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Never gonna give you up: Intrusive musical imagery as compulsions
Intrusive musical imagery (IMI) is characterized by recalling pieces of music,1 usually repetitions of 15 to 30 seconds,2 without pathology of the ear or nervous system.1 Also known as earworm—ohrwurm in German—or involuntary musical imagery, bits of music can become a constant cause of distress.1
IMI is prevalent in the general population; in an internet survey >85% of respondents reported experiencing IMI at least weekly.2 IMI can be generated by:
- hearing music
- reading song lyrics
- being in contact with an environment or people who are linked to specific song, such as department stores that play holiday music.2,3
IMI also is associated with stressful situations or neurological insult.1
Any song or segment of music can be the basis of IMI. The content of IMI change over time (ie, a new song can become a source of IMI).3 The frequency of experiencing IMI is correlated to how much music a person is exposed to and the importance a person places on music.2 Most episodes are intermittent; however, continuous musical episodes are known to occur.3 Episodes of IMI with obsessive-compulsive features can be classified as musical obsessions (MO).1 MO may be part of obsessive-compulsive symptoms, including washing, checking, aggression, sexual obsessions, and religious obsessions or other obsessions.1
Diagnosing musical obsessions
No current measures are adequate to diagnose MO. The Yale-Brown Obsessive Compulsive Scale does not distinguish MO from other intrusive auditory imagery.1
It is important to differentiate MO from:
- Musical preoccupations or recollections in which an individual repeatedly listens or recalls a particular song or part of a song, but does not have the urge to listen or recall music in an obsessive-compulsive pattern.1 These individuals do not display fear and avoidant behaviors that could be seen in patients with MO.1
- Musical hallucinations lack an input stimulus and the patient believes the music comes from an outside source and interprets it as reality. Misdiagnosing MO as a psychotic symptom is common and can result in improper treatment.1
Management
Pharmacotherapy. MO responds to the same medications used to treat obsessive-compulsive disorder, such as selective serotonin reuptake inhibitors and clomipramine.1 Cognitive-behavioral interventions could help patients address dysfunctional beliefs, without trying to suppress them.1
Distraction. Encourage patients to sing a different song that does not have obsessive quality1 or engage in a task that uses working memory.3
Exposure and response prevention therapy. Some case reports have reported efficacy in treating MO.1
1. Taylor S, McKay D, Miguel EC, et al. Musical obsessions: a comprehensive review of neglected clinical phenomena. J Anxiety Disord. 2014;28(6):580-589.
Intrusive musical imagery (IMI) is characterized by recalling pieces of music,1 usually repetitions of 15 to 30 seconds,2 without pathology of the ear or nervous system.1 Also known as earworm—ohrwurm in German—or involuntary musical imagery, bits of music can become a constant cause of distress.1
IMI is prevalent in the general population; in an internet survey >85% of respondents reported experiencing IMI at least weekly.2 IMI can be generated by:
- hearing music
- reading song lyrics
- being in contact with an environment or people who are linked to specific song, such as department stores that play holiday music.2,3
IMI also is associated with stressful situations or neurological insult.1
Any song or segment of music can be the basis of IMI. The content of IMI change over time (ie, a new song can become a source of IMI).3 The frequency of experiencing IMI is correlated to how much music a person is exposed to and the importance a person places on music.2 Most episodes are intermittent; however, continuous musical episodes are known to occur.3 Episodes of IMI with obsessive-compulsive features can be classified as musical obsessions (MO).1 MO may be part of obsessive-compulsive symptoms, including washing, checking, aggression, sexual obsessions, and religious obsessions or other obsessions.1
Diagnosing musical obsessions
No current measures are adequate to diagnose MO. The Yale-Brown Obsessive Compulsive Scale does not distinguish MO from other intrusive auditory imagery.1
It is important to differentiate MO from:
- Musical preoccupations or recollections in which an individual repeatedly listens or recalls a particular song or part of a song, but does not have the urge to listen or recall music in an obsessive-compulsive pattern.1 These individuals do not display fear and avoidant behaviors that could be seen in patients with MO.1
- Musical hallucinations lack an input stimulus and the patient believes the music comes from an outside source and interprets it as reality. Misdiagnosing MO as a psychotic symptom is common and can result in improper treatment.1
Management
Pharmacotherapy. MO responds to the same medications used to treat obsessive-compulsive disorder, such as selective serotonin reuptake inhibitors and clomipramine.1 Cognitive-behavioral interventions could help patients address dysfunctional beliefs, without trying to suppress them.1
Distraction. Encourage patients to sing a different song that does not have obsessive quality1 or engage in a task that uses working memory.3
Exposure and response prevention therapy. Some case reports have reported efficacy in treating MO.1
Intrusive musical imagery (IMI) is characterized by recalling pieces of music,1 usually repetitions of 15 to 30 seconds,2 without pathology of the ear or nervous system.1 Also known as earworm—ohrwurm in German—or involuntary musical imagery, bits of music can become a constant cause of distress.1
IMI is prevalent in the general population; in an internet survey >85% of respondents reported experiencing IMI at least weekly.2 IMI can be generated by:
- hearing music
- reading song lyrics
- being in contact with an environment or people who are linked to specific song, such as department stores that play holiday music.2,3
IMI also is associated with stressful situations or neurological insult.1
Any song or segment of music can be the basis of IMI. The content of IMI change over time (ie, a new song can become a source of IMI).3 The frequency of experiencing IMI is correlated to how much music a person is exposed to and the importance a person places on music.2 Most episodes are intermittent; however, continuous musical episodes are known to occur.3 Episodes of IMI with obsessive-compulsive features can be classified as musical obsessions (MO).1 MO may be part of obsessive-compulsive symptoms, including washing, checking, aggression, sexual obsessions, and religious obsessions or other obsessions.1
Diagnosing musical obsessions
No current measures are adequate to diagnose MO. The Yale-Brown Obsessive Compulsive Scale does not distinguish MO from other intrusive auditory imagery.1
It is important to differentiate MO from:
- Musical preoccupations or recollections in which an individual repeatedly listens or recalls a particular song or part of a song, but does not have the urge to listen or recall music in an obsessive-compulsive pattern.1 These individuals do not display fear and avoidant behaviors that could be seen in patients with MO.1
- Musical hallucinations lack an input stimulus and the patient believes the music comes from an outside source and interprets it as reality. Misdiagnosing MO as a psychotic symptom is common and can result in improper treatment.1
Management
Pharmacotherapy. MO responds to the same medications used to treat obsessive-compulsive disorder, such as selective serotonin reuptake inhibitors and clomipramine.1 Cognitive-behavioral interventions could help patients address dysfunctional beliefs, without trying to suppress them.1
Distraction. Encourage patients to sing a different song that does not have obsessive quality1 or engage in a task that uses working memory.3
Exposure and response prevention therapy. Some case reports have reported efficacy in treating MO.1
1. Taylor S, McKay D, Miguel EC, et al. Musical obsessions: a comprehensive review of neglected clinical phenomena. J Anxiety Disord. 2014;28(6):580-589.
1. Taylor S, McKay D, Miguel EC, et al. Musical obsessions: a comprehensive review of neglected clinical phenomena. J Anxiety Disord. 2014;28(6):580-589.
Suicide, depression, and CYP2D6: How are they linked?
Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.3 These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.
In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.
CYP2D6: Many variants
CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.4
Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).10
I the late 1970s, 2 groups of researchers noted unexpected serious adverse reactions in studies of debrisoquine,5 a sympatholytic antihypertensive drug, and sparteine,6 an antiarrhythmic and oxytocic alkaloid drug. They observed that 5% to 10% of patients were unable to efficiently metabolize debrisoquine and sparteine and went on to define a genetic polymorphism responsible for these metabolic differences. They also observed that metabolism of antidepressants, antipsychotics, and beta blockers also was defective in these patients.
Further investigations established that the enzyme responsible for debrisoquine metabolism was a cytochrome P450 (CYP) enzyme that is now termed CYP2D6.7 In addition to biochemical evidence, the colocalization of sparteine oxidation deficiency and of the CYP2D6 locus at chromosome 22q13.1 confirmed CYP2D6 as the target gene of the debrisoquine/sparteine polymorphism.8,9
Table
CYP450 enzymes involved in biotransformation of SSRIs
| SSRI | Enzymes involved in biotransformation |
|---|---|
| Citalopram | CYP2C19, CYP2D6, CYP3A4 |
| Escitalopram | CYP2C19, CYP2D6, CYP3A4 |
| Fluoxetine | CYP2D6, CYP2C9, CYP2C19, CYP3A4 |
| Fluvoxamine | CYP1A2, CYP2D6 |
| Paroxetine | CYP2D6, CYP3A4 |
| Sertraline | CYP2C9, CYP2C19, CYP2D6, CYP3A4 |
| CYP: cytochrome P450; SSRI: selective serotonin reuptake inhibitors Source: Reference 10 | |
Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.3 These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.11 PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.
Suicide and CYP2D6 status
The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.12 Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte12 found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.12 Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.16
A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.16 The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.17 The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.
Case reports and observational studies18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al18 described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al19 described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al20 found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al21 found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.
Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al22 found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al23 found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.24 Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.
Effects on serotonin, dopamine
CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.25 This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.26,27
Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.28 Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.29 Yu et al27 found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.30 Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.
Dopamine also is generated from tyramine through CYP2D6,31 and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.32 The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,33 and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,2 which play an important role in the development of anxiety and impulsivity.
CYP2D6 in clinical practice
Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.
Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.34 The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.
Related Resources
- Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
- Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.
Drug Brand Names
- Citalopram • Celexa
- Clomipramine • Anafranil
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Nortriptyline • Aventyl, Pamelor
- Paroxetine • Paxil
- Sertraline • Zoloft
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.
1. Meyer UA, Amrein R, Balant LP, et al. Antidepressants and drug-metabolizing enzymes—expert group report. Acta Psychiatr Scand. 1996;93(2):71-79.
2. Kroemer HK, Eichelbaum M. “It’s the genes stupid”. Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 1995;56(26):2285-2298.
3. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. CYP2D6 allele nomenclature. http://www.cypalleles.ki.se/cyp2d6.htm. Accessed February 25, 2013.
4. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37.
5. Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet. 1977;2(8038):584-586.
6. Eichelbaum M, Spannbrucker N, Steincke B, et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979;16(3):183-187.
7. Distlerath LM, Reilly PE, Martin MV, et al. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem. 1985;260(15):9057-9067.
8. Eichelbaum M, Baur MP, Dengler HJ, et al. Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br J Clin Pharmacol. 1987;23(4):455-458.
9. Gonzalez FJ, Vilbois F, Hardwick JP, et al. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Geonomics. 1988;2(2):174-179.
10. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30(7):1206-1227.
11. Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405(6788):857-865.
12. Ludwig J, Marcotte DE. Anti-depressants suicide, and drug regulation. J Policy Anal Manage. 2005;24(2):249-272.
13. Isacsson G. Suicide prevention—a medical breakthrough? Acta Psychiatr Scand. 2000;102(2):113-117.
14. Rihmer Z. Can better recognition and treatment of depression reduce suicide rates? A brief review. Eur Psychiatry. 2001;16(7):406-409.
15. Rihmer Z. Decreasing national suicide rates—fact or fiction? World J Biol Psychiatry. 2004;5(1):55-56.
16. Rihmer Z, Akiskal H. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006;94(1-3):3-13.
17. Correia C, Santos P, Coutinho AM, et al. Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample. Cell Biochem Funct. 2009;27(4):251-255.
18. Bertilsson L, Dahl ML, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet. 1993;341(8836):63.-
19. Baumann P, Broly F, Kosel M, et al. Ultrarapid metabolism of clomipramine in a therapy-resistant depressive patient, as confirmed by CYP2 D6 genotyping. Pharmacopsychiatry. 1998;31(2):72.-
20. Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther. 2004;75(5):386-393.
21. Kawanishi C, Lundgren S, Agren H, et al. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol. 2004;59(11):803-807.
22. Zackrisson AL, Lindblom B, Ahlner J. High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther. 2010;88(3):354-359.
23. Stingl JC, Viviani R. CYP2D6 in the brain: impact on suicidality. Clin Pharmacol Ther. 2011;89(3):352-353.
24. Peñas-Lledó EM, Dorado P, Agüera Z, et al. High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders. Mol Psychiatry. 2011;16(7):691-692.
25. Siegle I, Fritz P, Eckhardt K, et al. Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics. 2001;11(3):237-245.
26. Eichelbaum M. In search of endogenous CYP2D6 substrates. Pharmacogenetics. 2003;13(6):305-306.
27. Yu AM, Idle JR, Gonzalez FJ. Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates. Drug Metab Rev. 2004;36(2):243-277.
28. Cowen PJ. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci. 2008;29(9):433-436.
29. Kang S, Kang K, Lee K, et al. Characterization of tryptamine 5-hydroxylase and serotonin synthesis in rice plants. Plant Cell Rep. 2007;26(11):2009-2015.
30. Yu AM, Idle JR, Herraiz T, et al. Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase. Pharmacogenetics. 2003;13(6):307-319.
31. Hiroi T, Imaoka S, Funae Y. Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun. 1998;249(3):838-843.
32. Niznik HB, Tyndale RF, Sallee FR, et al. The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. Arch Biochem Biophys. 1990;276(2):424-432.
33. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153(4):466-476.
34. Jain KK. Applications of AmpliChip CYP450. Mol Diagn. 2005;9(3):119-127.
Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.3 These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.
In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.
CYP2D6: Many variants
CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.4
Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).10
I the late 1970s, 2 groups of researchers noted unexpected serious adverse reactions in studies of debrisoquine,5 a sympatholytic antihypertensive drug, and sparteine,6 an antiarrhythmic and oxytocic alkaloid drug. They observed that 5% to 10% of patients were unable to efficiently metabolize debrisoquine and sparteine and went on to define a genetic polymorphism responsible for these metabolic differences. They also observed that metabolism of antidepressants, antipsychotics, and beta blockers also was defective in these patients.
Further investigations established that the enzyme responsible for debrisoquine metabolism was a cytochrome P450 (CYP) enzyme that is now termed CYP2D6.7 In addition to biochemical evidence, the colocalization of sparteine oxidation deficiency and of the CYP2D6 locus at chromosome 22q13.1 confirmed CYP2D6 as the target gene of the debrisoquine/sparteine polymorphism.8,9
Table
CYP450 enzymes involved in biotransformation of SSRIs
| SSRI | Enzymes involved in biotransformation |
|---|---|
| Citalopram | CYP2C19, CYP2D6, CYP3A4 |
| Escitalopram | CYP2C19, CYP2D6, CYP3A4 |
| Fluoxetine | CYP2D6, CYP2C9, CYP2C19, CYP3A4 |
| Fluvoxamine | CYP1A2, CYP2D6 |
| Paroxetine | CYP2D6, CYP3A4 |
| Sertraline | CYP2C9, CYP2C19, CYP2D6, CYP3A4 |
| CYP: cytochrome P450; SSRI: selective serotonin reuptake inhibitors Source: Reference 10 | |
Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.3 These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.11 PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.
Suicide and CYP2D6 status
The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.12 Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte12 found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.12 Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.16
A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.16 The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.17 The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.
Case reports and observational studies18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al18 described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al19 described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al20 found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al21 found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.
Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al22 found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al23 found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.24 Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.
Effects on serotonin, dopamine
CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.25 This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.26,27
Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.28 Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.29 Yu et al27 found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.30 Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.
Dopamine also is generated from tyramine through CYP2D6,31 and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.32 The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,33 and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,2 which play an important role in the development of anxiety and impulsivity.
CYP2D6 in clinical practice
Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.
Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.34 The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.
Related Resources
- Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
- Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.
Drug Brand Names
- Citalopram • Celexa
- Clomipramine • Anafranil
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Nortriptyline • Aventyl, Pamelor
- Paroxetine • Paxil
- Sertraline • Zoloft
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.
Genetic variations in drug-metabolizing enzymes dramatically affect drug pharmacokinetics and can result in clinically relevant differences in drug efficacy or toxicity. Cytochrome P450 (CYP) enzymes such as CYP2D6 are involved in metabolism of antidepressants, including selective serotonin reuptake inhibitors (SSRIs), which often are a first-line choice for patients with major depressive disorder (MDD).1,2 CYP2D6 is a highly polymorphic gene with 75 allelic variants (CYP2D6*1 to *75) and >30 additional subvariants.3 These variants are associated with phenotypes where CYP2D6 activity is increased, reduced, or lost, which can increase the risk of adverse drug reactions, decrease efficacy, and possibly influence a patient’s suicide risk.
In this article, we review the pharmacogenetics of CYP2D6 and discuss a possible relationship between CYP2D6 genotype and suicidal events during antidepressant treatment for MDD.
CYP2D6: Many variants
CYP450 enzymes are a group of 57 proteins, each coded by a different gene. Five subfamilies in the CYP450 family metabolize most drugs: CYP1A2, CYP3A4, CYP2C19, CYP2E1, and CYP2D6.4
Researchers discovered CYP2D6 in studies of nonpsychotropics (Box).5-9 CYP2D6 is widely expressed in many tissues, with dominant expression in the liver. Although CYP2D6 accounts for 2% of the total CYP450 liver enzyme content, it mediates metabolism in 25% to 30% of drugs in common clinical use and has a major influence on the biotransformation of SSRIs (Table).10
I the late 1970s, 2 groups of researchers noted unexpected serious adverse reactions in studies of debrisoquine,5 a sympatholytic antihypertensive drug, and sparteine,6 an antiarrhythmic and oxytocic alkaloid drug. They observed that 5% to 10% of patients were unable to efficiently metabolize debrisoquine and sparteine and went on to define a genetic polymorphism responsible for these metabolic differences. They also observed that metabolism of antidepressants, antipsychotics, and beta blockers also was defective in these patients.
Further investigations established that the enzyme responsible for debrisoquine metabolism was a cytochrome P450 (CYP) enzyme that is now termed CYP2D6.7 In addition to biochemical evidence, the colocalization of sparteine oxidation deficiency and of the CYP2D6 locus at chromosome 22q13.1 confirmed CYP2D6 as the target gene of the debrisoquine/sparteine polymorphism.8,9
Table
CYP450 enzymes involved in biotransformation of SSRIs
| SSRI | Enzymes involved in biotransformation |
|---|---|
| Citalopram | CYP2C19, CYP2D6, CYP3A4 |
| Escitalopram | CYP2C19, CYP2D6, CYP3A4 |
| Fluoxetine | CYP2D6, CYP2C9, CYP2C19, CYP3A4 |
| Fluvoxamine | CYP1A2, CYP2D6 |
| Paroxetine | CYP2D6, CYP3A4 |
| Sertraline | CYP2C9, CYP2C19, CYP2D6, CYP3A4 |
| CYP: cytochrome P450; SSRI: selective serotonin reuptake inhibitors Source: Reference 10 | |
Approximately 100 polymorphic CYP2D6 alleles (variants) have been identified.3 These alleles are active, resulting in normal CYP2D6 enzyme activity, or inactive, leading to decreased enzyme activity. Genotyping for most common CYP2D6 alleles in ethnically defined populations can predict poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs) with high accuracy.11 PMs are compound heterozygous for inactivating alleles or homozygous for an inactivating variant. IMs carry one functional allele and one nonfunctional allele but may demonstrate a range of enzyme activity levels. EMs have 2 functional gene copies and UMs have >2 functional genes from gene duplication, resulting in ultra-rapid metabolism.
Suicide and CYP2D6 status
The widespread use of antidepressants appears to have led to significant decline in suicide rates in many countries.12 Based on an investigation of suicide mortality in 27 countries from 1980 to 2000, Ludwig and Marcotte12 found that faster growth in SSRI sales per capita was associated with larger declines in suicide rates. This finding was not confounded by other suicide risk factors such as unemployment, sex, age, or divorce rate.12 Countries such as Germany, Austria, Estonia, Switzerland, Sweden, Denmark, Hungary, and Slovenia—which had the highest suicide rate in the world 20 years ago (20 to 46 per 100,000 per year)—have had impressive declines in suicide rates (24% to 57% in the last 2 decades) with a marked (6- to 8-fold) increase in SSRI prescriptions during the same period.13-15 On the other hand, a few countries, such as Portugal and Spain, have experienced dramatic increases (58% and 86%, respectively) in the suicide rate with a similar increase in SSRI prescribing during the same 20-year period.16
A review of the distribution of CYP2D6 genotype among countries indicates a south/north gradient of CYP2D6 gene duplications, which indicate UM status.16 The proportion of UMs increases by almost 2-fold in southern European countries (8.4% and 7% to 10% for Portugal and Spain, respectively) compared with northern European countries (1% to 2% and 3.6% for Sweden and Germany, respectively); this south/north trend extends to Africa.17 The prevalence of CYP2D6 UMs is lower in northern countries, where increased anti-depressant use appears to have reduced suicide rates, and higher in southern countries, where suicide rates increased despite higher antidepressant use.
Case reports and observational studies18-21 suggest that compared with other CYP2D6 phenotypes, UMs may need to take higher doses of antidepressants to achieve therapeutic response. In a case report, Bertilsson et al18 described 2 patients who were UMs and required high doses of nortriptyline and clomipramine to obtain appropriate plasma drug concentrations. Baumann et al19 described a depressed patient with CYP2D6 gene duplication who required higher-than-usual doses of clomipramine. Rau et al20 found a 3-fold increase in the frequency of UMs in a group of 16 depressed German patients who did not respond to SSRIs or serotonin–norepinephrine reuptake inhibitors, both of which are metabolized by CYP2D6. Kawanishi et al21 found a significantly greater prevalence of UMs among 81 Nordic patients who did not respond to SSRIs compared with the general population.
Because suicidality may be caused by inadequately treated depressive illness, MDD patients who are UMs may be more likely to commit suicide because of suboptimal antidepressant levels. In a 2010 Swedish study, Zackrisson et al22 found that compared with those who died of other causes, significantly more individuals who committed suicide had >2 active CYP2D6 genes. Stingl et al23 found that among 285 depressed German patients, UMs had an elevated risk of having a high suicidality score compared with individuals with other genotypes, after adjusting for sex, baseline score on the Hamilton Depression Rating Scale (after excluding item 3 for suicidality), and number of previous depressive episodes. Other researchers found that patients with eating disorders who are UMs have a greater risk of suicidal behavior.24 Although none of these 3 studies specified if these patients were treated with antidepressants, the association between CYP2D6 gene duplication and suicide risk suggests CYP2D6’s role in suicide risk might not be related solely to antidepressant metabolism.
Effects on serotonin, dopamine
CYP2D6 is expressed in the brain and localized primarily in large principle cells of the hippocampus and Purkinje cells of the cerebellum, with no expression in other brain regions such as glial cells.25 This heterogeneous expression among brain regions and cell types indicates that in addition to its role in metabolizing drugs, CYP2D6 might influence neurotransmitter levels. In vitro and in vivo animal studies suggest that CYP2D6 plays a role in biotransformation of serotonin and dopamine.26,27
Serotonin is likely to play a causal role in the pathophysiology of depression, and depressed patients have abnormalities in serotonin activity.28 Serotonin is generated primarily from the transformation of tryptophan by tryptophan decarboxylase and tryptamine 5-hydroxylase.29 Yu et al27 found that CYP2D6 may be an additional pathway to regenerate serotonin through O-demethylation from 5-methoxytryptamine, but it is unclear what proportion of the physiologic pool of serotonin in synaptic nerve terminals is generated through the CYP2D6 pathway. However, this discovery provides a mechanistic basis of CYP2D6 involvement in the endogenous serotonin balance and by extension, in serotonergic physiology and neuropsychiatric disorders such as depression.30 Because SSRIs target the serotonergic pathway, baseline levels of serotonin and all related components of this pathway—including CYP2D6—are likely to help determine a patient’s response to SSRIs.
Dopamine also is generated from tyramine through CYP2D6,31 and distribution of CYP2D6 in the brain follows that of dopamine nerve terminals.32 The serotonergic system has strong anatomical and functional interaction with the dopaminergic system,33 and imbalance between serotonin and dopamine activity is thought to give rise to behavioral changes,2 which play an important role in the development of anxiety and impulsivity.
CYP2D6 in clinical practice
Although research into a possible link between CYP2D6 status and suicide risk in depressed patients treated with antidepressants is ongoing, at present this connection is speculative. More studies are warranted to reveal the exact role of CYP2D6 in response to SSRI treatment and suicide risk.
Knowledge of this potential association can help clinicians keep CYP450 genotyping in mind when prescribing antidepressants to depressed patients. The FDA has approved a pharmacogenetic test to analyze polymorphisms of CYP2D6 and CYP2C19.34 The results of such testing might guide pharmacotherapy for depressed patients, including medication selection and dosing. For example, a patient who is a PM might be started at a lower antidepressant dosage to avoid potential adverse drug effects, whereas it might be appropriate to prescribe a higher starting dose for a UM patient to achieve an effective drug concentration.
Related Resources
- Peñas-Lledó EM, Blasco-Fontecilla H, Dorado P, et al. CYP2D6 and the severity of suicide attempts. Pharmacogenomics. 2012;13(2):179-184.
- Blasco-Fontecilla H, Peñas-Lledó E, Vaquero-Lorenzo C, et al. CYP2D6 polymorphism and mental and personality disorders in suicide attempters [published online February 11, 2013]. J Pers Disord. doi: 10.1521/pedi_2013_27_080.
Drug Brand Names
- Citalopram • Celexa
- Clomipramine • Anafranil
- Escitalopram • Lexapro
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Nortriptyline • Aventyl, Pamelor
- Paroxetine • Paxil
- Sertraline • Zoloft
Disclosure
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Acknowledgment
The authors thank Marwah Shahid and Ijlal Yazdani for their assistance with this article.
1. Meyer UA, Amrein R, Balant LP, et al. Antidepressants and drug-metabolizing enzymes—expert group report. Acta Psychiatr Scand. 1996;93(2):71-79.
2. Kroemer HK, Eichelbaum M. “It’s the genes stupid”. Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 1995;56(26):2285-2298.
3. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. CYP2D6 allele nomenclature. http://www.cypalleles.ki.se/cyp2d6.htm. Accessed February 25, 2013.
4. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37.
5. Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet. 1977;2(8038):584-586.
6. Eichelbaum M, Spannbrucker N, Steincke B, et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979;16(3):183-187.
7. Distlerath LM, Reilly PE, Martin MV, et al. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem. 1985;260(15):9057-9067.
8. Eichelbaum M, Baur MP, Dengler HJ, et al. Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br J Clin Pharmacol. 1987;23(4):455-458.
9. Gonzalez FJ, Vilbois F, Hardwick JP, et al. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Geonomics. 1988;2(2):174-179.
10. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30(7):1206-1227.
11. Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405(6788):857-865.
12. Ludwig J, Marcotte DE. Anti-depressants suicide, and drug regulation. J Policy Anal Manage. 2005;24(2):249-272.
13. Isacsson G. Suicide prevention—a medical breakthrough? Acta Psychiatr Scand. 2000;102(2):113-117.
14. Rihmer Z. Can better recognition and treatment of depression reduce suicide rates? A brief review. Eur Psychiatry. 2001;16(7):406-409.
15. Rihmer Z. Decreasing national suicide rates—fact or fiction? World J Biol Psychiatry. 2004;5(1):55-56.
16. Rihmer Z, Akiskal H. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006;94(1-3):3-13.
17. Correia C, Santos P, Coutinho AM, et al. Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample. Cell Biochem Funct. 2009;27(4):251-255.
18. Bertilsson L, Dahl ML, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet. 1993;341(8836):63.-
19. Baumann P, Broly F, Kosel M, et al. Ultrarapid metabolism of clomipramine in a therapy-resistant depressive patient, as confirmed by CYP2 D6 genotyping. Pharmacopsychiatry. 1998;31(2):72.-
20. Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther. 2004;75(5):386-393.
21. Kawanishi C, Lundgren S, Agren H, et al. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol. 2004;59(11):803-807.
22. Zackrisson AL, Lindblom B, Ahlner J. High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther. 2010;88(3):354-359.
23. Stingl JC, Viviani R. CYP2D6 in the brain: impact on suicidality. Clin Pharmacol Ther. 2011;89(3):352-353.
24. Peñas-Lledó EM, Dorado P, Agüera Z, et al. High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders. Mol Psychiatry. 2011;16(7):691-692.
25. Siegle I, Fritz P, Eckhardt K, et al. Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics. 2001;11(3):237-245.
26. Eichelbaum M. In search of endogenous CYP2D6 substrates. Pharmacogenetics. 2003;13(6):305-306.
27. Yu AM, Idle JR, Gonzalez FJ. Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates. Drug Metab Rev. 2004;36(2):243-277.
28. Cowen PJ. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci. 2008;29(9):433-436.
29. Kang S, Kang K, Lee K, et al. Characterization of tryptamine 5-hydroxylase and serotonin synthesis in rice plants. Plant Cell Rep. 2007;26(11):2009-2015.
30. Yu AM, Idle JR, Herraiz T, et al. Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase. Pharmacogenetics. 2003;13(6):307-319.
31. Hiroi T, Imaoka S, Funae Y. Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun. 1998;249(3):838-843.
32. Niznik HB, Tyndale RF, Sallee FR, et al. The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. Arch Biochem Biophys. 1990;276(2):424-432.
33. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153(4):466-476.
34. Jain KK. Applications of AmpliChip CYP450. Mol Diagn. 2005;9(3):119-127.
1. Meyer UA, Amrein R, Balant LP, et al. Antidepressants and drug-metabolizing enzymes—expert group report. Acta Psychiatr Scand. 1996;93(2):71-79.
2. Kroemer HK, Eichelbaum M. “It’s the genes stupid”. Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sci. 1995;56(26):2285-2298.
3. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. CYP2D6 allele nomenclature. http://www.cypalleles.ki.se/cyp2d6.htm. Accessed February 25, 2013.
4. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37.
5. Mahgoub A, Idle JR, Dring LG, et al. Polymorphic hydroxylation of debrisoquine in man. Lancet. 1977;2(8038):584-586.
6. Eichelbaum M, Spannbrucker N, Steincke B, et al. Defective N-oxidation of sparteine in man: a new pharmacogenetic defect. Eur J Clin Pharmacol. 1979;16(3):183-187.
7. Distlerath LM, Reilly PE, Martin MV, et al. Purification and characterization of the human liver cytochromes P-450 involved in debrisoquine 4-hydroxylation and phenacetin O-deethylation, two prototypes for genetic polymorphism in oxidative drug metabolism. J Biol Chem. 1985;260(15):9057-9067.
8. Eichelbaum M, Baur MP, Dengler HJ, et al. Chromosomal assignment of human cytochrome P-450 (debrisoquine/sparteine type) to chromosome 22. Br J Clin Pharmacol. 1987;23(4):455-458.
9. Gonzalez FJ, Vilbois F, Hardwick JP, et al. Human debrisoquine 4-hydroxylase (P450IID1): cDNA and deduced amino acid sequence and assignment of the CYP2D locus to chromosome 22. Geonomics. 1988;2(2):174-179.
10. Spina E, Santoro V, D’Arrigo C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin Ther. 2008;30(7):1206-1227.
11. Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405(6788):857-865.
12. Ludwig J, Marcotte DE. Anti-depressants suicide, and drug regulation. J Policy Anal Manage. 2005;24(2):249-272.
13. Isacsson G. Suicide prevention—a medical breakthrough? Acta Psychiatr Scand. 2000;102(2):113-117.
14. Rihmer Z. Can better recognition and treatment of depression reduce suicide rates? A brief review. Eur Psychiatry. 2001;16(7):406-409.
15. Rihmer Z. Decreasing national suicide rates—fact or fiction? World J Biol Psychiatry. 2004;5(1):55-56.
16. Rihmer Z, Akiskal H. Do antidepressants t(h)reat(en) depressives? Toward a clinically judicious formulation of the antidepressant-suicidality FDA advisory in light of declining national suicide statistics from many countries. J Affect Disord. 2006;94(1-3):3-13.
17. Correia C, Santos P, Coutinho AM, et al. Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample. Cell Biochem Funct. 2009;27(4):251-255.
18. Bertilsson L, Dahl ML, Sjöqvist F, et al. Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet. 1993;341(8836):63.-
19. Baumann P, Broly F, Kosel M, et al. Ultrarapid metabolism of clomipramine in a therapy-resistant depressive patient, as confirmed by CYP2 D6 genotyping. Pharmacopsychiatry. 1998;31(2):72.-
20. Rau T, Wohlleben G, Wuttke H, et al. CYP2D6 genotype: impact on adverse effects and nonresponse during treatment with antidepressants-a pilot study. Clin Pharmacol Ther. 2004;75(5):386-393.
21. Kawanishi C, Lundgren S, Agren H, et al. Increased incidence of CYP2D6 gene duplication in patients with persistent mood disorders: ultrarapid metabolism of antidepressants as a cause of nonresponse. A pilot study. Eur J Clin Pharmacol. 2004;59(11):803-807.
22. Zackrisson AL, Lindblom B, Ahlner J. High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther. 2010;88(3):354-359.
23. Stingl JC, Viviani R. CYP2D6 in the brain: impact on suicidality. Clin Pharmacol Ther. 2011;89(3):352-353.
24. Peñas-Lledó EM, Dorado P, Agüera Z, et al. High risk of lifetime history of suicide attempts among CYP2D6 ultrarapid metabolizers with eating disorders. Mol Psychiatry. 2011;16(7):691-692.
25. Siegle I, Fritz P, Eckhardt K, et al. Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics. 2001;11(3):237-245.
26. Eichelbaum M. In search of endogenous CYP2D6 substrates. Pharmacogenetics. 2003;13(6):305-306.
27. Yu AM, Idle JR, Gonzalez FJ. Polymorphic cytochrome P450 2D6: humanized mouse model and endogenous substrates. Drug Metab Rev. 2004;36(2):243-277.
28. Cowen PJ. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci. 2008;29(9):433-436.
29. Kang S, Kang K, Lee K, et al. Characterization of tryptamine 5-hydroxylase and serotonin synthesis in rice plants. Plant Cell Rep. 2007;26(11):2009-2015.
30. Yu AM, Idle JR, Herraiz T, et al. Screening for endogenous substrates reveals that CYP2D6 is a 5-methoxyindolethylamine O-demethylase. Pharmacogenetics. 2003;13(6):307-319.
31. Hiroi T, Imaoka S, Funae Y. Dopamine formation from tyramine by CYP2D6. Biochem Biophys Res Commun. 1998;249(3):838-843.
32. Niznik HB, Tyndale RF, Sallee FR, et al. The dopamine transporter and cytochrome P45OIID1 (debrisoquine 4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins. Arch Biochem Biophys. 1990;276(2):424-432.
33. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153(4):466-476.
34. Jain KK. Applications of AmpliChip CYP450. Mol Diagn. 2005;9(3):119-127.
Hallucinations: Common features and causes
Not all patients who experience hallucinations have a psychotic disorder. Many physical and psychiatric disorders can manifest with hallucinations, and some patients have >1 disorder that could cause different types of hallucinations. To avoid providing unnecessary or ineffective treatments—and to ensure that patients receive proper care for nonpsychiatric conditions—it is important to accurately diagnose the disorder causing a patient’s hallucinations.
In this article we describe common features and psychiatric and nonpsychiatric causes of auditory, visual, olfactory, gustatory, tactile, and somatic hallucinations. Awareness of typical presentations of hallucinations associated with specific disorders can help narrow the diagnosis and provide appropriate treatment.
Auditory hallucinations
Also known as paracusia, auditory hallucinations are perceptions of sounds without identifiable external stimuli. This type of hallucination has various causes (Table 1).1 A frequent symptom of schizophrenia, auditory hallucinations can cause substantial distress and functional disability.2 Approximately 60% to 90% of patients with schizophrenia and up to 80% of those with affective psychoses experience auditory hallucinations.1
Auditory hallucinations in psychosis usually are formed and complex.3 A common manifestation is hearing ≥1 voices. A patient might experience 2 voices talking about him in the third person. The voices may be perceived as coming from inside or outside the patient’s head. Some might hear their own thoughts spoken aloud. According to DSM-IV-TR, “hearing voices” is sufficient to diagnose schizophrenia if the hallucinations consist of a voice keeping up a running commentary on the person’s behavior or ≥2 voices conversing with each other.4 Auditory hallucinations also are seen in mood disorders but tend to be milder than their psychosis-induced counterparts.
Simple (unformed) auditory hallucinations—referred to as tinnitus—can be caused by disease of the middle ear (otosclerosis) or inner ear. These unformed hallucinations consist of buzzing or tones of varying pitch and timbre.1
Partial seizures may cause auditory hallucinations. Perceptions of music have been associated with partial seizures.5 Curie and colleagues found that 17% of 514 patients with temporal lobe epilepsy had auditory hallucinations as a component of their seizures.6 These hallucinations typically are brief, stereotyped sensory impressions and, if formed, may be trivial sentences, previously heard phrases, or commands.
Alcoholic hallucinosis is a hallucinatory syndrome caused by alcohol withdrawal. These hallucinations usually are vocal and typically consist of accusatory, threatening, and/or critical voices directed at the patient.1 Patients with alcohol hallucinosis also may experience musical auditory hallucinations.7,8
CNS neoplasms can produce auditory hallucinations in 3% to 10% of patients.9 Hemorrhages and arteriovenous malformations in the pontine tegmentum and lower midbrain have been associated with acute onset of auditory hallucinations. The sounds typically are unformed mechanical or seashell-like noises or music.10
Patients with migraines rarely report auditory hallucinations. When they occur, they typically consist of perceived unilateral tinnitus, phonophobia, or hearing loss.
Table 1
Common causes of auditory hallucinations
| Peripheral lesions |
| Middle ear disease |
| Inner ear disease |
| Auditory nerve disease |
| CNS disorders |
| Temporal lobe epilepsy |
| Pontine lesions |
| Stroke |
| Arteriovenous malformations |
| Syncope |
| Toxic metabolic disturbances |
| Alcoholic hallucinosis |
| Delirium |
| Hallucinogens |
| Schizophrenia |
| Mania |
| Psychotic depression |
| Dissociative identity disorder |
| Posttraumatic stress disorder |
| Source: Reference 1 |
Visual hallucinations
Visual hallucinations manifest as visual sensory perceptions in the absence of external stimuli.11 These false perceptions may consist of formed images (eg, people) or unformed images (eg, flashes of light).12 Visual hallucinations occur in numerous ophthalmologic, neurologic, medical, and psychiatric disorders (Table 2).13
DSM-IV-TR lists visual hallucinations as a primary diagnostic criterion for several psychotic disorders, including schizophrenia and schizoaffective disorder,4 and they occur in 16% to 72% of patients with these conditions.14,15 Patients with major depressive disorder or bipolar disorder also may experience visual hallucinations. Visual hallucinations in those with schizophrenia tend to involve vivid scenes with family members, religious figures, and/or animals.16
Delirium is a transient, reversible cause of cerebral dysfunction that often presents with hallucinations. Several studies have shown that visual hallucinations are the most common type among patients with delirium. Webster and Holroyd found visual hallucinations in 27% of 227 delirium patients.17
Delirium tremens typically is accompanied by visual hallucinations. Visions of small animals and crawling insects are common.18 Hallucinations due to drug intoxication or withdrawal generally vary in duration from brief to continuous; such experiences often contribute to agitation.19
Migraines are a well-recognized cause of visual hallucinations. Up to 31% of those with migraines experience an aura, and nearly 99% of those with aura have visual symptoms.20,21 The classic visual aura starts as an irregular colored crescent of light with multi-colored edges in the center of the visual field that gradually progresses toward the periphery, lasting <60 minutes. These simple visual hallucinations are most common; more complex hallucinations are seen more frequently in migraine coma and familial hemiplegic migraine.
Approximately 5% of patients with epilepsy have occipital seizures, which almost always have visual manifestations. Epileptic visual hallucinations often are simple, brief, stereotyped, and fragmentary. They usually consist of small, brightly colored spots or shapes that flash.22 Complex visual hallucinations in epilepsy are similar to hypnagogic hallucinations but are rare. Intracranial electroencephalography recordings have shown that pathological excitation of visual cortical areas may be responsible for complex visual hallucinations in epilepsy.19
Dementia with Lewy bodies (DLB) is associated with visual hallucinations.23 Visual hallucinations occur in >20% of patients with DLB.24 Patients with DLB may see complex scenarios of people and items that are not present. Visual hallucinations have an 83% positive predictive value for distinguishing DLB from dementia of the Alzheimer’s type.25 There is a strong correlation between Lewy bodies located in the amygdala and parahippocampus and well-formed visual hallucinations.26
Visual hallucinations are common in Parkinson’s disease and may occur in up to one-half of patients.27 Patients with Parkinson’s disease may experience hallucinations similar to those observed in DLB, which can range from seeing a person or animal to more complex, formed, and mobile people, animals, or objects.
Table 2
Common causes of visual hallucinations
| Neurologic disorders |
| Migraine |
| Epilepsy |
| Hemispheric lesions |
| Optic nerve disorders |
| Brain stem lesions (peduncular hallucinosis) |
| Narcolepsy |
| Ophthalmologic diseases |
| Glaucoma |
| Retinal disease |
| Enucleation |
| Cataract formation |
| Choroidal disorder |
| Macular abnormalities |
| Toxic and metabolic conditions |
| Toxic-metabolic encephalopathy |
| Drug and alcohol withdrawal syndromes |
| Hallucinogens |
| Schizophrenia |
| Affective disorders |
| Conversion disorders |
| Sensory deprivation |
| Sleep deprivation |
| Hypnosis |
| Intense emotional experiences |
| Source: Reference 13 |
Olfactory hallucinations
Also known as phantosmia, olfactory hallucinations involve smelling odors that are not derived from any physical stimulus. They can occur with several psychiatric conditions, including schizophrenia, depression, bipolar disorder, eating disorders, and substance abuse.28 Olfactory hallucinations caused by epileptic activity are rare. They constitute approximately 0.9% of all auras and typically are described as unpleasant. Tumors that affect the medial temporal lobe and mesial temporal sclerosis are associated with olfactory hallucinations.29 Olfactory hallucinations also have been reported in patients with multi-infarct dementia, Alzheimer’s disease, and alcoholic psychosyndromes. In patients with schizophrenia, the smell may be perceived as coming from an external source, whereas patients with depression may perceive the source as internal.30 Patients who perceive that they are the source of an offensive odor—a condition known as olfactory reference syndrome—may wash excessively, overuse deodorants and perfumes, or become socially withdrawn.30
Gustatory hallucinations
Patients with gustatory hallucinations may experience salivation, sensation of thirst, or taste alterations. These hallucinations can be observed when the sylvian fissure that extends to the insula is stimulated electrically.31 Similar to olfactory hallucinations, gustatory hallucinations are associated with temporal lobe disease and parietal operculum lesions.31,32 Sinus diseases have been associated with olfactory and gustatory hallucinations.33 Brief gustatory hallucinations can be elicited with stimulation of the right rolandic operculum, parietal operculum, amygdala, hippocampus, medial temporal gyrus, and anterior part of right temporal gyrus.34
Tactile hallucinations
These hallucinations may include perceptions of insects crawling over or under the skin (formication) or simulation of pressure on skin.35 They have been associated with substance abuse, toxicity, or withdrawal.28 Tactile hallucinations are characteristic of cocaine or amphetamine intoxication.35
Tactile hallucinations are a rare symptom of schizophrenia. Heveling and colleagues reported a case of a woman, age 68, with chronic schizophrenia who experienced touching and being touched by a “shadow man” several times a day in addition to auditory and visual hallucinations.36 Her symptoms disappeared after 4 weeks of antipsychotic and mood stabilizer therapy.
Tactile hallucinations have been associated with obsessive-compulsive disorder (OCD).37 Fontenelle and colleagues suggested that OCD and psychotic disorders may share dysfunctional dopaminergic circuits.37
Somatic hallucinations
Patients who have somatic hallucinations report perceptions of abnormal body sensations or physical experiences. For example, a patient may have sense of not having a stomach while eating.35
This type of hallucination has been associated with activation of postcentral gyrus, parietal operculum, insula, and inferior parietal lobule on stereoelectroencephalography.34 In a study of cerebral blood flow in 20 geriatric patients with delusional disorder, somatic type who were experiencing somatic hallucinations, positron emission testing scan demonstrated increased perfusion in somatic sensory processing regions, particularly the left postcentral gyrus and the right paracentral lobule.38 Other researchers have linked somatic hallucinations with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception.39
Related Resource
- Teeple RC, Caplan JP, Stern TA. Visual hallucinations: differential diagnosis and treatment. Prim Care Companion J Clin Psychiatry. 2009;11(1):26-32.
Disclosures
Drs. Ali, Patel, Avenido, Bailey, and Jabeen report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Riley is on the board of directors for Vertex Pharmaceuticals.
Acknowledgment
The authors would like to thank Marwah Shahid, Research Associate, Vanderbilt University, Nashville, TN.
1. Cummings JL, Mega MS. Hallucinations. In: Cummings JL Mega MS, eds. Neuropsychiatry and behavioral neuroscience. New York, NY: Oxford University Press; 2003: 187–199.
2. Shergill SS, Murray RM, McGuire PK. Auditory hallucinations: a review of psychological treatments. Schizophr Res. 1998;32(3):137-150.
3. Goodwin DW, Alderson P, Rosenthal R. Clinical significance of hallucinations in psychiatric disorders. A study of 116 hallucinatory patients. Arch Gen Psychiatry. 1971;24(1):76-80.
4. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
5. Kasper BS, Kasper EM, Pauli E, et al. Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology. Epilepsy Behav. 2010;18(1-2):13-23.
6. Currie S, Heathfield KW, Henson RA, et al. Clinical course and prognosis of temporal lobe epilepsy. A survey of 666 patients. Brain. 1971;94(1):173-190.
7. Keshavan MS, David AS, Steingard S, et al. Musical hallucinations: a review and synthesis. Cogn Behav Neurol. 1992;5(3):211-223.
8. Duncan R, Mitchell JD, Critchley EMR. Hallucinations and music. Behav Neurol. 1989;2(2):115-124.
9. Tarachow S. The clinical value of hallucinations in localizing brain tumors. Am J Psychiatry. 1941;97:1434-1442.
10. Lanska DJ, Lanska MJ, Mendez MF. Brainstem auditory hallucinosis. Neurology. 1987;37(10):1685.-
11. Norton JW, Corbett JJ. Visual perceptual abnormalities: hallucinations and illusions. Semin Neurol. 2000;20(1):111-121.
12. Kaplan HI, Sadock BJ, Grebb JA. Typical signs and symptoms of psychiatric illness defined. In: Kaplan HI Sadock BJ, Grebb JA, eds. Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences, clinical psychiatry. Baltimore, MD: Williams and Wilkins; 1994:300.
13. Cummings JL, Miller BL. Visual hallucinations. Clinical occurrence and use in differential diagnosis. West J Med. 1987;146(1):46-51.
14. First MB, Tasman A. Schizophrenia and other psychoses. In: First MB Tasman A, eds. Clinical guide to the diagnosis and treatment of mental disorders. San Francisco, CA: John Wiley and Sons; 2009:245–278.
15. Mueser KT, Bellack AS, Brady EU. Hallucinations in schizophrenia. Acta Psychiatr Scand. 1990;82(1):26-29.
16. Small IF, Small JG, Andersen JM. Clinical characteristics of hallucinations of schizophrenia. Dis Nerv Syst. 1966;27(5):349-353.
17. Webster R, Holroyd S. Prevalence of psychotic symptoms in delirium. Psychosomatics. 2000;41(6):519-522.
18. Gastfriend DR, Renner JA, Hackett TP. Alcoholic patients: acute and chronic. In: Stern TA Fricchione G, Cassem NH, et al, eds. Massachusetts General Hospital handbook of general hospital psychiatry. 5th ed. Philadelphia, PA: Mosby; 2004:203–216.
19. Manford M, Andermann F. Complex visual hallucinations. Clinical and neurobiological insights. Brain. 1998;121(Pt 10):1819-1840.
20. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257-270.
21. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain. 1996;119(Pt 2):355-361.
22. Panayiotopoulos CP. Elementary visual hallucinations blindness, and headache in idiopathic occipital epilepsy: differentiation from migraine. J Neurol Neurosurg Psychiatry. 1999;66(4):536-540.
23. Ballard CG, O’Brien JT, Swann AG, et al. The natural history of psychosis and depression in dementia with Lewy bodies and Alzheimer’s disease: persistence and new cases over 1 year of follow-up. J Clin Psychiatry. 2001;62(1):46-49.
24. Ala TA, Yang KH, Sung JH, et al. Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer’s disease at presentation: a clinicopathological study. J Neurol Neurosurg Psychiatry. 1997;62(1):16-21.
25. Tiraboschi P, Salmon DP, Hansen LA, et al. What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain. 2006;129(Pt 3):729-735.
26. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain. 2002;125(Pt 2):391-403.
27. Williams DR, Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol. 2005;4(10):605-610.
28. Lewandowski KE, DePaola J, Camsari GB, et al. Tactile, olfactory, and gustatory hallucinations in psychotic disorders: a descriptive study. Ann Acad Med Singapore. 2009;38(5):383-385.
29. Acharya V, Acharya J, Lüders H. Olfactory epileptic auras. Neurology. 1998;51(1):56-61.
30. Ropper AH, Samuels MA. Disorders of smell and taste. In: Ropper AH Samuels MA, eds. Adams and Victor’s principles of neurology. 9th ed. New York, NY: McGraw-Hill Companies; 2009:216–224.
31. Ropper AH, Samuels MA. Epilepsy and other seizure disorders. In: Ropper AH Samuels MA, eds. Adams and Victor’s principles of neurology. 9th ed. New York, NY: McGraw-Hill Companies; 2009:304–338.
32. Capampangan DJ, Hoerth MT, Drazkowski JF, et al. Olfactory and gustatory hallucinations presenting as partial status epilepticus because of glioblastoma multiforme. Ann Emerg Med. 2010;56(4):374-377.
33. Frasnelli J, Reden J, Landis BN, et al. Comment on “Olfactory hallucinations as a manifestation of hidden rhinosinusitis”. J Clin Neurosci. 2010;17(4):543.-
34. Elliott B, Joyce E, Shorvon S. Delusions illusions and hallucinations in epilepsy: 1. Elementary phenomena. Epilepsy Res. 2009;85(2-3):162-171.
35. Nurcombe B, Ebert MH. The psychiatric interview. In: Ebert MH Nurcombe B, Loosen PT, et al, eds. Current diagnosis and treatment: psychiatry. 2nd ed. New York, NY: McGraw-Hill Companies; 2008:95–114.
36. Heveling T, Emrich HM, Dietrich DE. Treatment of a rare psychopathological phenomenon: tactile hallucinations and the delusional other. Eur Psychiatry. 2004;19(6):387-388.
37. Fontenelle LF, Lopes AP, Borges MC, et al. Auditory, visual, tactile, olfactory, and bodily hallucinations in patients with obsessive-compulsive disorder. CNS Spectr. 2008;13(2):125-130.
38. Nemoto K, Mizukami K, Hori T, et al. Hyperperfusion in primary somatosensory region related to somatic hallucination in the elderly. Psychiatry Clin Neurosci. 2010;64(4):421-425.
39. Shergill SS, Cameron LA, Brammer MJ, et al. Modality specific neural correlates of auditory and somatic hallucinations. J Neurol Neurosurg Psychiatry. 2001;71(5):688-690.
Not all patients who experience hallucinations have a psychotic disorder. Many physical and psychiatric disorders can manifest with hallucinations, and some patients have >1 disorder that could cause different types of hallucinations. To avoid providing unnecessary or ineffective treatments—and to ensure that patients receive proper care for nonpsychiatric conditions—it is important to accurately diagnose the disorder causing a patient’s hallucinations.
In this article we describe common features and psychiatric and nonpsychiatric causes of auditory, visual, olfactory, gustatory, tactile, and somatic hallucinations. Awareness of typical presentations of hallucinations associated with specific disorders can help narrow the diagnosis and provide appropriate treatment.
Auditory hallucinations
Also known as paracusia, auditory hallucinations are perceptions of sounds without identifiable external stimuli. This type of hallucination has various causes (Table 1).1 A frequent symptom of schizophrenia, auditory hallucinations can cause substantial distress and functional disability.2 Approximately 60% to 90% of patients with schizophrenia and up to 80% of those with affective psychoses experience auditory hallucinations.1
Auditory hallucinations in psychosis usually are formed and complex.3 A common manifestation is hearing ≥1 voices. A patient might experience 2 voices talking about him in the third person. The voices may be perceived as coming from inside or outside the patient’s head. Some might hear their own thoughts spoken aloud. According to DSM-IV-TR, “hearing voices” is sufficient to diagnose schizophrenia if the hallucinations consist of a voice keeping up a running commentary on the person’s behavior or ≥2 voices conversing with each other.4 Auditory hallucinations also are seen in mood disorders but tend to be milder than their psychosis-induced counterparts.
Simple (unformed) auditory hallucinations—referred to as tinnitus—can be caused by disease of the middle ear (otosclerosis) or inner ear. These unformed hallucinations consist of buzzing or tones of varying pitch and timbre.1
Partial seizures may cause auditory hallucinations. Perceptions of music have been associated with partial seizures.5 Curie and colleagues found that 17% of 514 patients with temporal lobe epilepsy had auditory hallucinations as a component of their seizures.6 These hallucinations typically are brief, stereotyped sensory impressions and, if formed, may be trivial sentences, previously heard phrases, or commands.
Alcoholic hallucinosis is a hallucinatory syndrome caused by alcohol withdrawal. These hallucinations usually are vocal and typically consist of accusatory, threatening, and/or critical voices directed at the patient.1 Patients with alcohol hallucinosis also may experience musical auditory hallucinations.7,8
CNS neoplasms can produce auditory hallucinations in 3% to 10% of patients.9 Hemorrhages and arteriovenous malformations in the pontine tegmentum and lower midbrain have been associated with acute onset of auditory hallucinations. The sounds typically are unformed mechanical or seashell-like noises or music.10
Patients with migraines rarely report auditory hallucinations. When they occur, they typically consist of perceived unilateral tinnitus, phonophobia, or hearing loss.
Table 1
Common causes of auditory hallucinations
| Peripheral lesions |
| Middle ear disease |
| Inner ear disease |
| Auditory nerve disease |
| CNS disorders |
| Temporal lobe epilepsy |
| Pontine lesions |
| Stroke |
| Arteriovenous malformations |
| Syncope |
| Toxic metabolic disturbances |
| Alcoholic hallucinosis |
| Delirium |
| Hallucinogens |
| Schizophrenia |
| Mania |
| Psychotic depression |
| Dissociative identity disorder |
| Posttraumatic stress disorder |
| Source: Reference 1 |
Visual hallucinations
Visual hallucinations manifest as visual sensory perceptions in the absence of external stimuli.11 These false perceptions may consist of formed images (eg, people) or unformed images (eg, flashes of light).12 Visual hallucinations occur in numerous ophthalmologic, neurologic, medical, and psychiatric disorders (Table 2).13
DSM-IV-TR lists visual hallucinations as a primary diagnostic criterion for several psychotic disorders, including schizophrenia and schizoaffective disorder,4 and they occur in 16% to 72% of patients with these conditions.14,15 Patients with major depressive disorder or bipolar disorder also may experience visual hallucinations. Visual hallucinations in those with schizophrenia tend to involve vivid scenes with family members, religious figures, and/or animals.16
Delirium is a transient, reversible cause of cerebral dysfunction that often presents with hallucinations. Several studies have shown that visual hallucinations are the most common type among patients with delirium. Webster and Holroyd found visual hallucinations in 27% of 227 delirium patients.17
Delirium tremens typically is accompanied by visual hallucinations. Visions of small animals and crawling insects are common.18 Hallucinations due to drug intoxication or withdrawal generally vary in duration from brief to continuous; such experiences often contribute to agitation.19
Migraines are a well-recognized cause of visual hallucinations. Up to 31% of those with migraines experience an aura, and nearly 99% of those with aura have visual symptoms.20,21 The classic visual aura starts as an irregular colored crescent of light with multi-colored edges in the center of the visual field that gradually progresses toward the periphery, lasting <60 minutes. These simple visual hallucinations are most common; more complex hallucinations are seen more frequently in migraine coma and familial hemiplegic migraine.
Approximately 5% of patients with epilepsy have occipital seizures, which almost always have visual manifestations. Epileptic visual hallucinations often are simple, brief, stereotyped, and fragmentary. They usually consist of small, brightly colored spots or shapes that flash.22 Complex visual hallucinations in epilepsy are similar to hypnagogic hallucinations but are rare. Intracranial electroencephalography recordings have shown that pathological excitation of visual cortical areas may be responsible for complex visual hallucinations in epilepsy.19
Dementia with Lewy bodies (DLB) is associated with visual hallucinations.23 Visual hallucinations occur in >20% of patients with DLB.24 Patients with DLB may see complex scenarios of people and items that are not present. Visual hallucinations have an 83% positive predictive value for distinguishing DLB from dementia of the Alzheimer’s type.25 There is a strong correlation between Lewy bodies located in the amygdala and parahippocampus and well-formed visual hallucinations.26
Visual hallucinations are common in Parkinson’s disease and may occur in up to one-half of patients.27 Patients with Parkinson’s disease may experience hallucinations similar to those observed in DLB, which can range from seeing a person or animal to more complex, formed, and mobile people, animals, or objects.
Table 2
Common causes of visual hallucinations
| Neurologic disorders |
| Migraine |
| Epilepsy |
| Hemispheric lesions |
| Optic nerve disorders |
| Brain stem lesions (peduncular hallucinosis) |
| Narcolepsy |
| Ophthalmologic diseases |
| Glaucoma |
| Retinal disease |
| Enucleation |
| Cataract formation |
| Choroidal disorder |
| Macular abnormalities |
| Toxic and metabolic conditions |
| Toxic-metabolic encephalopathy |
| Drug and alcohol withdrawal syndromes |
| Hallucinogens |
| Schizophrenia |
| Affective disorders |
| Conversion disorders |
| Sensory deprivation |
| Sleep deprivation |
| Hypnosis |
| Intense emotional experiences |
| Source: Reference 13 |
Olfactory hallucinations
Also known as phantosmia, olfactory hallucinations involve smelling odors that are not derived from any physical stimulus. They can occur with several psychiatric conditions, including schizophrenia, depression, bipolar disorder, eating disorders, and substance abuse.28 Olfactory hallucinations caused by epileptic activity are rare. They constitute approximately 0.9% of all auras and typically are described as unpleasant. Tumors that affect the medial temporal lobe and mesial temporal sclerosis are associated with olfactory hallucinations.29 Olfactory hallucinations also have been reported in patients with multi-infarct dementia, Alzheimer’s disease, and alcoholic psychosyndromes. In patients with schizophrenia, the smell may be perceived as coming from an external source, whereas patients with depression may perceive the source as internal.30 Patients who perceive that they are the source of an offensive odor—a condition known as olfactory reference syndrome—may wash excessively, overuse deodorants and perfumes, or become socially withdrawn.30
Gustatory hallucinations
Patients with gustatory hallucinations may experience salivation, sensation of thirst, or taste alterations. These hallucinations can be observed when the sylvian fissure that extends to the insula is stimulated electrically.31 Similar to olfactory hallucinations, gustatory hallucinations are associated with temporal lobe disease and parietal operculum lesions.31,32 Sinus diseases have been associated with olfactory and gustatory hallucinations.33 Brief gustatory hallucinations can be elicited with stimulation of the right rolandic operculum, parietal operculum, amygdala, hippocampus, medial temporal gyrus, and anterior part of right temporal gyrus.34
Tactile hallucinations
These hallucinations may include perceptions of insects crawling over or under the skin (formication) or simulation of pressure on skin.35 They have been associated with substance abuse, toxicity, or withdrawal.28 Tactile hallucinations are characteristic of cocaine or amphetamine intoxication.35
Tactile hallucinations are a rare symptom of schizophrenia. Heveling and colleagues reported a case of a woman, age 68, with chronic schizophrenia who experienced touching and being touched by a “shadow man” several times a day in addition to auditory and visual hallucinations.36 Her symptoms disappeared after 4 weeks of antipsychotic and mood stabilizer therapy.
Tactile hallucinations have been associated with obsessive-compulsive disorder (OCD).37 Fontenelle and colleagues suggested that OCD and psychotic disorders may share dysfunctional dopaminergic circuits.37
Somatic hallucinations
Patients who have somatic hallucinations report perceptions of abnormal body sensations or physical experiences. For example, a patient may have sense of not having a stomach while eating.35
This type of hallucination has been associated with activation of postcentral gyrus, parietal operculum, insula, and inferior parietal lobule on stereoelectroencephalography.34 In a study of cerebral blood flow in 20 geriatric patients with delusional disorder, somatic type who were experiencing somatic hallucinations, positron emission testing scan demonstrated increased perfusion in somatic sensory processing regions, particularly the left postcentral gyrus and the right paracentral lobule.38 Other researchers have linked somatic hallucinations with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception.39
Related Resource
- Teeple RC, Caplan JP, Stern TA. Visual hallucinations: differential diagnosis and treatment. Prim Care Companion J Clin Psychiatry. 2009;11(1):26-32.
Disclosures
Drs. Ali, Patel, Avenido, Bailey, and Jabeen report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Riley is on the board of directors for Vertex Pharmaceuticals.
Acknowledgment
The authors would like to thank Marwah Shahid, Research Associate, Vanderbilt University, Nashville, TN.
Not all patients who experience hallucinations have a psychotic disorder. Many physical and psychiatric disorders can manifest with hallucinations, and some patients have >1 disorder that could cause different types of hallucinations. To avoid providing unnecessary or ineffective treatments—and to ensure that patients receive proper care for nonpsychiatric conditions—it is important to accurately diagnose the disorder causing a patient’s hallucinations.
In this article we describe common features and psychiatric and nonpsychiatric causes of auditory, visual, olfactory, gustatory, tactile, and somatic hallucinations. Awareness of typical presentations of hallucinations associated with specific disorders can help narrow the diagnosis and provide appropriate treatment.
Auditory hallucinations
Also known as paracusia, auditory hallucinations are perceptions of sounds without identifiable external stimuli. This type of hallucination has various causes (Table 1).1 A frequent symptom of schizophrenia, auditory hallucinations can cause substantial distress and functional disability.2 Approximately 60% to 90% of patients with schizophrenia and up to 80% of those with affective psychoses experience auditory hallucinations.1
Auditory hallucinations in psychosis usually are formed and complex.3 A common manifestation is hearing ≥1 voices. A patient might experience 2 voices talking about him in the third person. The voices may be perceived as coming from inside or outside the patient’s head. Some might hear their own thoughts spoken aloud. According to DSM-IV-TR, “hearing voices” is sufficient to diagnose schizophrenia if the hallucinations consist of a voice keeping up a running commentary on the person’s behavior or ≥2 voices conversing with each other.4 Auditory hallucinations also are seen in mood disorders but tend to be milder than their psychosis-induced counterparts.
Simple (unformed) auditory hallucinations—referred to as tinnitus—can be caused by disease of the middle ear (otosclerosis) or inner ear. These unformed hallucinations consist of buzzing or tones of varying pitch and timbre.1
Partial seizures may cause auditory hallucinations. Perceptions of music have been associated with partial seizures.5 Curie and colleagues found that 17% of 514 patients with temporal lobe epilepsy had auditory hallucinations as a component of their seizures.6 These hallucinations typically are brief, stereotyped sensory impressions and, if formed, may be trivial sentences, previously heard phrases, or commands.
Alcoholic hallucinosis is a hallucinatory syndrome caused by alcohol withdrawal. These hallucinations usually are vocal and typically consist of accusatory, threatening, and/or critical voices directed at the patient.1 Patients with alcohol hallucinosis also may experience musical auditory hallucinations.7,8
CNS neoplasms can produce auditory hallucinations in 3% to 10% of patients.9 Hemorrhages and arteriovenous malformations in the pontine tegmentum and lower midbrain have been associated with acute onset of auditory hallucinations. The sounds typically are unformed mechanical or seashell-like noises or music.10
Patients with migraines rarely report auditory hallucinations. When they occur, they typically consist of perceived unilateral tinnitus, phonophobia, or hearing loss.
Table 1
Common causes of auditory hallucinations
| Peripheral lesions |
| Middle ear disease |
| Inner ear disease |
| Auditory nerve disease |
| CNS disorders |
| Temporal lobe epilepsy |
| Pontine lesions |
| Stroke |
| Arteriovenous malformations |
| Syncope |
| Toxic metabolic disturbances |
| Alcoholic hallucinosis |
| Delirium |
| Hallucinogens |
| Schizophrenia |
| Mania |
| Psychotic depression |
| Dissociative identity disorder |
| Posttraumatic stress disorder |
| Source: Reference 1 |
Visual hallucinations
Visual hallucinations manifest as visual sensory perceptions in the absence of external stimuli.11 These false perceptions may consist of formed images (eg, people) or unformed images (eg, flashes of light).12 Visual hallucinations occur in numerous ophthalmologic, neurologic, medical, and psychiatric disorders (Table 2).13
DSM-IV-TR lists visual hallucinations as a primary diagnostic criterion for several psychotic disorders, including schizophrenia and schizoaffective disorder,4 and they occur in 16% to 72% of patients with these conditions.14,15 Patients with major depressive disorder or bipolar disorder also may experience visual hallucinations. Visual hallucinations in those with schizophrenia tend to involve vivid scenes with family members, religious figures, and/or animals.16
Delirium is a transient, reversible cause of cerebral dysfunction that often presents with hallucinations. Several studies have shown that visual hallucinations are the most common type among patients with delirium. Webster and Holroyd found visual hallucinations in 27% of 227 delirium patients.17
Delirium tremens typically is accompanied by visual hallucinations. Visions of small animals and crawling insects are common.18 Hallucinations due to drug intoxication or withdrawal generally vary in duration from brief to continuous; such experiences often contribute to agitation.19
Migraines are a well-recognized cause of visual hallucinations. Up to 31% of those with migraines experience an aura, and nearly 99% of those with aura have visual symptoms.20,21 The classic visual aura starts as an irregular colored crescent of light with multi-colored edges in the center of the visual field that gradually progresses toward the periphery, lasting <60 minutes. These simple visual hallucinations are most common; more complex hallucinations are seen more frequently in migraine coma and familial hemiplegic migraine.
Approximately 5% of patients with epilepsy have occipital seizures, which almost always have visual manifestations. Epileptic visual hallucinations often are simple, brief, stereotyped, and fragmentary. They usually consist of small, brightly colored spots or shapes that flash.22 Complex visual hallucinations in epilepsy are similar to hypnagogic hallucinations but are rare. Intracranial electroencephalography recordings have shown that pathological excitation of visual cortical areas may be responsible for complex visual hallucinations in epilepsy.19
Dementia with Lewy bodies (DLB) is associated with visual hallucinations.23 Visual hallucinations occur in >20% of patients with DLB.24 Patients with DLB may see complex scenarios of people and items that are not present. Visual hallucinations have an 83% positive predictive value for distinguishing DLB from dementia of the Alzheimer’s type.25 There is a strong correlation between Lewy bodies located in the amygdala and parahippocampus and well-formed visual hallucinations.26
Visual hallucinations are common in Parkinson’s disease and may occur in up to one-half of patients.27 Patients with Parkinson’s disease may experience hallucinations similar to those observed in DLB, which can range from seeing a person or animal to more complex, formed, and mobile people, animals, or objects.
Table 2
Common causes of visual hallucinations
| Neurologic disorders |
| Migraine |
| Epilepsy |
| Hemispheric lesions |
| Optic nerve disorders |
| Brain stem lesions (peduncular hallucinosis) |
| Narcolepsy |
| Ophthalmologic diseases |
| Glaucoma |
| Retinal disease |
| Enucleation |
| Cataract formation |
| Choroidal disorder |
| Macular abnormalities |
| Toxic and metabolic conditions |
| Toxic-metabolic encephalopathy |
| Drug and alcohol withdrawal syndromes |
| Hallucinogens |
| Schizophrenia |
| Affective disorders |
| Conversion disorders |
| Sensory deprivation |
| Sleep deprivation |
| Hypnosis |
| Intense emotional experiences |
| Source: Reference 13 |
Olfactory hallucinations
Also known as phantosmia, olfactory hallucinations involve smelling odors that are not derived from any physical stimulus. They can occur with several psychiatric conditions, including schizophrenia, depression, bipolar disorder, eating disorders, and substance abuse.28 Olfactory hallucinations caused by epileptic activity are rare. They constitute approximately 0.9% of all auras and typically are described as unpleasant. Tumors that affect the medial temporal lobe and mesial temporal sclerosis are associated with olfactory hallucinations.29 Olfactory hallucinations also have been reported in patients with multi-infarct dementia, Alzheimer’s disease, and alcoholic psychosyndromes. In patients with schizophrenia, the smell may be perceived as coming from an external source, whereas patients with depression may perceive the source as internal.30 Patients who perceive that they are the source of an offensive odor—a condition known as olfactory reference syndrome—may wash excessively, overuse deodorants and perfumes, or become socially withdrawn.30
Gustatory hallucinations
Patients with gustatory hallucinations may experience salivation, sensation of thirst, or taste alterations. These hallucinations can be observed when the sylvian fissure that extends to the insula is stimulated electrically.31 Similar to olfactory hallucinations, gustatory hallucinations are associated with temporal lobe disease and parietal operculum lesions.31,32 Sinus diseases have been associated with olfactory and gustatory hallucinations.33 Brief gustatory hallucinations can be elicited with stimulation of the right rolandic operculum, parietal operculum, amygdala, hippocampus, medial temporal gyrus, and anterior part of right temporal gyrus.34
Tactile hallucinations
These hallucinations may include perceptions of insects crawling over or under the skin (formication) or simulation of pressure on skin.35 They have been associated with substance abuse, toxicity, or withdrawal.28 Tactile hallucinations are characteristic of cocaine or amphetamine intoxication.35
Tactile hallucinations are a rare symptom of schizophrenia. Heveling and colleagues reported a case of a woman, age 68, with chronic schizophrenia who experienced touching and being touched by a “shadow man” several times a day in addition to auditory and visual hallucinations.36 Her symptoms disappeared after 4 weeks of antipsychotic and mood stabilizer therapy.
Tactile hallucinations have been associated with obsessive-compulsive disorder (OCD).37 Fontenelle and colleagues suggested that OCD and psychotic disorders may share dysfunctional dopaminergic circuits.37
Somatic hallucinations
Patients who have somatic hallucinations report perceptions of abnormal body sensations or physical experiences. For example, a patient may have sense of not having a stomach while eating.35
This type of hallucination has been associated with activation of postcentral gyrus, parietal operculum, insula, and inferior parietal lobule on stereoelectroencephalography.34 In a study of cerebral blood flow in 20 geriatric patients with delusional disorder, somatic type who were experiencing somatic hallucinations, positron emission testing scan demonstrated increased perfusion in somatic sensory processing regions, particularly the left postcentral gyrus and the right paracentral lobule.38 Other researchers have linked somatic hallucinations with activation in the primary somatosensory and posterior parietal cortex, areas that normally mediate tactile perception.39
Related Resource
- Teeple RC, Caplan JP, Stern TA. Visual hallucinations: differential diagnosis and treatment. Prim Care Companion J Clin Psychiatry. 2009;11(1):26-32.
Disclosures
Drs. Ali, Patel, Avenido, Bailey, and Jabeen report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Riley is on the board of directors for Vertex Pharmaceuticals.
Acknowledgment
The authors would like to thank Marwah Shahid, Research Associate, Vanderbilt University, Nashville, TN.
1. Cummings JL, Mega MS. Hallucinations. In: Cummings JL Mega MS, eds. Neuropsychiatry and behavioral neuroscience. New York, NY: Oxford University Press; 2003: 187–199.
2. Shergill SS, Murray RM, McGuire PK. Auditory hallucinations: a review of psychological treatments. Schizophr Res. 1998;32(3):137-150.
3. Goodwin DW, Alderson P, Rosenthal R. Clinical significance of hallucinations in psychiatric disorders. A study of 116 hallucinatory patients. Arch Gen Psychiatry. 1971;24(1):76-80.
4. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
5. Kasper BS, Kasper EM, Pauli E, et al. Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology. Epilepsy Behav. 2010;18(1-2):13-23.
6. Currie S, Heathfield KW, Henson RA, et al. Clinical course and prognosis of temporal lobe epilepsy. A survey of 666 patients. Brain. 1971;94(1):173-190.
7. Keshavan MS, David AS, Steingard S, et al. Musical hallucinations: a review and synthesis. Cogn Behav Neurol. 1992;5(3):211-223.
8. Duncan R, Mitchell JD, Critchley EMR. Hallucinations and music. Behav Neurol. 1989;2(2):115-124.
9. Tarachow S. The clinical value of hallucinations in localizing brain tumors. Am J Psychiatry. 1941;97:1434-1442.
10. Lanska DJ, Lanska MJ, Mendez MF. Brainstem auditory hallucinosis. Neurology. 1987;37(10):1685.-
11. Norton JW, Corbett JJ. Visual perceptual abnormalities: hallucinations and illusions. Semin Neurol. 2000;20(1):111-121.
12. Kaplan HI, Sadock BJ, Grebb JA. Typical signs and symptoms of psychiatric illness defined. In: Kaplan HI Sadock BJ, Grebb JA, eds. Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences, clinical psychiatry. Baltimore, MD: Williams and Wilkins; 1994:300.
13. Cummings JL, Miller BL. Visual hallucinations. Clinical occurrence and use in differential diagnosis. West J Med. 1987;146(1):46-51.
14. First MB, Tasman A. Schizophrenia and other psychoses. In: First MB Tasman A, eds. Clinical guide to the diagnosis and treatment of mental disorders. San Francisco, CA: John Wiley and Sons; 2009:245–278.
15. Mueser KT, Bellack AS, Brady EU. Hallucinations in schizophrenia. Acta Psychiatr Scand. 1990;82(1):26-29.
16. Small IF, Small JG, Andersen JM. Clinical characteristics of hallucinations of schizophrenia. Dis Nerv Syst. 1966;27(5):349-353.
17. Webster R, Holroyd S. Prevalence of psychotic symptoms in delirium. Psychosomatics. 2000;41(6):519-522.
18. Gastfriend DR, Renner JA, Hackett TP. Alcoholic patients: acute and chronic. In: Stern TA Fricchione G, Cassem NH, et al, eds. Massachusetts General Hospital handbook of general hospital psychiatry. 5th ed. Philadelphia, PA: Mosby; 2004:203–216.
19. Manford M, Andermann F. Complex visual hallucinations. Clinical and neurobiological insights. Brain. 1998;121(Pt 10):1819-1840.
20. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257-270.
21. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain. 1996;119(Pt 2):355-361.
22. Panayiotopoulos CP. Elementary visual hallucinations blindness, and headache in idiopathic occipital epilepsy: differentiation from migraine. J Neurol Neurosurg Psychiatry. 1999;66(4):536-540.
23. Ballard CG, O’Brien JT, Swann AG, et al. The natural history of psychosis and depression in dementia with Lewy bodies and Alzheimer’s disease: persistence and new cases over 1 year of follow-up. J Clin Psychiatry. 2001;62(1):46-49.
24. Ala TA, Yang KH, Sung JH, et al. Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer’s disease at presentation: a clinicopathological study. J Neurol Neurosurg Psychiatry. 1997;62(1):16-21.
25. Tiraboschi P, Salmon DP, Hansen LA, et al. What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain. 2006;129(Pt 3):729-735.
26. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain. 2002;125(Pt 2):391-403.
27. Williams DR, Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol. 2005;4(10):605-610.
28. Lewandowski KE, DePaola J, Camsari GB, et al. Tactile, olfactory, and gustatory hallucinations in psychotic disorders: a descriptive study. Ann Acad Med Singapore. 2009;38(5):383-385.
29. Acharya V, Acharya J, Lüders H. Olfactory epileptic auras. Neurology. 1998;51(1):56-61.
30. Ropper AH, Samuels MA. Disorders of smell and taste. In: Ropper AH Samuels MA, eds. Adams and Victor’s principles of neurology. 9th ed. New York, NY: McGraw-Hill Companies; 2009:216–224.
31. Ropper AH, Samuels MA. Epilepsy and other seizure disorders. In: Ropper AH Samuels MA, eds. Adams and Victor’s principles of neurology. 9th ed. New York, NY: McGraw-Hill Companies; 2009:304–338.
32. Capampangan DJ, Hoerth MT, Drazkowski JF, et al. Olfactory and gustatory hallucinations presenting as partial status epilepticus because of glioblastoma multiforme. Ann Emerg Med. 2010;56(4):374-377.
33. Frasnelli J, Reden J, Landis BN, et al. Comment on “Olfactory hallucinations as a manifestation of hidden rhinosinusitis”. J Clin Neurosci. 2010;17(4):543.-
34. Elliott B, Joyce E, Shorvon S. Delusions illusions and hallucinations in epilepsy: 1. Elementary phenomena. Epilepsy Res. 2009;85(2-3):162-171.
35. Nurcombe B, Ebert MH. The psychiatric interview. In: Ebert MH Nurcombe B, Loosen PT, et al, eds. Current diagnosis and treatment: psychiatry. 2nd ed. New York, NY: McGraw-Hill Companies; 2008:95–114.
36. Heveling T, Emrich HM, Dietrich DE. Treatment of a rare psychopathological phenomenon: tactile hallucinations and the delusional other. Eur Psychiatry. 2004;19(6):387-388.
37. Fontenelle LF, Lopes AP, Borges MC, et al. Auditory, visual, tactile, olfactory, and bodily hallucinations in patients with obsessive-compulsive disorder. CNS Spectr. 2008;13(2):125-130.
38. Nemoto K, Mizukami K, Hori T, et al. Hyperperfusion in primary somatosensory region related to somatic hallucination in the elderly. Psychiatry Clin Neurosci. 2010;64(4):421-425.
39. Shergill SS, Cameron LA, Brammer MJ, et al. Modality specific neural correlates of auditory and somatic hallucinations. J Neurol Neurosurg Psychiatry. 2001;71(5):688-690.
1. Cummings JL, Mega MS. Hallucinations. In: Cummings JL Mega MS, eds. Neuropsychiatry and behavioral neuroscience. New York, NY: Oxford University Press; 2003: 187–199.
2. Shergill SS, Murray RM, McGuire PK. Auditory hallucinations: a review of psychological treatments. Schizophr Res. 1998;32(3):137-150.
3. Goodwin DW, Alderson P, Rosenthal R. Clinical significance of hallucinations in psychiatric disorders. A study of 116 hallucinatory patients. Arch Gen Psychiatry. 1971;24(1):76-80.
4. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington DC: American Psychiatric Association; 2000.
5. Kasper BS, Kasper EM, Pauli E, et al. Phenomenology of hallucinations, illusions, and delusions as part of seizure semiology. Epilepsy Behav. 2010;18(1-2):13-23.
6. Currie S, Heathfield KW, Henson RA, et al. Clinical course and prognosis of temporal lobe epilepsy. A survey of 666 patients. Brain. 1971;94(1):173-190.
7. Keshavan MS, David AS, Steingard S, et al. Musical hallucinations: a review and synthesis. Cogn Behav Neurol. 1992;5(3):211-223.
8. Duncan R, Mitchell JD, Critchley EMR. Hallucinations and music. Behav Neurol. 1989;2(2):115-124.
9. Tarachow S. The clinical value of hallucinations in localizing brain tumors. Am J Psychiatry. 1941;97:1434-1442.
10. Lanska DJ, Lanska MJ, Mendez MF. Brainstem auditory hallucinosis. Neurology. 1987;37(10):1685.-
11. Norton JW, Corbett JJ. Visual perceptual abnormalities: hallucinations and illusions. Semin Neurol. 2000;20(1):111-121.
12. Kaplan HI, Sadock BJ, Grebb JA. Typical signs and symptoms of psychiatric illness defined. In: Kaplan HI Sadock BJ, Grebb JA, eds. Kaplan and Sadock’s synopsis of psychiatry: behavioral sciences, clinical psychiatry. Baltimore, MD: Williams and Wilkins; 1994:300.
13. Cummings JL, Miller BL. Visual hallucinations. Clinical occurrence and use in differential diagnosis. West J Med. 1987;146(1):46-51.
14. First MB, Tasman A. Schizophrenia and other psychoses. In: First MB Tasman A, eds. Clinical guide to the diagnosis and treatment of mental disorders. San Francisco, CA: John Wiley and Sons; 2009:245–278.
15. Mueser KT, Bellack AS, Brady EU. Hallucinations in schizophrenia. Acta Psychiatr Scand. 1990;82(1):26-29.
16. Small IF, Small JG, Andersen JM. Clinical characteristics of hallucinations of schizophrenia. Dis Nerv Syst. 1966;27(5):349-353.
17. Webster R, Holroyd S. Prevalence of psychotic symptoms in delirium. Psychosomatics. 2000;41(6):519-522.
18. Gastfriend DR, Renner JA, Hackett TP. Alcoholic patients: acute and chronic. In: Stern TA Fricchione G, Cassem NH, et al, eds. Massachusetts General Hospital handbook of general hospital psychiatry. 5th ed. Philadelphia, PA: Mosby; 2004:203–216.
19. Manford M, Andermann F. Complex visual hallucinations. Clinical and neurobiological insights. Brain. 1998;121(Pt 10):1819-1840.
20. Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med. 2002;346(4):257-270.
21. Russell MB, Olesen J. A nosographic analysis of the migraine aura in a general population. Brain. 1996;119(Pt 2):355-361.
22. Panayiotopoulos CP. Elementary visual hallucinations blindness, and headache in idiopathic occipital epilepsy: differentiation from migraine. J Neurol Neurosurg Psychiatry. 1999;66(4):536-540.
23. Ballard CG, O’Brien JT, Swann AG, et al. The natural history of psychosis and depression in dementia with Lewy bodies and Alzheimer’s disease: persistence and new cases over 1 year of follow-up. J Clin Psychiatry. 2001;62(1):46-49.
24. Ala TA, Yang KH, Sung JH, et al. Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer’s disease at presentation: a clinicopathological study. J Neurol Neurosurg Psychiatry. 1997;62(1):16-21.
25. Tiraboschi P, Salmon DP, Hansen LA, et al. What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain. 2006;129(Pt 3):729-735.
26. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain. 2002;125(Pt 2):391-403.
27. Williams DR, Lees AJ. Visual hallucinations in the diagnosis of idiopathic Parkinson’s disease: a retrospective autopsy study. Lancet Neurol. 2005;4(10):605-610.
28. Lewandowski KE, DePaola J, Camsari GB, et al. Tactile, olfactory, and gustatory hallucinations in psychotic disorders: a descriptive study. Ann Acad Med Singapore. 2009;38(5):383-385.
29. Acharya V, Acharya J, Lüders H. Olfactory epileptic auras. Neurology. 1998;51(1):56-61.
30. Ropper AH, Samuels MA. Disorders of smell and taste. In: Ropper AH Samuels MA, eds. Adams and Victor’s principles of neurology. 9th ed. New York, NY: McGraw-Hill Companies; 2009:216–224.
31. Ropper AH, Samuels MA. Epilepsy and other seizure disorders. In: Ropper AH Samuels MA, eds. Adams and Victor’s principles of neurology. 9th ed. New York, NY: McGraw-Hill Companies; 2009:304–338.
32. Capampangan DJ, Hoerth MT, Drazkowski JF, et al. Olfactory and gustatory hallucinations presenting as partial status epilepticus because of glioblastoma multiforme. Ann Emerg Med. 2010;56(4):374-377.
33. Frasnelli J, Reden J, Landis BN, et al. Comment on “Olfactory hallucinations as a manifestation of hidden rhinosinusitis”. J Clin Neurosci. 2010;17(4):543.-
34. Elliott B, Joyce E, Shorvon S. Delusions illusions and hallucinations in epilepsy: 1. Elementary phenomena. Epilepsy Res. 2009;85(2-3):162-171.
35. Nurcombe B, Ebert MH. The psychiatric interview. In: Ebert MH Nurcombe B, Loosen PT, et al, eds. Current diagnosis and treatment: psychiatry. 2nd ed. New York, NY: McGraw-Hill Companies; 2008:95–114.
36. Heveling T, Emrich HM, Dietrich DE. Treatment of a rare psychopathological phenomenon: tactile hallucinations and the delusional other. Eur Psychiatry. 2004;19(6):387-388.
37. Fontenelle LF, Lopes AP, Borges MC, et al. Auditory, visual, tactile, olfactory, and bodily hallucinations in patients with obsessive-compulsive disorder. CNS Spectr. 2008;13(2):125-130.
38. Nemoto K, Mizukami K, Hori T, et al. Hyperperfusion in primary somatosensory region related to somatic hallucination in the elderly. Psychiatry Clin Neurosci. 2010;64(4):421-425.
39. Shergill SS, Cameron LA, Brammer MJ, et al. Modality specific neural correlates of auditory and somatic hallucinations. J Neurol Neurosurg Psychiatry. 2001;71(5):688-690.