Antidepressants: Side Effects in the Mouth

Oral reactions to medications are common and affect patients’ quality of life. Almost all classes of drugs, particularly those used continuously, such as antidepressants, antihypertensives, anxiolytics, hypnotics, diuretics, antipsychotics among others, including vitamins, minerals and phyto-pharmaceuticals, may cause oral alterations. If not suitably treated, these may aggravate the patient’s general state of health and affect his/her oral health (Lamy, 1984; Smith & Burtner, 1994; Rees, 1998; Ciancio, 2004; American Dental Association [ADA], 2005; Scelza et al., 2010). Prescribed and over-the-counter medications are frequently used in large quantities and by many adults, particularly by those over the age of 65 years. The abusive use of drugs, mainly by elderly patients, may generate oral side effects (Lamy, 1984; Ciancio, 2004; ADA, 2005). The number of prescriptions in the USA is mainly due to the therapeutic advances in the treatment of various medical conditions and the increase in the geriatric population. Josephe et al. (2003) observed that 21% of the 1,800 patient dental records reviewed showed antidepressant use. It is suspected that the prevalence of oral lesions increases in direct relation to the increase in the use of necessary drugs, mainly to control chronic diseases. Over 200 drugs are involved in adverse reactions and side effects on oral tissues. Smith & Burtner (1994) founded as oral side-effects of the most frequently prescribed drugs: dry mouth (80.5%), dysgeusia (47.5%) and stomatitis (33.9%). Xerostomia, a subjective dry mouth sensation, is a side effect of around 400 medications. Moreover, it is one of the major problems in the USA at present, affecting millions of persons. Diminishment or absence of saliva may affect the emotional well being, cause significant morbidity and a reduction in the patient’s quality of life (Ciancio, 2004; Fox et al., 1985; Sreebny & Schwartz, 1986; Sreebny & Valdini, 1987; Butt, 1991; Guggenheimer & Moore, 2003). Thus, a dental and medical record of the patient is necessary, with regular updating of the prescribed medications, because of the potential side effects of drugs and interactions among them. It is also important for dentists to know about the problems related to medication and the impact of this on diagnosis and the treatment plan (Keene et al., 2003).

. The antidepressant effect of lithium, a mood stabilizing agent used to treat the depressive phase of bipolar disorder, may derive from its ability to increase the serotonin levels in the SNC (Schou, 1999). The majority of antidepressant medications prescribed is associated with a number of significant oral reactions (Friedlander & Mahler, 2001). These complications, including xerostomia, sialoadenitis, gingivitis, dysgeusia, glossitis, tongue edema and discoloration and stomatitis, almost always appear due to dysfunction of the salivary gland induced by the medication. But in patients that make use of mirtazapine, the development of stomatitis may represent the initial signs of bone marrow suppression induced by the medication, such as: agranulocytosis, leukopenia or granulocytosis, a potentially fatal event (Friedlander & Norman, 2002). Bertini et al. (2009) reports a case of ulceration of the oral mucosa induced by antidepressant medication. Rindal et al. (2005) suggest that antidepressant drugs do not generate a raise in the overall restoration risk level when compared with a group on non-xerogenic drug. Instead, that antidepressant medication raises the quantity of disease for persons already at risk. The non-xerogenic group had a superior restoration rate than the no medication group but not as high as the antidepressant group rate. Studies that assessed the oral health of patients that use antidepressants observed extensive tooth losses. This may occur because of various factors: lack of interest in oral hygiene, preference for carbohydrates (probably because of the reduction of serotonin in the SNC), preference for sweetened foods because of alterations in the sense of taste (dysgeusia), by the diminishment of saliva release and by the high lactobacillus counts (Rundegren et al., 1985;Christensen & Somers, 1996;Anttila et al., 1999). Persons with depression are also at high risk of developing periodontal disease, because neglected oral hygiene, increased smoking and altered immune response, associated with xerostomia facilitate increased colonization by pathologic bacteria in the mouth, leading to collapse of the periodontium (Moss et al., 1996;Elter et al., 1999). Patients that receive SSRIs or atypical antidepressants may sometimes develop movement disorders that include bruxism or tooth-grinding, which may aggravate the patient's periodontal status (Brow & Hong, 1999). These drugs raise the extrapyramidal serotonin levels, thus inhibiting the dopaminergic pathways that control the movements (Bostwick & Jaffee, 1999). There is consensus among various authors that xerostomia is the main and the commonest side effect of antidepressant drugs (Smith & Burtner, 1994;Pajukoski et al., 2001;Ciancio, 2004;Scully, 2003;Josephe et al., 2003;Thomson et al., 2006;Uher et al., 2009), in addition to this, patients that receive antidepressant therapy frequently complain about diminished salivation and changes in salivary viscosity (Astor et al., 1999).

Role of saliva in oral health
Saliva is a true mirror of the body that contains a large number of organic and inorganic compounds, and can be seen as a very important health indicator. Salivary secretion is controlled by the autonomic nervous system through receptors present in the salivary gland. Many studies show that medicine and diseases can affect the function of salivary glands as regards the quality and quantity of saliva secreted (Greabu et al. 2009;Gregio et al., 2006). Salivary secretion is complex and occurs subsequent to neurotransmitter stimuli. The principal control of secretion is derived from sympathetic and parasymphatetic innervation which regulates the secretory function on the acinar cell level and controls the reabsorption process in the striated ducts of salivary glands. Parasympathetic stimulation increases the volume of secreted saliva, whereas sympathetic stimulation mainly affects protein content and composition. The salivary gland may serve as a model to determine the peripheral effects of different antidepressants on the monoaminergic and the cholinergic systems. Salivary gland function depends on the integrity of both parasympathetic and sympathetic innervation. Normal salivation is an essential demand for oral health, due to its important contributions to the oral defense mechanisms. Diminished salivary secretion could lead to serious disease and deterioration of the mucosa (Von Knorring & Mornstad, 1986;Hunter& Wilson, 1995) The saliva has several important functions in the mouth, including protection of the oral mucosa, chemical buffering, digestion, taste, antimicrobial action, and maintaining the integrity of the teeth. Due to its glycoprotein contents saliva has a viscous aspect that protects the oral mucosa by the formation of a barrier against noxious stimuli, microbial toxins, and minor trauma. Its fluid nature facilitates the removal of cell debris and non-adherent bacteria (Edgar, 1992).

Antidepressant and xerostomia
Xerostomia means a subjective dry mouth sensation and represents a symptom related by the patient. It may occur in the presence of systemic diseases or conditions, such as displayed on Table 1, or as consequence of use of drugs (Table 2) (Lamy, 1984;Sreebny & Schwartz, 1997;Stack & Papas, 2001;Scully, 2003;Guggenheimer & Moore, 2003). Between the drugs stands out the antidepressants (Table 3). Patients with xerostomia displayed various degrees of discomfort related to the quality of life according to the aetiology of their conditions (Cho et al., 2010). Around 1 in 5 people complain of dry mouth, and a rising occurrence in the elderly, it is essential to have a complete understanding of this subject (Hopcraft & Tan, 2010). Of the conditions mentioned above, salivary hypofunction secondary to the use of medications is the commonest (Nederfors, 1996;Fox, 1998). They inhibit the cholinergic signals in the salivary tissues and thus diminish the excretion of fluids by the glands, and interferences in central pathways (serotoninergics and dopaminergics) may also alter salivary composition (Atkinson & Baum, 2001). The normal stimulated salivary flow rate is between 0.7 to 1 mL/min, whereas hyposalivation is considered when the salivar production is under 0.7 mL/min (Tenovuo & Lagerlöf, 1994). Aging has a minimum impact on salivary flow, but the advance of age and the appearance of chronic diseases lead to the use of drugs that may diminish the salivary flow by up to 40% (Sreebny & Schwartz, 1997;Ben-Aryeh et al., 2001). Complaints of xerostomia may increase three-fold in elderly patients that receive xerogenic medication (Osterberg et al., 1984). In a study comparing the use of escitalopram and nortriptyline, Uher et al. (2009) observed that dry mouth was the most commonly reported adverse effect, and that it was more common during treatment with either nortriptyline or escitalopram than in the medicationfree state. The authors also demonstrated a positive correlation with the dose of both antidepressants. There is evidence that the prevalence of dry mouth is correlated to polymedication (Locker, 1995;Nederfors et al., 1997). But, Persson et al. (1991) verified that the use of up to 4 different xerogenic medications did not result in significantly additional reduction in the salivary flow speed in his patients. The subjective dry mouth sensation may occur even in the presence of a normal salivary flow that is, not necessarily being associated with a diminution in the amount of saliva (Fox et al., 1985;Närhi, 1994). According to Mandel & Wotman (1994) the quality of salivary secretion (especially the mucin content) is more important than the quantity in the dry mouth sensation. The type of saliva (rest or stimulated), procedures and time of collection, composition and source (larger or smaller salivary glands) are factors that can contribute to the patient's report of dry mouth and it relationship with hyposalivation (Mandel & Wotman, 1994;Von Knorring & Mörnstad, 1981). According to Nagler (2004), in up to one third of cases, xerostomia does not reflect a real reduction in salivary flow speed. As regards dry mouth, it is due to the reduction in saliva secretion or when its composition is altered, and it may cause various clinical problems (Table 4) (Nagler, 2004;Ursache et al., 2006;Tuner et al., 2007). chew and swallow dried food without water; by quantifying the volume of residual saliva on mucosal surfaces using filter paper and micro-moisture meter and calculating thickness; and mucosal wetness devices (Osailan et al., 2011). Also, sialometry (salivary flow rate measurement) is indicated as part of the diagnostic procedures for hyposalivation (Tenovuo & Lagerlöf, 1994), and the composition of saliva can be verified by means of biochemical salivary exams. Antidepressants have anticolinergic or antimuscarinic action, which acts to block the actions of the parasympathetic system by inhibiting the effects of acetylcholine on the salivary gland receptors. This results in a dry mouth sensation, probably because the sympathetic portion of the independent nervous system predominates over the "blocked" parasympathetic system (Wynn et al., 2001). According to Schubert & Izutsu (1987), the drugs may affect the salivary flow and its composition by interferences in the acinary and duct functions, and by means of alterations in the blood flow of the salivary glands. According to Douglas (2002) diminishment of the salivary flow is due to the reduction in the blood flow of the gland, produced by adrenergic sympathetic vasoconstriction. Therefore, when there is sympathetic hyperactivity the mouth presents dry. It is important to emphasize that the dry mouth sensation and alteration in salivary composition may occur during periods of stress and/or acute anxiety, frequently present in depressive disorders, due to predominant stimulation of the sympathetic system, irrespective of the use of anxiolytic and/or antidepressant medication (Guggenheimer & Moore, 2003). Isolated depression is related to diminishment of salivary secretion and to xerostomia, due an anticolinergic action (Stack & Papas, 2001;Brown, 1970). Therefore, it may be difficult to determine whether these side effects and their intensity arise from the medical condition that led to the treatment, or from the medication prescribed for it (Smith & Burtner, 1994), it probably is as a result of both.

Treatment of hyposalivation
Various treatments are proposed for enhanced salivary secretion, among them, the use of a salivary flow stimulating drug pilocarpine chloride which acts by stimulating the parasympathetic ANS (Vivino et al., 1999). This drug has been used because it stimulates the cholinergic receptors, among them the muscarinicM3 receptor present in the salivary glands, resulting in the expulsion of the stored salivary contents (Ferguson, 1993), thus an increase in saliva production and release was observed with the use of cholinergic drugs. The next table shows the types of hyposalivation treatment according to Turner & Ship (2007), treatment strategies include salivary replacement therapies, as well as use of statory, masticatory and pharmacological stimulants.
Gustatory and tactile sialogogues Acid-tasting substances Acidic (sugar-free) sweets Acidic or effervescent drinks (lemon juice, citric acid, buttermilk) Citric acid crystals Cotton-wool gauze soaked in a citric acid and glycerine solution Lemon pastilles Lemon slices Vitamin C tablets Miscellaneous substances Dried pieces of reed root (calami rhizome) Sugar-free chewing gum Sugar-free sweets Vegetables or fruits Anetholetrithione Benzapyrone Betanechol chloride Carbachol Cevimeline Folia Jaborandi and tinctura Jaborandi Neostigmine, neostigmine bromide, pyridostigmine bromide Destigmine bromide Nicotinamide and nicotine acid Pilocarpine hydrochloridey, pilocarpine nitrate Potassium iodide Trithioparamethoxyphenylpropene

Conclusion
Xerostomia is the main oral side effect associated with the various classes of drugs, particularly those used continuously. There is, however, not always a positive correlation between hyposalivation and xerostomia. This symptom may be the result of both diminished salivary secretion and an alteration in saliva composition. Nevertheless, when present, xerostomia may affect the patient's emotional well being, aggravate his/her general state of health, as well as affect his/her oral health, as other reactions such as dygeusia, candidosis, caries and stomatitis are reported as being the consequence of xerostomia. It is important to emphasize the dentists' role as regards patients that make use of medications, mainly for treating chronic diseases. It is their obligation to keep a detailed and updated medical history of their patients, in order to be alert to problems related to medication, and the impact of this on the diagnosis and treatment plan, as well as to prepare the most adequate and effective preventive programs possible. In order to determine whether or not the patient presents hyposalivation, the dentist can have a complementary exam, called sialometry (salivary flow speed measurement), may be performed. If there is any doubt about the composition of the saliva, there are biochemical tests that can reveal alteration in its composition. Communication between the doctor and dentist is extremely important, so that together, they re-establish the patient's general and oral health as far as possible.