with therapeutic doses of alprazolam than men, which could be related to drug withdrawal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • American Psychiatric Association (1987) DSM-III-R: diagnostic and statistical manual of mental disorders, 3rd edn, revised. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Berchou R, Block RI (1983) Use of computerized psychomotor testing in determining CNS effects of drugs. Percept Mot Skills 57:691–700

    PubMed  CAS  Google Scholar 

  • Biggio G, Dazzi L, Biggio F, Mancuso L, Talani G, Busonero F, Mostallino MC, Sanna EE, Follesa P (2003) Molecular mechanisms of tolerance to and withdrawal of GABA(A) receptor modulators. Eur Neuropsychopharmacol 13:411–423

    Article  PubMed  CAS  Google Scholar 

  • Blank T, Nijholt I, Eckart K, Spiess J (2002) Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J Neurosci 22:3788–3794

    PubMed  CAS  Google Scholar 

  • Buschke H, Fuld PA (1974) Evaluating storage, retention, and retrieval in disordered memory and learning. Neurology 24:1019–1025

    PubMed  CAS  Google Scholar 

  • Cole JO, Kando JC (1993) Adverse behavioral events reported in patients taking alprazolam and other benzodiazepines. J Clin Psychiatry 54(Suppl):49–61

    PubMed  Google Scholar 

  • Cotreau MM, von Moltke LL, Greenblatt DJ (2005) The influence of age and sex on the clearance of cytochrome P450 3A substrates. Clin Pharmacokinet 44:33–60

    Article  PubMed  CAS  Google Scholar 

  • Fingerhood M (2000) Substance abuse in older people. J Am Geriatr Soc 48:985–995

    PubMed  CAS  Google Scholar 

  • Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF (2004) Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44:499–523

    Article  PubMed  CAS  Google Scholar 

  • Grant SJ, Galloway MP, Mayor R, Fenerty JP, Finkelstein MF, Roth RH, Redmond DE Jr (1985) Precipitated diazepam withdrawal elevates noradrenergic metabolism in primate brain. Eur J Pharmacol 107:127–132

    Article  PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Javaid JI, Locniskar A, Harmatz JS, Shader RI (1990) Gas chromatographic analysis of alprazolam in plasma: replicability, stability, and specificity. J Chromatogr 534:202–207

    Article  PubMed  CAS  Google Scholar 

  • Greenblatt DJ, Harmatz JS, von Moltke LL, Wright CE, Shader RI (2004) Age and sex effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin Pharmacol Ther 76:467–479

    Article  PubMed  CAS  Google Scholar 

  • Hallstrom C, Lader M (1981) Benzodiazepine withdrawal phenomena. Int Pharmacopsychiatry 16:235–244

    PubMed  CAS  Google Scholar 

  • Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol 32:52–55

    Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62

    PubMed  CAS  Google Scholar 

  • Heinrichs SC, Koob GF (2004) Corticotropin-releasing factor in brain: a role in activation, arousal, and affect regulation. J Pharmacol Exp Ther 311:427–440. Epub 2004 Aug 5

    Article  PubMed  CAS  Google Scholar 

  • Herman JB, Brotman AW, Rosenbaum JF (1987) Rebound anxiety in panic disorder patients treated with shorter-acting benzodiazepines. J Clin Psychiatry 48 Suppl:22–28

    PubMed  Google Scholar 

  • Holroyd S, Duryee JJ (1997) Substance use disorders in a geriatric psychiatry outpatient clinic: prevalence and epidemiologic characteristics. J Nerv Ment Dis 185:627–632

    Article  PubMed  CAS  Google Scholar 

  • Kales A, Soldatos CR, Bixler EO, Kales JD (1983) Early morning insomnia with rapidly eliminated benzodiazepines. Science 220:95–97

    Article  PubMed  CAS  Google Scholar 

  • Kales A, Bixler EO, Vela-Bueno A, Soldatos CR, Manfredi RL (1987) Alprazolam: effects on sleep and withdrawal phenomena. J Clin Pharmacol 27:508–515

    PubMed  CAS  Google Scholar 

  • Mellman TA, Uhde TW (1986) Withdrawal syndrome with gradual tapering of alprazolam. Am J Psychiatry 143:1464–1466

    PubMed  CAS  Google Scholar 

  • Miller LG, Woolverton S, Greenblatt DJ, Lopez F, Roy RB, Shader RI (1989) Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration. Biochem Pharmacol 38:3773–3777

    Article  PubMed  CAS  Google Scholar 

  • Newcomer JW, Selke G, Melson AK, Hershey T, Craft S, Richards K, Alderson AL (1999) Decreased memory performance in healthy humans induced by stress-level cortisol treatment. Arch Gen Psychiatry 56:527–533

    Article  PubMed  CAS  Google Scholar 

  • Noyes R Jr, Clancy J, Coryell WH, Crowe RR, Chaudhry DR, Domingo DV (1985) A withdrawal syndrome after abrupt discontinuation of alprazolam. Am J Psychiatry 142:114–116

    PubMed  Google Scholar 

  • Noyes R Jr, Garvey MJ, Cook BL, Perry PJ (1988) Benzodiazepine withdrawal: a review of the evidence. J Clin Psychiatry 49:382–389

    PubMed  Google Scholar 

  • Owens MJ, Vargas MA, Knight DL, Nemeroff CB (1991) The effects of alprazolam on corticotropin-releasing factor neurons in the rat brain: acute time course, chronic treatment and abrupt withdrawal. J Pharmacol Exp Ther 258:349–356

    PubMed  CAS  Google Scholar 

  • Pesce ME, Acevedo X, Pinardi G, Miranda HF (1994) Sex differences in diazepam withdrawal syndrome in mice. Pharmacol Toxicol 75:353–355

    Article  PubMed  CAS  Google Scholar 

  • Pires JG, Monteiro KC, Alvarenga SO, Costa MG, Gomes MA, Futuro-Neto HA (1998) Evidence suggesting that gonadal hormones influence benzodiazepine withdrawal-induced weight loss in rats. Prog Neuro-psychopharmacol Biol Psychiatry 22:425–433

    Article  CAS  Google Scholar 

  • Pomara N, Tun H, DaSilva D, Hernando R, Deptula D, Greenblatt DJ (1998) The acute and chronic performance effects of alprazolam and lorazepam in the elderly: relationship to duration of treatment and self-rated sedation. Psychopharmacol Bull 34:139–153

    PubMed  CAS  Google Scholar 

  • Pomara N, Willoughby LM, Ritchie JC, Sidtis JJ, Greenblatt DJ, Nemeroff CB (2004) Interdose elevation in plasma cortisol during chronic treatment with alprazolam but not lorazepam in the elderly. Neuropsychopharmacology 29:605–611

    Article  PubMed  CAS  Google Scholar 

  • Ritchie JC, Carroll BJ, Olton PR, Shively V, Feinberg M (1985) Plasma cortisol determination for the dexamethasone suppression test. Comparison of competitive protein-binding and commercial radioimmunoassay methods. Arch Gen Psychiatry 42:493–497

    PubMed  CAS  Google Scholar 

  • Roozendaal B, Brunson KL, Holloway BL, McGaugh JL, Baram TZ (2002) Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation. Proc Natl Acad Sci U S A 99:13908–13. Epub 2002 Oct 02

    Article  PubMed  CAS  Google Scholar 

  • Schweizer E, Rickels K (1998) Benzodiazepine dependence and withdrawal: a review of the syndrome and its clinical management. Acta Psychiatr Scand Suppl 393:95–101

    Article  PubMed  CAS  Google Scholar 

  • Skelton KH, Nemeroff CB, Knight DL, Owens MJ (2000) Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. J Neurosci 20:1240–1248

    PubMed  CAS  Google Scholar 

  • Skelton KH, Nemeroff CB, Owens MJ (2004) Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression. J Neurosci 24:9303–9312

    Article  PubMed  CAS  Google Scholar 

  • Stock H, Ford K, Biscardi R, Wilson MA (1999) Lack of sex differences in anxiety behaviors during precipitated benzodiazepine withdrawal in rats. Physiol Behav 66:125–130

    Article  PubMed  CAS  Google Scholar 

  • Szwabo PA (1993) Substance abuse in older women. Clin Geriatr Med 9:197–208

    PubMed  CAS  Google Scholar 

  • Uhart M, McCaul ME, Oswald LM, Choi L, Wand GS (2004) GABRA6 gene polymorphism and an attenuated stress response. Mol Psychiatry 9:998–1006

    Article  PubMed  CAS  Google Scholar 

  • Wechsler D (1945) A standardized memory scale for clinical use. J Psychol 19:87–95

    Google Scholar 

  • Wechsler D (1981) WAIS-revised manual. The Psychological Corporation, Cleveland, OH

    Google Scholar 

  • Widlitz M, Marin DB (2002) Substance abuse in older adults: an overview. Geriatrics 57:29–34

    PubMed  Google Scholar 

  • Wilson MA, Biscardi R (1992) Effects of sex and gonadectomy on responses to chronic benzodiazepine receptor agonist exposure in rats. Eur J Pharmacol 215:99–107

    Article  PubMed  CAS  Google Scholar 

  • Wilson MA, Biscardi R (1993) Divergent alterations in gamma-aminobutyric acid responses of male and ovariectomized rats after chronic benzodiazepine agonist exposure: analysis of gamma-aminobutyric acid-activated chloride influx. J Pharmacol Exp Ther 266:768–773

    PubMed  CAS  Google Scholar 

  • Wilson MA, Biscardi R, Smith MD, Wilson SP (1996) Effects of benzodiazepine agonist exposure on corticotropin-releasing factor content and hormonal stress responses: divergent responses in male and ovariectomized female rats. J Pharmacol Exp Ther 278:1073–1082

    PubMed  CAS  Google Scholar 

  • Woods JH, Katz JL, Winger G (1992) Benzodiazepines: use, abuse, and consequences. Pharmacol Rev 44:151–347

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported in part by grant R01 MH42499 (N.P.), MH42088 (C.B.N.), DA-05258 (D.J.G.), and MH52899 (C.B.N.).

Author information

Authors and Affiliations

  1. Geriatric Psychiatry Program, Nathan S. Kline Institute, 140 Old Orangeburg Road, Building 35, Orangeburg, NY, 10962, USA

    Nunzio Pomara, Lisa M. Willoughby & John J. Sidtis

  2. Department of Psychiatry, New York University School of Medicine, New York, NY, USA

    Nunzio Pomara, Lisa M. Willoughby & John J. Sidtis

  3. Department of Pathology, Emory School of Medicine, Atlanta, GA, USA

    James C. Ritchie

  4. Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA

    David J. Greenblatt

  5. Department of Psychiatry, Emory School of Medicine, Atlanta, GA, USA

    Charles B. Nemeroff

Authors
  1. Nunzio Pomara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa M. Willoughby
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James C. Ritchie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John J. Sidtis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David J. Greenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Charles B. Nemeroff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nunzio Pomara.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pomara, N., Willoughby, L.M., Ritchie, J.C. et al. Sex-related elevation in cortisol during chronic treatment with alprazolam associated with enhanced cognitive performance. Psychopharmacology 182, 414–419 (2005). https://doi.org/10.1007/s00213-005-0088-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-005-0088-2

Keywords

Search

Navigation