Evidence-Based Reviews

Serotonin-mediated anxiety: How to recognize and treat it

Current Psychiatry. 2021 November;20(11):37-40 | doi: 10.12788/cp.0168

References

1. Shelton CI. Diagnosis and management of anxiety disorders. J Am Osteopath Assoc. 2004;104(3 Suppl 3):S2-S5.

2. Ruscio AM, Hallion LS, Lim CCW, et al. Cross-sectional comparison of the epidemiology of DSM-5 generalized anxiety disorder across the globe. JAMA Psychiatry. 2017;74(5):465-475.

3. Locke AB, Kirst N, Shultz CG. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am Fam Physician. 2015;91(9):617-624.

4. Hariri AR, Mattay VS, Tessitore A, et al. Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology. 2002;27(6):1036-1040.

5. Colombo AC, de Oliveira AR, Reimer AE, et al. Dopaminergic mechanisms underlying catalepsy, fear and anxiety: do they interact? Behav Brain Res. 2013;257:201-207.

6. Togay B, El-Mallakh RS. Posttraumatic stress disorder: from pathophysiology to pharmacology. Curr Psychiatry. 2020;19(5):33-39.

7. Provensi G, Passani MB, Costa A, et al. Neuronal histamine and the memory of emotionally salient events. Br J Pharmacol. 2020;177(3):557-569.

8. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 2nd ed. Sinauer Associates; 2001.

9. Pytliak M, Vargová V, Mechírová V, et al. Serotonin receptors – from molecular biology to clinical applications. Physiol Res. 2011;60(1):15-25.

10. Meneses A, Liy-Salmeron G. Serotonin and emotion, learning and memory. Rev Neurosci. 2012;23(5-6):543-553.

11. Whitaker-Azmitia PM. Serotonin and brain development: role in human developmental diseases. Brain Res Bull. 2001;56(5):479-485.

12. Towle AC, Breese GR, Mueller RA, et al. Early postnatal administration of 5,7-DHT: effects on serotonergic neurons and terminals. Brain Res. 1984;310(1):67-75.

13. Rok-Bujko P, Krzs´cik P, Szyndler J, et al. The influence of neonatal serotonin depletion on emotional and exploratory behaviours in rats. Behav Brain Res. 2012;226(1):87-95.

14. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology. 1999;21(2 Suppl):106S-115S.

15. Calabrese EJ. 5-Hydroxytryptamine (serotonin): biphasic dose responses. Crit Rev Toxicol. 2001;31(4-5):553-561.

16. Zuardi AW. 5-HT-related drugs and human experimental anxiety. Neurosci Biobehav Rev. 1990;14(4):507-510.

17. Sánchez C, Meier E. Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike? Psychopharmacology (Berl). 1997;129(3):197-205.

18. Koek W, Mitchell NC, Daws LC. Biphasic effects of selective serotonin reuptake inhibitors on anxiety: rapid reversal of escitalopram’s anxiogenic effects in the novelty-induced hypophagia test in mice? Behav Pharmacol. 2018;29(4):365-369.

19. van Zijderveld GA, Veltman DJ, van Dyck R, et al. Epinephrine-induced panic attacks and hyperventilation. J Psychiatr Res. 1999;33(1):73-78.

20. Ho EV, Thompson SL, Katzka WR, et al. Clinically effective OCD treatment prevents 5-HT1B receptor-induced repetitive behavior and striatal activation. Psychopharmacology (Berl). 2016;233(1):57-70.

21. Stein DJ, Costa DLC, Lochner C, et al. Obsessive-compulsive disorder. Nat Rev Dis Primers. 2019;5(1):52.

22. Luddington NS, Mandadapu A, Husk M, et al. Clinical implications of genetic variation in the serotonin transporter promoter region: a review. Prim Care Companion J Clin Psychiatry. 2009;11(3):93-102.

23. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215-235.

24. Chaouloff F, Berton O, Mormède P. Serotonin and stress. Neuropsychopharmacology. 1999;21(2 Suppl):28S-32S.

25. Siafis S, Tzachanis D, Samara M, et al. Antipsychotic drugs: From receptor-binding profiles to metabolic side effects. Curr Neuropharmacol. 2018;16(8):1210-1223.

26. Carrithers B, El-Mallakh RS. Transdermal asenapine in schizophrenia: a systematic review. Patient Prefer Adherence. 2020;14:1541-1551.

27. Citrome L. Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol. 2014;10(6):893-903.

28. Pratts M, Citrome L, Grant W, et al. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130(1):61-68.

29. Biswas AB, Bhaumik S, Branford D. Treatment-emergent behavioural side effects with selective serotonin re-uptake inhibitors in adults with learning disabilities. Hum Psychopharmacol. 2001;16(2):133-137.

30. Perlis RH, Mischoulon D, Smoller JW, et al. Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry. 2003;54(9):879-883.

31. Ipser JC, Carey P, Dhansay Y, et al. Pharmacotherapy augmentation strategies in treatment-resistant anxiety disorders. Cochrane Database Syst Rev. 2006;(4):CD005473.

32. Kane JM, Mackle M, Snow-Adami L, et al. A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. J Clin Psychiatry. 2011;72(3):349-355.

33. Bozzatello P, Rocca P, Uscinska M, et al. Efficacy and tolerability of asenapine compared with olanzapine in borderline personality disorder: an open-label randomized controlled trial. CNS Drugs. 2017;31(9):809-819.

34. El-Mallakh RS, Nuss S, Gao D, et al. Asenapine in the treatment of bipolar depression. Psychopharmacol Bull. 2020;50(1):8-18.

A key difference: No motor system involvement

What distinguishes 5-HT from the other amine transmitters as a mediator of anxiety is the lack of involvement of the motor system. Multiple studies in rats illustrate that exogenously augmenting 5-HT has no effect on levels of locomotor activity. Dopamine depletion is well-characterized in the motor dysfunction of Parkinson’s disease, and DA excess can cause repetitive, stereotyped movements, such as seen in tardive dyskinesia or Huntington’s disease.⁸ In humans, serotonin-mediated anxiety is usually without a motoric component; patients appear calm but complain of extreme anxiety or agitation. Agitation has been reported after initiation of an SSRI,²⁹ and is more likely to occur in patients with the short form of the 5-HT transporter.³⁰ Motoric activation has been reported in some of these studies, but does not seem to cluster with the complaint of agitation.²⁹ The reduced number of available transporters means a chronic steady-state elevation of serotonin, because less serotonin is being removed from the synapse after it is released. This is one of the reasons patients with the short form of the 5-HT transporter may be more susceptible to serotonin-mediated anxiety.

What you need to keep in mind

Pharmacologic treatment of anxiety begins with an SSRI, a serotonin-norepinephrine reuptake inhibitor (SNRI), or buspirone. Second-line treatments include hydroxyzine, gabapentin, pregabalin, and quetiapine.^3,31 However, clinicians need to be aware that a fraction of their patients will report anxiety that will not have any external manifestations, but will be experienced as an unpleasant internal energy. These patients may report an increase in their anxiety levels when started on an SSRI or SNRI.^29,30 This anxiety is most likely mediated by increases of synaptic 5-HT. This occurs because many serotonergic receptors may have a biphasic response, so that too much stimulation is experienced as excessive internal energy.^16-18 In such patients, blockade of key 5-HT receptors may reduce that internal agitation. The advantage of recognizing serotonin-mediated anxiety is that one can specifically tailor treatment to address the patient’s specific physiology.

It is important to note that the anxiolytic effect of asenapine is specific to patients with serotonin-mediated anxiety. Unlike quetiapine, which is effective as augmentation therapy in generalized anxiety disorder,³¹ asenapine does not appear to reduce anxiety in patients with schizophrenia³² or borderline personality disorder³³ when administered for other reasons. However, it may reduce anxiety in patients with the short form of the 5-HT transporter.^30,34

Bottom Line

Serotonin-mediated anxiety occurs when levels of synaptic serotonin (5-HT) are high. Patients with serotonin-mediated anxiety appear calm but will report experiencing an unpleasant internal energy. Interventions that block multiple postsynaptic 5-HT receptors or discontinuation of a selective serotonin reuptake inhibitor (if applicable) will alleviate the anxiety.

Related Resource

• Bhatt NV. Anxiety disorders. https://emedicine.medscape. com/article/286227-overview

Drug Brand Names

Asenapine • Saphris, Secuado

Gabapentin • Neurontin

Hydroxyzine • Vistaril

Pregabalin • Lyrica

Quetiapine • Seroquel

Trazodone • Oleptro

References

1. Shelton CI. Diagnosis and management of anxiety disorders. J Am Osteopath Assoc. 2004;104(3 Suppl 3):S2-S5.

2. Ruscio AM, Hallion LS, Lim CCW, et al. Cross-sectional comparison of the epidemiology of DSM-5 generalized anxiety disorder across the globe. JAMA Psychiatry. 2017;74(5):465-475.

3. Locke AB, Kirst N, Shultz CG. Diagnosis and management of generalized anxiety disorder and panic disorder in adults. Am Fam Physician. 2015;91(9):617-624.

4. Hariri AR, Mattay VS, Tessitore A, et al. Dextroamphetamine modulates the response of the human amygdala. Neuropsychopharmacology. 2002;27(6):1036-1040.

5. Colombo AC, de Oliveira AR, Reimer AE, et al. Dopaminergic mechanisms underlying catalepsy, fear and anxiety: do they interact? Behav Brain Res. 2013;257:201-207.

6. Togay B, El-Mallakh RS. Posttraumatic stress disorder: from pathophysiology to pharmacology. Curr Psychiatry. 2020;19(5):33-39.

7. Provensi G, Passani MB, Costa A, et al. Neuronal histamine and the memory of emotionally salient events. Br J Pharmacol. 2020;177(3):557-569.

8. Purves D, Augustine GJ, Fitzpatrick D, et al (eds). Neuroscience. 2nd ed. Sinauer Associates; 2001.

9. Pytliak M, Vargová V, Mechírová V, et al. Serotonin receptors – from molecular biology to clinical applications. Physiol Res. 2011;60(1):15-25.

10. Meneses A, Liy-Salmeron G. Serotonin and emotion, learning and memory. Rev Neurosci. 2012;23(5-6):543-553.

11. Whitaker-Azmitia PM. Serotonin and brain development: role in human developmental diseases. Brain Res Bull. 2001;56(5):479-485.

12. Towle AC, Breese GR, Mueller RA, et al. Early postnatal administration of 5,7-DHT: effects on serotonergic neurons and terminals. Brain Res. 1984;310(1):67-75.

13. Rok-Bujko P, Krzs´cik P, Szyndler J, et al. The influence of neonatal serotonin depletion on emotional and exploratory behaviours in rats. Behav Brain Res. 2012;226(1):87-95.

14. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology. 1999;21(2 Suppl):106S-115S.

15. Calabrese EJ. 5-Hydroxytryptamine (serotonin): biphasic dose responses. Crit Rev Toxicol. 2001;31(4-5):553-561.

16. Zuardi AW. 5-HT-related drugs and human experimental anxiety. Neurosci Biobehav Rev. 1990;14(4):507-510.

17. Sánchez C, Meier E. Behavioral profiles of SSRIs in animal models of depression, anxiety and aggression. Are they all alike? Psychopharmacology (Berl). 1997;129(3):197-205.

18. Koek W, Mitchell NC, Daws LC. Biphasic effects of selective serotonin reuptake inhibitors on anxiety: rapid reversal of escitalopram’s anxiogenic effects in the novelty-induced hypophagia test in mice? Behav Pharmacol. 2018;29(4):365-369.

19. van Zijderveld GA, Veltman DJ, van Dyck R, et al. Epinephrine-induced panic attacks and hyperventilation. J Psychiatr Res. 1999;33(1):73-78.

20. Ho EV, Thompson SL, Katzka WR, et al. Clinically effective OCD treatment prevents 5-HT1B receptor-induced repetitive behavior and striatal activation. Psychopharmacology (Berl). 2016;233(1):57-70.

21. Stein DJ, Costa DLC, Lochner C, et al. Obsessive-compulsive disorder. Nat Rev Dis Primers. 2019;5(1):52.

22. Luddington NS, Mandadapu A, Husk M, et al. Clinical implications of genetic variation in the serotonin transporter promoter region: a review. Prim Care Companion J Clin Psychiatry. 2009;11(3):93-102.

23. Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51(3):215-235.

24. Chaouloff F, Berton O, Mormède P. Serotonin and stress. Neuropsychopharmacology. 1999;21(2 Suppl):28S-32S.

25. Siafis S, Tzachanis D, Samara M, et al. Antipsychotic drugs: From receptor-binding profiles to metabolic side effects. Curr Neuropharmacol. 2018;16(8):1210-1223.

26. Carrithers B, El-Mallakh RS. Transdermal asenapine in schizophrenia: a systematic review. Patient Prefer Adherence. 2020;14:1541-1551.

27. Citrome L. Asenapine review, part I: chemistry, receptor affinity profile, pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol. 2014;10(6):893-903.

28. Pratts M, Citrome L, Grant W, et al. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130(1):61-68.

29. Biswas AB, Bhaumik S, Branford D. Treatment-emergent behavioural side effects with selective serotonin re-uptake inhibitors in adults with learning disabilities. Hum Psychopharmacol. 2001;16(2):133-137.

30. Perlis RH, Mischoulon D, Smoller JW, et al. Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment. Biol Psychiatry. 2003;54(9):879-883.

31. Ipser JC, Carey P, Dhansay Y, et al. Pharmacotherapy augmentation strategies in treatment-resistant anxiety disorders. Cochrane Database Syst Rev. 2006;(4):CD005473.

32. Kane JM, Mackle M, Snow-Adami L, et al. A randomized placebo-controlled trial of asenapine for the prevention of relapse of schizophrenia after long-term treatment. J Clin Psychiatry. 2011;72(3):349-355.

33. Bozzatello P, Rocca P, Uscinska M, et al. Efficacy and tolerability of asenapine compared with olanzapine in borderline personality disorder: an open-label randomized controlled trial. CNS Drugs. 2017;31(9):809-819.

34. El-Mallakh RS, Nuss S, Gao D, et al. Asenapine in the treatment of bipolar depression. Psychopharmacol Bull. 2020;50(1):8-18.

Serotonin-mediated anxiety: How to recognize and treat it

References

A key difference: No motor system involvement

What you need to keep in mind

Bottom Line

Related Resource

Drug Brand Names

Pages

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