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Year : 2015  |  Volume : 5  |  Issue : 1  |  Page : 40-42

Nicotine dependence in resistant schizophrenia: A compensation for trihexyphenidyl dependence or just comorbidity

Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication27-Jan-2015

Correspondence Address:
Sujita Kumar Kar
Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2231-0738.150076

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A 42-year-old male, suffering from schizophrenia with nicotine dependence and on regular treatment, had reported the overuse of trihexyphenidyl (40-50 mg/day) for the last 2 years in a dependence pattern, which was temporally correlated with increased consumption of nicotine over the same time frame. The patient used to report withdrawal symptoms and craving for trihexyphenidyl, when it was not available. This case report attempts to discover the possible links between nicotine dependence and trihexyphenidyl dependence in schizophrenia with emphasis on the compensatory measure to counter the imbalance in cholinergic system.

Keywords: Nicotine dependence, schizophrenia, trihexyphenidyl dependence

How to cite this article:
Kar SK. Nicotine dependence in resistant schizophrenia: A compensation for trihexyphenidyl dependence or just comorbidity. Int J Nutr Pharmacol Neurol Dis 2015;5:40-2

How to cite this URL:
Kar SK. Nicotine dependence in resistant schizophrenia: A compensation for trihexyphenidyl dependence or just comorbidity. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2022 Dec 8];5:40-2. Available from:

   Introduction Top

Nicotine (tobacco) dependence is very common and more severe in patients suffering from schizophrenia. [1],[2],[3] It is away patients deal with the illness-related difficulties. [1] The exact cause that links nicotine dependence as comorbidity with schizophrenia is uncertain. [3] Nicotine is a known inducer of liver cytochrome P450 enzyme system, through which most psychotropic medications are metabolized. [4] Nicotine use decreases the efficacy of psychotropic medications by increasing their metabolism. [4] A recent study has reported that the use of nicotine is less in patients treated with clozapine. [4] However, the risk of nicotine consumption is more with the use of typical antipsychotics like haloperidol. [4],[5],[6] The reason may be to compensate the dopaminergic blockade effects of the antipsychotics at the reward pathway. [5],[6] Some antipsychotic drugs also have anticholinergic effects and nicotine is a strong cholinomimetic agent likely to be abused to compensate the acetylcholine deficiency. Evidence is still scarce in this regard.

Trihexyphenidyl is an anticholinergic agent, commonly used for treatment of antipsychotic mediated extrapyramidal side effects (EPS) as well as Parkinson's disease. [7] In these conditions, the drug is for long-term use. It also carries the risk of abuse due to its stimulating and mood-elevating properties. [7],[8],[9],[10] Schizophrenic patients abuse trihexyphenidyl in very high doses in order to get a high. [8] The high dose of trihexyphenidyl may produce a psychotic-like state which may be indistinguishable from the background primary psychotic illness. [8] Chronic schizophrenic patients often feel better with add-on trihexyphenidyl and report subjective distress when weaned off from it. [9]

The association of nicotine dependence and trihexyphenidyl dependence is unclear. There is no direct research evidence discussing such association.

   Case report Top

A 42-year-old unemployed male suffering from resistant schizophrenia for14 years, along with nicotine dependence for 10 years, was brought for psychiatric consultation by his father. The patient was on antipsychotic clozapine 300mg/day and risperidone 6mg/day in divided doses for the past 3 years and was clinically stable. He was also prescribed trihexyphenidyl 4mg/day in divided doses; however, he used to take 8-10 tablets of trihexyphenidyl of 5mg strength per day. On exploration, he mentioned anxiety, discomfort, laziness, and inactivity when he used to reduce the dose or missed taking trihexyphenidyl on any given day. He had reported craving for trihexyphenidyl and used to remain preoccupied with thoughts of procuring the drug. He did not report any anticholinergic side effects despite consumption of a high dose of trihexyphenidyl. The patient was using trihexyphenidyl in the prescribed dose for the initial 1 year but since the last 2 years, he had increased the amount of trihexyphenidyl of his own.

The patient had history of use of chewable tobacco since the last 15 years, with a dependent pattern of use over the last 10 years. His tobacco consumption had increased in the last 2 years (30 to 40 pouches per day).

Despite the treatment, he had some residual symptoms in the form of fluctuating irritability, unprovoked aggression, and occasional muttering to self though he denied any hallucinations. These symptoms were stable over the last 3 years. In the initial days, he was treated with adequate doses of olanzapine, trifluperazine, and risperidone for a considerable period of time, both separately and in combination. He did not respond well to higher doses of clozapine and responded best to the current combination of antipsychotics. Thus, he was kept on the same dose with regular monitoring of blood cell count and metabolic parameters.

The patient's past history, personal history, and family history did not contribute to the current illness. Pre-morbidly, he was well-adjusted to life. His general physical examination and systemic examination did not reveal any abnormality. Hematological investigations, including blood cell count were within normal limits. The patient was advised to continue antipsychotics in the same prescribed doses. Nicotine dependence was addressed through a replacement regimen (nicotine lozenge 24 mg/day in divided doses and 4mg as and when needed) with advice for gradual tapering. For trihexyphenidyl dependence, he was asked to cut down 25% of the total dose biweekly.

   Discussion Top

In this patient, the symptoms of schizophrenia were stable on treatment. There was a dependence on nicotine and trihexyphenidyl. The dependence on nicotine in schizophrenic patients can be explained through several mechanisms:

  • Regular use of nicotine leading to dependence (as seen in individuals without any other psychiatric disorders) [1]
  • Increased use of nicotine to compensate for the negative, cognitive, and depressive symptoms of schizophrenia [1],[3],[4]
  • Nicotine use also reduced psychotropic drug-induced side effects [1],[4]
  • As a reinforcement measure [3]
  • Impaired judgment due to schizophrenia, leading to unrestrained use of nicotine [1]
  • To compensate for the antipsychotic induced dopaminergic blockade at the reward pathway [4],[5],[6]
  • To compensate for the cholinergic deficiency (anticholinergic effects) due to trihexyphenidyl dependence.

The first six possibilities are well known; however, the last possibility indicates an interesting association of nicotine dependence to compensate for the drug-induced anticholinergic effects. As nicotine use compensates for the antipsychotic-induced dopaminergic blockade at the reward pathway, it is quite possible that similar compensatory mechanisms might be attributing to counter the drug-induced anticholinergic effects.

In this patient, there were no anticholinergic side effects despite of the use of clozapine (300 mg/day), risperidone (6 mg/day), and trihexyphenidyl (40-50 mg/day). Increased use of nicotine in the past 2 years was temporally correlated with the increased use of trihexyphenidyl, which was in favor of compensation of the anticholinergic side effects with cholinomimetic action of nicotine. In a few studies, it was found that trihexyphenidyl abusers differ from trihexyphenidyl users in having more genetic loading of psychiatric disorder, a higher risk of smoking, and poly-substance abuse. [11],[12] This finding indirectly indicates the association of nicotine use with anticholinergic drug use.

Consumption of nicotine, upregulates the expression of nicotinic acetylcholine receptors in certain brain regions. [13] The endogenous opioid system also plays some role in nicotine dependence. [14] Other than this, nicotine acts through glutamine, gamma-aminobutyric acid (GABA), dopamine, cannabinoid, and adenosine receptor modulation. [15],[16] Similarly, trihexyphenidyl involves the dopaminergic system due to its dependence. There might be some intricate biological connection between concurrent trihexyphenidyl and nicotine dependence other than the above explanation related to cholinergic compensation. Further studies are required to see the association between nicotine and trihexyphenidyl dependence.

The use of anticholinergic agents has been relatively reduced over last decade due to reasons including the development of newer antipsychotics with fewer propensities of extrapyramidal side effects. However, many a time, patients receive trihexyphenidyl in combination with antipsychotics risperidone, chlorpromazine, and trifluperazine in fixed dose. When the doses of antipsychotics were increased, the dose of anticholinergic agent also increased due to fixed-dose combination. Use of fixed-dose combination increases the risk of needless administration of trihexyphenidyl, thus greater risk of drug dependence.

   References Top

de Oliveira RM, Siqueira Júnior AC, Santos JL, Furegato AR. Nicotine dependence in the mental disorders, relationship with clinical indicators, and the meaning for the user. Rev Lat Am Enfermagem 2014;22:685-92.  Back to cited text no. 1
Tidey JW, Colby SM, Xavier EM. Effects of smoking abstinence on cigarette craving, nicotine withdrawal, and nicotine reinforcement in smokers with and without schizophrenia. Nicotine Tob Res 2014;16:326-34.  Back to cited text no. 2
Freeman TP, Stone JM, Orgaz B, Noronha LA, Minchin SL, Curran HV. Tobacco smoking in schizophrenia: Investigating the role of incentive salience. Psychol Med 2013;1-9.  Back to cited text no. 3
Wijesundera H, Hanwella R, de Silva VA. Antipsychotic medication and tobacco use among outpatients with schizophrenia: A cross-sectional study. Ann Gen Psychiatry 2014;13:7.  Back to cited text no. 4
Montoya ID, Vocci F. Medications development for the treatment of nicotine dependence in individuals with schizophrenia. J Dual Diagn 2007;3:113-50.  Back to cited text no. 5
Dawe S, Gerada C, Russell MA, Gray JA. Nicotine intake in smokers increases following a single dose of haloperidol. Psychopharmacology (Berl) 1995;117:110-5.  Back to cited text no. 6
McInnis M, Petursson H. Trihexyphenidyl dependence. Acta Psychiatr Scand 1984;69:538-42.  Back to cited text no. 7
Lo Y, Tsai SJ. Trihexyphenidyl abuse in schizophrenic patient: A case report. Zhonghua Yi Xue Za Zhi (Taipei) 1996;57:157-60.  Back to cited text no. 8
Fisch RZ. Trihexyphenidyl abuse: Therapeutic implications for negative symptoms of schizophrenia? Acta Psychiatr Scand 1987;75:91-4.  Back to cited text no. 9
Zemishlany Z, Aizenberg D, Weiner Z, Weizman A. Trihexyphenidyl (Artane) abuse in schizophrenic patients. Int Clin Psychopharmacol 1996;11:199-202.  Back to cited text no. 10
Qureshi NA, Al Amri AH, Abdelgadir MH, El-Haraka EA. Trihexyphenidyl (Artane) dependence: A controlled investigation between users and abusers. Ann Saudi Med 1997;17:185-90.  Back to cited text no. 11
Nappo SA, de Oliveira LG, Sanchez Zv, Carlini Ede A. Trihexyphenidyl (Artane): A Brazilian study of its abuse. Subst Use Misuse 2005;40:473-82.  Back to cited text no. 12
Brody AL, Mukhin AG, Mamoun MS, Luu T, Neary M, Liang L, et al. Brain nicotinic acetylcholine receptor availability and response to smoking cessation treatment: A randomized trial. JAMA Psychiatry 2014;71:797-805.  Back to cited text no. 13
Ueno K, Kiguchi N, Kobayashi Y, Saika F, Wakida N, Yamamoto C, et al. Possible involvement of endogenous opioid system located downstream of α7 nicotinic acetylcholine receptor in mice with physical dependence on nicotine. J Pharmacol Sci 2014;124:47-53.  Back to cited text no. 14
Jastrzêbska J, Nowak E, Smaga I, Bystrowska B, Frankowska M, Bader M, et al . Adenosine (A)(2A) receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach. Neuropharmacology 2014;81:318-26.  Back to cited text no. 15
Berrendero F, Robledo P, Trigo JM, Martín-García E, Maldonado R. Neurobiological mechanisms involved in nicotine dependence and reward: Participation of the endogenous opioid system. Neurosci Biobehav Rev 2010;35:220-31.  Back to cited text no. 16


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