Psychiatr Q DOI 10.1007/s11126-014-9319-1 ORIGINAL PAPER
Antipsychotic Medication-Induced Dysphoria: Its Meaning, Association with Typical vs. Atypical Medications and Impact on Adherence Hanjing Emily Wu • Olaoluwa O. Okusaga
Ó Springer Science+Business Media New York 2014
Abstract Antipsychotic medication-induced dysphoria is a relatively under-recognized and understudied effect of antipsychotic medication. Although the term is encountered in clinical practice and in the literature, there is no consensus regarding its exact meaning. This article is a narrative review of the literature on antipsychotic medication and dysphoria based on a pubmed database search. We found that antipsychotic medication-induced dysphoria is a term used to describe a negative and unpleasant affective state which seems to be more often associated with high potency first-generation antipsychotics and could potentially lead to medication non-adherence. Though it is plausible to expect antipsychotic medicationinduced dysphoria to be related to extrapyramidal symptoms, most especially akathisia, the nature of the association remains unspecified. Furthermore, there is some evidence that dopamine blockade maybe involved in the pathogenesis of antipsychotic medication-induced dysphoria. However, the limited methods of the currently available studies make it impossible to conclusively address the question of which class of antipsychotic (first- or secondgeneration) has a higher prevalence and severity of the syndrome. Keywords Dysphoria Neuroleptics First-generation antipsychotics Secondgeneration antipsychotics Schizophrenia Adherence
Introduction Antipsychotic medications are the mainstay of treatment for schizophrenia. First-generation antipsychotic medications (also called typical or conventional antipsychotics) such as
H. E. Wu O. O. Okusaga (&) University of Texas Harris County Psychiatric Center, 2800 South MacGregor Way, Houston, TX 77021, USA e-mail: [email protected] H. E. Wu O. O. Okusaga Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
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chlorpromazine, fluphenazine and haloperidol have been used for the treatment of schizophrenia since the 1950s. Second-generation antipsychotic medications (also called atypical antipsychotics) were first approved for the treatment of schizophrenia in the early 1990s. Relative to most second-generation antipsychotics, first-generation antipsychotic medications generally have a higher propensity to induce a range of extrapyramidal side effects (EPS) such as dystonia, akathisia, tardive dyskinesia, and parkinsonism [1, 2]. The second generation antipsychotics have been reported to be better tolerated than first-generation antipsychotics [3]. The term antipsychotic medication-induced dysphoria or neuroleptic-induced dysphoria is often used by clinicians when referring to unpleasant feelings reported by patients after receiving antipsychotic medications and even though the term is frequently encountered in clinical practice and in the literature, there is no consensus regarding its exact meaning. The word ‘‘dysphoria’’ when used in psychiatric practice, usually has an affective connotation to it; for example a manic episode characterized by angry and irritable mood might be referred to as ‘‘dysphoric mania’’. Therefore many clinicians using the term neuroleptic-induced dysphoria are probably referring to negative and unpleasant affective states which are assumed to be directly related to the use of antipsychotic medication. On the other hand, there are other clinicians who use the term to refer to features related to the EPS, most especially a state of akathisia, induced by antipsychotics. Antipsychotic induced-dysphoria has not only been reported in schizophrenia patients but it has also been reported in healthy volunteers given antipsychotics as part of an experimental protocol [4, 5]. Most clinicians are of the opinion that feelings of dysphoria are more frequently associated with first-generation antipsychotic medications than second-generation antipsychotics though this belief may just be pure conjecture. Antipsychotic medicationinduced dysphoria is an important phenomenon relevant to clinical therapeutic outcomes in schizophrenia, including patient’s adherence to medications and possibly, use of illicit substance [6–8]. Since the early 1990s, subjective tolerability and quality of life have been recognized as important aspects of the treatment of schizophrenia [9]. In this review we have aimed to: (1) clarify the meaning and manifestations of the term neuroleptic (or antipsychotic)-induced dysphoria; (2) evaluate the general belief that second-generation antipsychotics are less likely to be associated with dysphoria in comparison to first generation antipsychotics and; (3) clarify whether antipsychotic drug-induced dysphoria leads to poor adherence and its implication for clinical practice.
Methods This is a narrative review of the literature on antipsychotic medication and dysphoria based on a pubmed database search. Search terms used included ‘‘neuroleptic induced dysphoria’’, ‘‘antipsychotic medication induced dysphoria’’, ‘‘drug induced dysphoria’’, ‘‘neuroleptic induced depression’’ and ‘‘neuroleptic induced anxiety’’. Potentially relevant papers were identified by their titles and the decision to retrieve full text of such papers was based on a perusal of the abstract. We also examined the references of identified papers for additional articles that could be included in this review. We reviewed only papers written in English.
Results The pubmed search yielded a total of 3, 749 documents but a perusal of the title and abstracts revealed that most of these documents were not applicable for this review.
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Twenty-six articles were identified which we felt were applicable for this narrative review and most of them were published between 1973 and 2007. The relevant papers are cited in the following subsections which address the aims of this paper. Clarifying the Meaning and Manifestations of Antipsychotic Medication-Induced Dysphoria Singh and Smith in their study of the kinetics and dynamics of response to haloperidol in acute schizophrenia described the dysphoria associated with the use of haloperidol as a mood state characterized by anxiety, tension, depression, feelings of guilt and somatic concerns [10]. The subset of patients that experienced dysphoria expressed significant dissatisfaction with their present state and felt that the medication had made them worse. Singh and Smith also reported that the dysphoria associated with haloperidol was unlikely to be explained solely by EPS as the non-dysphoric (‘‘euphoric’’) patients also experienced significant EPS. Caine and Polinsky [11] described cases of haloperidol-induced dysphoria in patients with Tourette’s syndrome and all the cases reported mood symptoms akin to a depressive episode. For example, one patient reportedly stated ‘‘it was as if a shade suddenly came down’’; the same patient also complained of sadness, crying and loss of energy. Another patient became ‘‘depressed and despondent’’ and one became ‘‘inappropriately sad and tearful’’. None of the patients described by Caine and Polinsky had a history of depression and their dysphoric symptoms were thought to be unrelated to EPS, cognitive impairment or drowsiness secondary to haloperidol treatment. Furthermore, all the patients seemed to experience the depressive symptoms only when the dose of haloperidol was increased beyond a certain threshold value. Bruun [12] also reporting on cases of Tourette’s syndrome treated with haloperidol, considered neuroleptic-induced dysphoria to be synonymous with an affective state characterized by depressive features. She reported a case of a child who became tearful, clingy, whiny and became reluctant to attend school and also developed thoughts of self-harm. The child’s depressive symptoms resolved after the dose of haloperidol was reduced. In their study, Weiden et al. [13] defined neurolepticinduced dysphoria as ‘‘a generalized feeling of unwellness that the patient attributes to the neuroleptic’’. However, Newcomer et al. [14] used the term in relation to akathisia-related affective symptoms that did not meet the threshold for a depressive episode. Awad and Voruganti [15] in their review wrote that patients’ report of antipsychotic medicationinduced dysphoria included use of descriptors such as ‘‘feeling blah, listless, tired, and lacking interest and ambition.’’ Voruganti and Awad also recommended that antipsychotic medication-induced dysphoria (like EPS) be considered as a variant or manifestation of dopaminergic blockade by antipsychotics. In other studies, the dysphoria induced by antipsychotics included subjective changes such as anger, depression, and hostility [16, 17]. Is Antipsychotic Medication-Induced Dysphoria More Prevalent and/or Worse with First-Generation Antipsychotics Relative to Second-Generation Antipsychotics? The prevalence of antipsychotic medication induced-dysphoric response is estimated to range between 10 and 60 % in patients who receive conventional antipsychotic medications [13, 18] and the dysphoria seem to be more prevalent in patients treated with highpotency antipsychotic medications such as haloperidol which has strong D2 blocking effects [11, 19]. On the other hand, second-generation antipsychotics appear to have a lower risk of inducing dypshoric responses in schizophrenia patients [20–24]. The results of a number of studies indicate that second-generation antipsychotics may offer better
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subjective tolerability [21, 25–27]. For instance, a study by Opjordsmoen et al. [28] showed that 16.5 % of patients treated with first-generation antipsychotics reported dysphoria, in contrast to 4.6 % of patients treated with second-generation antipsychotics. In another study Marder et al. [29] compared subjective response and EPS in patients treated with risperidone and low dose haloperidol in a 2 years study. Patients who received risperidone had better subjective feelings including less anxiety and depression. However, there was also less EPS in the patients treated with risperidone which could have contributed to better subjective feelings in this group. Hogan and Awad also assessed the prevalence of dysphoria in patients treated with first-generation versus second-generation antipsychotic medications. They found a significantly higher proportion of dysphoric responders among patients treated with first-generation than those treated with secondgeneration antipsychotics [30]. Does Antipsychotic Medication-Induced Dysphoria Lead to Poor Adherence? Poor adherence to antipsychotic medications is a major problem in the treatment of schizophrenia. Regarding antipsychotic medication-induced dysphoria and clinical outcomes, Singh and Smith [10] were the first to point out that dysphoria is associated with less favorable clinical outcomes. Van Putten et al. [31] documented the effect of dysphoria on clinical therapeutic outcome and in one of these studies, 63 schizophrenia patients were treated with thiothixene and 22 % reported dysphoric symptoms which ultimately resulted in refusal of treatment by these patients. In another study, Van Putten and May [32] found that dysphoria was associated with poor treatment response in schizophrenia patients treated with chlorpromazine and they suggested that patients’ subjective report of feelings related to antipsychotic medications should be elicited and this information should be taken into consideration in selecting medication. In another study, 35 previously unmedicated schizophrenia patients were given chlorpromazine or haloperidol and the experience of dysphoria was strongly related to poor clinical outcome [33]. Opojordsmeon et al. [28] found higher tolerability and adherence rates in first-episode psychotic patients treated with second-generation antipsychotic medication compared to those treated with low-dose firstgeneration antipsychotics. Similar findings were reported by Ascher-Svanum et al. [34] in patients with chronic schizophrenia treated with first- or second-generation antipsychotics; the atypical antipsychotic group had longer treatment duration than the typical antipsychotic treatment group during 1 year of follow-up.
Discussion Antipsychotic-induced dysphoria is a negative affective state with an equivocal relationship with the onset of EPS (specifically, akathisia). The literature seems to support the notion that there is a higher incidence of antipsychotic-induced dysphoria in patients treated with first-generation antipsychotics (especially those with very strong D2 blocakde) in comparison with those treated with second-generation antipsychotics. The possible mechanisms underlying neuroleptic-induced dysphoria could serve as a template to better understand why neuroleptic-induced dysphoria may be more prevalent in high potency first-generation antipsychotics than second-generation antipsychotics. Some researchers have suggested that dysphoria results from dopamine blockade and decreased dopamine neurotransmission has been associated with dysphoria [35–38]. The potential involvement of dopamine in the genesis of neroleptic-induced dysphoria was evaluated by Voruganti
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et al. [16] by experimentally depleting dopamine in medication-free schizophrenia patients. The chemical agent alphamethyl paratyrosine (AMPT) inhibits one of the enzymes involved in dopamine synthesis and it was administered to deplete dopamine after which dysphoric responses were assessed and imaging studies were carried out. Voruganti et al. [39] found that patients with higher synaptic dopamine activity at baseline had reduced risk of dysphoria compared with those with a relatively reduced synaptic dopamine activity. Antipsychotic-induced dysphoria is associated with poor adherence, the extreme form of which is outright refusal of medication by the patient. A physician’s unawareness of antipsychotic-induced dysphoria as a potential cause of refusal of medication could damage the physician-patient relationship and weaken the therapeutic alliance. This is because on the patient’s part, there are no perceived benefits in continuing to take the medication, while the physician perceives the patient as uncooperative and non-adherent to treatment recommendations. It has also been suggested that dysphoric reactions to antipsychotics may be associated with substance abuse (i.e. patients may use illicit substances to ‘‘self-medicate’’ the unpleasant feelings induced by antipsychotic medication) [6–8] but because this is a relatively understudied area, the link between the two requires further study.
Conclusion Antipsychotic medication-induced dysphoria remains an important phenomenon relevant to clinical practice and treatment outcomes. Though the extant literature suggests that second-generation antipsychotics maybe less likely to induce dysphoria, the limited methods of the few currently available studies make it impossible to conclusively address the question of which class of antipsychotic (first- or second-generation) has a higher prevalence and severity of the syndrome. Studies designed to further elucidate the underlying mechanisms of antipsychotic medication-induced dysphoria, characterize the subset of patients likely to experience the syndrome and directly compare equivalent doses of first and second-generation medications on the prevalence and severity of antipsychotic medication-induced dysphoria are warranted. There is also a need to develop evidencebased criteria for diagnosing antipsychotic medication-induced dysphoria as this will not only be useful for clinicians and their patients but would also enhance research on this relatively understudied syndrome.
References 1. King C, Voruganti LN: What’s in a name? The evolution of the nomenclature of antipsychotic drugs. Journal of Psychiatry and Neuroscience 27:168–175, 2002. 2. Harrison PJ: The neuropathological effects of antipsychotic drugs. Schizophrenia Research 40:87–99, 1999. 3. Leucht S, Pitschel-Walz G, Abraham D, Kissling W: Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophrenia Research 35:51–68, 1999. 4. King DJ, Burke M, Lucas RA: Antipsychotic drug-induced dysphoria. The British Journal of Psychiatry 167:480–482, 1995. 5. Lynch G, Green JF, King DJ: Antipsychotic drug-induced dysphoria. The British Journal of Psychiatry 169:524, 1996.
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Psychiatr Q 6. Noordsy DL, Drake RE, Teague GB, Osher FC, Hurlbut SC, Beaudett MS, et al.: Subjective experiences related to alcohol use among schizophrenics. The Journal of nervous and mental disease 179:410–414, 1991. 7. Mueser KT, Drake RE, Wallach MA: Dual diagnosis: a review of etiological theories. Addictive Behaviors 23:717–734, 1998. 8. Voruganti LN, Heslegrave RJ, Awad AG: Neuroleptic dysphoria may be the missing link between schizophrenia and substance abuse. The Journal of Nervous and Mental Disease 185:463–465, 1997. 9. Awad AG, Voruganti LN: Quality of life and new antipsychotics in schizophrenia. Are patients better off? International Journal of Social Psychiatry 45:268–275, 1999. 10. Singh MM, Smith JM: Kinetics and dynamics of response to haloperidol in acute schizophrenia–A longitudinal study of the therapeutic process. Comprehensive Psychiatry 14:393–414, 1973. 11. Caine ED, Polinsky RJ: Haloperidol-induced dysphoria in patients with Tourette syndrome. The American journal of psychiatry 136:1576, 1979. 12. Bruun RD: Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette’s disorder. The American Journal of Psychiatry 145:621–624, 1988. 13. Weiden PJ, John Mann J, Dixon L, Haas G, Dechillo N, Frances AJ: Is neuroleptic dysphoria a healthy response? Comprehensive Psychiatry 30:546–552, 1989. 14. Newcomer JW, Miller LS, Faustman WO, Wetzel MW, Vogler GP, Csernansky JG: Correlations between akathisia and residual psychopathology: a by-product of neuroleptic-induced dysphoria. The British Journal of Psychiatry 164:834–838, 1994. 15. Awad AG, Voruganti L: New antipsychotics, compliance, quality of life, and subjective tolerability–are patients better off? Canadian Journal of Psychiatry 49:297–302, 2004. 16. Voruganti L, Slomka P, Zabel P, Costa G, So A, Mattar A, et al: Subjective effects of AMPT-induced dopamine depletion in schizophrenia: correlation between dysphoric responses and striatal D(2) binding ratios on SPECT imaging. Neuropsychopharmacology 25:642–650, 2001. 17. Voruganti L, Awad AG: Brain imaging research on subjective responses to psychotropic drugs. Acta Psychiatrica Scandinavica 111:22–28, 2005. 18. Voruganti L, Awad AG: Neuroleptic dysphoria: towards a new synthesis. Psychopharmacology (Berl) 171:121–132, 2004. 19. Caine ED, Polinsky RJ: Haloperidol-induced dysphoria in patients with Tourette syndrome. The American Journal of Psychiatry 136:1216–1217, 1979. 20. Voruganti L, Cortese L, Oyewumi L, Cernovsky Z, Zirul S, Awad A: Comparative evaluation of conventional and novel antipsychotic drugs with reference to their subjective tolerability, side-effect profile and impact on quality of life. Schizophrenia Research 43:135–145, 2000. 21. Voruganti L, Cortese L, Owyeumi L, Kotteda V, Cernovsky Z, Zirul S, et al.: Switching from conventional to novel antipsychotic drugs: results of a prospective naturalistic study. Schizophrenia Research 57:201–208, 2002. 22. Cook PE, Goldberg JO, and Van Lieshout RJ: Benefits of switching from typical to atypical antipsychotic medications: a longitudinal study in a community-based setting. Canadian Journal of Psychiatry 47:870–874, 2002. 23. Naber D, Karow A, Lambert M: Subjective well-being under the neuroleptic treatment and its relevance for compliance. Acta Psychiatrica Scandinavica. Supplementum 111:29–34, 2005. 24. Naber D, Moritz S, Lambert M, Pajonk FG, Holzbach R, Mass R, et al.: Improvement of schizophrenic patients’ subjective well-being under atypical antipsychotic drugs. Schizophrenia Research 50:79–88, 2001. 25. Harvey PD, Rabinowitz J, Eerdeken S, Davidson M: Treatment of cognitive impairment in early psychosis: a comparison of risperidone and haloperidol in a large long-term trial. The American Journal of Psychiatry 162:1888–1895, 2005. 26. Marder SR: Lessons from each drug trial. The American Journal of Psychiatry 164:375–376, 2007. 27. Naber D. Subjective effects of antipsychotic treatment. Acta Psychiatrica Scandinavica 111:81–83, 2005. 28. Opjordsmoen S, Melle I, Friis S, Haahr U, Johannessen JO, Larsen TK et al.: Stability of medication in early psychosis: a comparison between second-generation and low-dose first-generation antipsychotics. Early Intervention in Psychiatry 3:58–65, 2009. 29. Marder SR, Glynn SM, Wirshing WC, Wirshing DA, Ross D, Widmark C et al.: Maintenance treatment of schizophrenia with risperidone or haloperidol: 2 year outcomes. American Journal of Psychiatry 160:1405–1412, 2003. 30. Awad A, Hogan T: Subjective response to neuroleptics and the quality of life: implications for treatment outcome. Acta Psychiatrica Scandinavica 89:27–32, 1994.
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Psychiatr Q 31. Van Putten T, May PR, Marder SR, Wittmann LA: Subjective response to antipsychotic drugs. Archives of General Psychiatry 38:187–190, 1981. 32. Van Putten T, May R: Subjective response as a predictor of outcome in pharmacotherapy: the consumer has a point. Archives of General Psychiatry 35:477–480, 1978. 33. Hogan T, Awad A: Subjective response to neuroleptics and outcome in schizophrenia: a re-examination comparing two measures. Psychological Medicine 22:347–352, 1992. 34. Ascher-Svanum H, Zhu B, Faries D, Landbloom R, Swartz M, Swanson J: Time to discontinuation of atypical versus typical antipsychotics in the naturalistic treatment of schizophrenia. BMC Psychiatry 6:8, 2006. 35. Koob GF, Le Moal M: Drug abuse: hedonic homeostatic dysregulation. Science 278:52–58, 1997. 36. Fibiger HC: Neurobiology of depression: focus on dopamine. Advances in Biochemical Psychopharmacology 49:1–17, 1995. 37. Self DW, Nestler EJ: Molecular mechanisms of drug reinforcement and addiction. Annual Review of Neuroscience 18:463–495, 1995. 38. Wise RA: Addictive drugs and brain stimulation reward. Annual Review of Neuroscience 19:319–340, 1996. 39. Voruganti L, Slomka P, Zabel P, Costa G, So A, Mattar A, et al.: Subjective effects of AMPT induced dopamine depletion in schizophrenia; the correlation between D2 binding ratio and dysphoric responses. Neuropsychopharmacology 25:642–650, 2001.
Hanjing Emily Wu, MD, PhD is a resident in the Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Houston/Harris County Psychiatric Center, 2800 South MacGregor Way, Houston, TX. Her research interests are focused on psychopharmacology and immunology related to psychiatric disorders as well as innovative treatments for mood disorders and schizophrenia. Olaoluwa O. Okusaga, MD, MScPHR is Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Houston/Harris County Psychiatric Center, 2800 South MacGregor Way, Houston, TX. His research interests are focused on examining how the environment (biological and physical) interact with brain and body processes in the etiology and exacerbation of mental illness. His current interests involve elucidating possible mechanisms of inflammation and abnormal amino acid metabolism in the pathophysiology of schizophrenia.
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Antipsychotic Medication-Induced Dysphoria: Its Meaning, Association with Typical vs. Atypical Medications and Impact on Adherence Hanjing Emily Wu • Olaoluwa O. Okusaga
Ó Springer Science+Business Media New York 2014
Abstract Antipsychotic medication-induced dysphoria is a relatively under-recognized and understudied effect of antipsychotic medication. Although the term is encountered in clinical practice and in the literature, there is no consensus regarding its exact meaning. This article is a narrative review of the literature on antipsychotic medication and dysphoria based on a pubmed database search. We found that antipsychotic medication-induced dysphoria is a term used to describe a negative and unpleasant affective state which seems to be more often associated with high potency first-generation antipsychotics and could potentially lead to medication non-adherence. Though it is plausible to expect antipsychotic medicationinduced dysphoria to be related to extrapyramidal symptoms, most especially akathisia, the nature of the association remains unspecified. Furthermore, there is some evidence that dopamine blockade maybe involved in the pathogenesis of antipsychotic medication-induced dysphoria. However, the limited methods of the currently available studies make it impossible to conclusively address the question of which class of antipsychotic (first- or secondgeneration) has a higher prevalence and severity of the syndrome. Keywords Dysphoria Neuroleptics First-generation antipsychotics Secondgeneration antipsychotics Schizophrenia Adherence
Introduction Antipsychotic medications are the mainstay of treatment for schizophrenia. First-generation antipsychotic medications (also called typical or conventional antipsychotics) such as
H. E. Wu O. O. Okusaga (&) University of Texas Harris County Psychiatric Center, 2800 South MacGregor Way, Houston, TX 77021, USA e-mail: [email protected] H. E. Wu O. O. Okusaga Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston, Houston, TX, USA
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chlorpromazine, fluphenazine and haloperidol have been used for the treatment of schizophrenia since the 1950s. Second-generation antipsychotic medications (also called atypical antipsychotics) were first approved for the treatment of schizophrenia in the early 1990s. Relative to most second-generation antipsychotics, first-generation antipsychotic medications generally have a higher propensity to induce a range of extrapyramidal side effects (EPS) such as dystonia, akathisia, tardive dyskinesia, and parkinsonism [1, 2]. The second generation antipsychotics have been reported to be better tolerated than first-generation antipsychotics [3]. The term antipsychotic medication-induced dysphoria or neuroleptic-induced dysphoria is often used by clinicians when referring to unpleasant feelings reported by patients after receiving antipsychotic medications and even though the term is frequently encountered in clinical practice and in the literature, there is no consensus regarding its exact meaning. The word ‘‘dysphoria’’ when used in psychiatric practice, usually has an affective connotation to it; for example a manic episode characterized by angry and irritable mood might be referred to as ‘‘dysphoric mania’’. Therefore many clinicians using the term neuroleptic-induced dysphoria are probably referring to negative and unpleasant affective states which are assumed to be directly related to the use of antipsychotic medication. On the other hand, there are other clinicians who use the term to refer to features related to the EPS, most especially a state of akathisia, induced by antipsychotics. Antipsychotic induced-dysphoria has not only been reported in schizophrenia patients but it has also been reported in healthy volunteers given antipsychotics as part of an experimental protocol [4, 5]. Most clinicians are of the opinion that feelings of dysphoria are more frequently associated with first-generation antipsychotic medications than second-generation antipsychotics though this belief may just be pure conjecture. Antipsychotic medicationinduced dysphoria is an important phenomenon relevant to clinical therapeutic outcomes in schizophrenia, including patient’s adherence to medications and possibly, use of illicit substance [6–8]. Since the early 1990s, subjective tolerability and quality of life have been recognized as important aspects of the treatment of schizophrenia [9]. In this review we have aimed to: (1) clarify the meaning and manifestations of the term neuroleptic (or antipsychotic)-induced dysphoria; (2) evaluate the general belief that second-generation antipsychotics are less likely to be associated with dysphoria in comparison to first generation antipsychotics and; (3) clarify whether antipsychotic drug-induced dysphoria leads to poor adherence and its implication for clinical practice.
Methods This is a narrative review of the literature on antipsychotic medication and dysphoria based on a pubmed database search. Search terms used included ‘‘neuroleptic induced dysphoria’’, ‘‘antipsychotic medication induced dysphoria’’, ‘‘drug induced dysphoria’’, ‘‘neuroleptic induced depression’’ and ‘‘neuroleptic induced anxiety’’. Potentially relevant papers were identified by their titles and the decision to retrieve full text of such papers was based on a perusal of the abstract. We also examined the references of identified papers for additional articles that could be included in this review. We reviewed only papers written in English.
Results The pubmed search yielded a total of 3, 749 documents but a perusal of the title and abstracts revealed that most of these documents were not applicable for this review.
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Twenty-six articles were identified which we felt were applicable for this narrative review and most of them were published between 1973 and 2007. The relevant papers are cited in the following subsections which address the aims of this paper. Clarifying the Meaning and Manifestations of Antipsychotic Medication-Induced Dysphoria Singh and Smith in their study of the kinetics and dynamics of response to haloperidol in acute schizophrenia described the dysphoria associated with the use of haloperidol as a mood state characterized by anxiety, tension, depression, feelings of guilt and somatic concerns [10]. The subset of patients that experienced dysphoria expressed significant dissatisfaction with their present state and felt that the medication had made them worse. Singh and Smith also reported that the dysphoria associated with haloperidol was unlikely to be explained solely by EPS as the non-dysphoric (‘‘euphoric’’) patients also experienced significant EPS. Caine and Polinsky [11] described cases of haloperidol-induced dysphoria in patients with Tourette’s syndrome and all the cases reported mood symptoms akin to a depressive episode. For example, one patient reportedly stated ‘‘it was as if a shade suddenly came down’’; the same patient also complained of sadness, crying and loss of energy. Another patient became ‘‘depressed and despondent’’ and one became ‘‘inappropriately sad and tearful’’. None of the patients described by Caine and Polinsky had a history of depression and their dysphoric symptoms were thought to be unrelated to EPS, cognitive impairment or drowsiness secondary to haloperidol treatment. Furthermore, all the patients seemed to experience the depressive symptoms only when the dose of haloperidol was increased beyond a certain threshold value. Bruun [12] also reporting on cases of Tourette’s syndrome treated with haloperidol, considered neuroleptic-induced dysphoria to be synonymous with an affective state characterized by depressive features. She reported a case of a child who became tearful, clingy, whiny and became reluctant to attend school and also developed thoughts of self-harm. The child’s depressive symptoms resolved after the dose of haloperidol was reduced. In their study, Weiden et al. [13] defined neurolepticinduced dysphoria as ‘‘a generalized feeling of unwellness that the patient attributes to the neuroleptic’’. However, Newcomer et al. [14] used the term in relation to akathisia-related affective symptoms that did not meet the threshold for a depressive episode. Awad and Voruganti [15] in their review wrote that patients’ report of antipsychotic medicationinduced dysphoria included use of descriptors such as ‘‘feeling blah, listless, tired, and lacking interest and ambition.’’ Voruganti and Awad also recommended that antipsychotic medication-induced dysphoria (like EPS) be considered as a variant or manifestation of dopaminergic blockade by antipsychotics. In other studies, the dysphoria induced by antipsychotics included subjective changes such as anger, depression, and hostility [16, 17]. Is Antipsychotic Medication-Induced Dysphoria More Prevalent and/or Worse with First-Generation Antipsychotics Relative to Second-Generation Antipsychotics? The prevalence of antipsychotic medication induced-dysphoric response is estimated to range between 10 and 60 % in patients who receive conventional antipsychotic medications [13, 18] and the dysphoria seem to be more prevalent in patients treated with highpotency antipsychotic medications such as haloperidol which has strong D2 blocking effects [11, 19]. On the other hand, second-generation antipsychotics appear to have a lower risk of inducing dypshoric responses in schizophrenia patients [20–24]. The results of a number of studies indicate that second-generation antipsychotics may offer better
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subjective tolerability [21, 25–27]. For instance, a study by Opjordsmoen et al. [28] showed that 16.5 % of patients treated with first-generation antipsychotics reported dysphoria, in contrast to 4.6 % of patients treated with second-generation antipsychotics. In another study Marder et al. [29] compared subjective response and EPS in patients treated with risperidone and low dose haloperidol in a 2 years study. Patients who received risperidone had better subjective feelings including less anxiety and depression. However, there was also less EPS in the patients treated with risperidone which could have contributed to better subjective feelings in this group. Hogan and Awad also assessed the prevalence of dysphoria in patients treated with first-generation versus second-generation antipsychotic medications. They found a significantly higher proportion of dysphoric responders among patients treated with first-generation than those treated with secondgeneration antipsychotics [30]. Does Antipsychotic Medication-Induced Dysphoria Lead to Poor Adherence? Poor adherence to antipsychotic medications is a major problem in the treatment of schizophrenia. Regarding antipsychotic medication-induced dysphoria and clinical outcomes, Singh and Smith [10] were the first to point out that dysphoria is associated with less favorable clinical outcomes. Van Putten et al. [31] documented the effect of dysphoria on clinical therapeutic outcome and in one of these studies, 63 schizophrenia patients were treated with thiothixene and 22 % reported dysphoric symptoms which ultimately resulted in refusal of treatment by these patients. In another study, Van Putten and May [32] found that dysphoria was associated with poor treatment response in schizophrenia patients treated with chlorpromazine and they suggested that patients’ subjective report of feelings related to antipsychotic medications should be elicited and this information should be taken into consideration in selecting medication. In another study, 35 previously unmedicated schizophrenia patients were given chlorpromazine or haloperidol and the experience of dysphoria was strongly related to poor clinical outcome [33]. Opojordsmeon et al. [28] found higher tolerability and adherence rates in first-episode psychotic patients treated with second-generation antipsychotic medication compared to those treated with low-dose firstgeneration antipsychotics. Similar findings were reported by Ascher-Svanum et al. [34] in patients with chronic schizophrenia treated with first- or second-generation antipsychotics; the atypical antipsychotic group had longer treatment duration than the typical antipsychotic treatment group during 1 year of follow-up.
Discussion Antipsychotic-induced dysphoria is a negative affective state with an equivocal relationship with the onset of EPS (specifically, akathisia). The literature seems to support the notion that there is a higher incidence of antipsychotic-induced dysphoria in patients treated with first-generation antipsychotics (especially those with very strong D2 blocakde) in comparison with those treated with second-generation antipsychotics. The possible mechanisms underlying neuroleptic-induced dysphoria could serve as a template to better understand why neuroleptic-induced dysphoria may be more prevalent in high potency first-generation antipsychotics than second-generation antipsychotics. Some researchers have suggested that dysphoria results from dopamine blockade and decreased dopamine neurotransmission has been associated with dysphoria [35–38]. The potential involvement of dopamine in the genesis of neroleptic-induced dysphoria was evaluated by Voruganti
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et al. [16] by experimentally depleting dopamine in medication-free schizophrenia patients. The chemical agent alphamethyl paratyrosine (AMPT) inhibits one of the enzymes involved in dopamine synthesis and it was administered to deplete dopamine after which dysphoric responses were assessed and imaging studies were carried out. Voruganti et al. [39] found that patients with higher synaptic dopamine activity at baseline had reduced risk of dysphoria compared with those with a relatively reduced synaptic dopamine activity. Antipsychotic-induced dysphoria is associated with poor adherence, the extreme form of which is outright refusal of medication by the patient. A physician’s unawareness of antipsychotic-induced dysphoria as a potential cause of refusal of medication could damage the physician-patient relationship and weaken the therapeutic alliance. This is because on the patient’s part, there are no perceived benefits in continuing to take the medication, while the physician perceives the patient as uncooperative and non-adherent to treatment recommendations. It has also been suggested that dysphoric reactions to antipsychotics may be associated with substance abuse (i.e. patients may use illicit substances to ‘‘self-medicate’’ the unpleasant feelings induced by antipsychotic medication) [6–8] but because this is a relatively understudied area, the link between the two requires further study.
Conclusion Antipsychotic medication-induced dysphoria remains an important phenomenon relevant to clinical practice and treatment outcomes. Though the extant literature suggests that second-generation antipsychotics maybe less likely to induce dysphoria, the limited methods of the few currently available studies make it impossible to conclusively address the question of which class of antipsychotic (first- or second-generation) has a higher prevalence and severity of the syndrome. Studies designed to further elucidate the underlying mechanisms of antipsychotic medication-induced dysphoria, characterize the subset of patients likely to experience the syndrome and directly compare equivalent doses of first and second-generation medications on the prevalence and severity of antipsychotic medication-induced dysphoria are warranted. There is also a need to develop evidencebased criteria for diagnosing antipsychotic medication-induced dysphoria as this will not only be useful for clinicians and their patients but would also enhance research on this relatively understudied syndrome.
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Hanjing Emily Wu, MD, PhD is a resident in the Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Houston/Harris County Psychiatric Center, 2800 South MacGregor Way, Houston, TX. Her research interests are focused on psychopharmacology and immunology related to psychiatric disorders as well as innovative treatments for mood disorders and schizophrenia. Olaoluwa O. Okusaga, MD, MScPHR is Assistant Professor, Department of Psychiatry and Behavioral Sciences, University of Texas Medical School at Houston/Harris County Psychiatric Center, 2800 South MacGregor Way, Houston, TX. His research interests are focused on examining how the environment (biological and physical) interact with brain and body processes in the etiology and exacerbation of mental illness. His current interests involve elucidating possible mechanisms of inflammation and abnormal amino acid metabolism in the pathophysiology of schizophrenia.
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