Ffect of Sertralin Antidepressant Drug on Submandibular Salivary Gland

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FFECT OF SERTRALIN ANTIDEPRESSANT DRUG ON SUBMANDIBULAR SALIVARY GLAND AND MOLARS OF OLD MALE ALBINO RATS (HISTOLOGICAL, TOTAL PROTEIN CONTENT AND SCANNING ELECTRON MICROSCOPIC STUDY)

Thesis

Submitted to the Oral Biology Department, Faculty of Oral And Dental Medicine, Cairo University,

In partial fulfillment of the requirements for Master Degree in Oral Biology

Ahmed Osama Hafez Galal B.D.S. (6th October University) Demonstrator, Oral Biology Department, Faculty of Dentistry, October University for Modern Sciences and Arts

Oral Biology Department Faculty of Oral And Dental Medicine Cairo University 2012

1 Acknowledgements Supervisors

Prof. Dr. Zoba Hassan Ali

Assistant Professor of Oral Biology

Faculty of Oral and Dental Medicine

Cairo University

Dr. Rehab Ali Abdel Moneim

Lecturer of Oral Biology

Faculty of Oral and Dental Medicine

Cairo University

2 In the beginning, I would like to thank ALLAH firstly, lastly and forever.

I would like to express my deepest feeling and gratitude to Prof. Dr. Zoba Hassan Ali, Assistant Professor of Oral Biology, Faculty of Oral and Dental Medicine, Cairo University for her instructive leading comments and supervision during the progress of this study, continuous encouragement and kind advise.

I am deeply grateful and thankful to Dr. Rehab Ali Abdel Moneim, Lecturer of Oral Biology, Faculty of Oral and Dental Medicine, Cairo University, for her faithful assistance, cooperation, patience, willing support and constant advice.

I would like to express my grateful thanks to Prof. Dr. Sahar Shawkat, Head of oral biology department, Prof. Dr. Tarek El Essawy, Prof. Dr. Hala Zaatar and my dear colleagues in the Oral Biology Department, MSA University for offering their great cooperation. I would like to express my deepest feeling to my parents for their supplications, support and faithful advices.

Finally, I am deeply grateful and thankful to my dear wife for her willing support, patience, sincerity and continuous help.

3 List of Abbreviations

ACDRs adverse cutaneous drug reactions DDW double distilled water FDA Food and Drug Administration HEPES hydroxyl ethyl piperazine ethane sulfuric acid MAOIs monoamine oxidase inhibitors NE/DARI norepinephrine and dopamine reuptake inhibitors NREM non rapid eye movement OCD obsessive-compulsive disorder PNDD premenstrual dysphoric disorder PTSD post traumatic stress disorder REM rapid eye movement SARIs serotonin-2 receptor antagonist/serotonin reuptake inhibitors SSRIs selective serotonin reuptake inhibitors TCAs tricyclic antidepressants

4 Introduction & Review of literature

Sleep is a necessary and vital biological function. It is essential to a person's physical and emotional well being. Human sleep is composed of two states: the non rapid eye movement state (NREM) and the rapid eye movement state (REM). NREM sleep is divided into four stages, which parallel the continum of sleep depth, with 1 being the shallowest stage and 4 being the deepest. Normal sleep moves through the NREM and REM stages in a continuous cycle that averages approximately 90– 100 minutes per cycle. This repeating pattern is collectively referred to as sleep architecture which is influenced by age, sleep history, temperature, drug therapies, and alcohol consumption. (Carskadon and Dement, 2000)

Sleep enables the body and mind to rejuvenate, reenergize, and restore. As a person sleeps, the brain performs vital tasks, such as organizing long-term memory, integrating new information, and repairing and renewing tissue, nerve cells and other biochemicals. Sleep allows the body to rest and the mind to sort out past, present, and future activities and feelings. (Dang-vu et al., 2006).

Kirov et al., (2007) reported that sleep deficits were linked to obesity, diabetes and heart failure. Fibromyalgia and arthritic-like joint complaints were also associated with sleep deprivation. In children, sleep deficits were linked to attention-deficit/hyperactivity disorder and an increased risk of childhood injury.

5 Buscemi et al., (2007) found that sleep disorders were generally associated with an underlying illness, such as chronic obstructive pulmonary disease, congestive heart failure, substance abuse, restless leg, and depression. Thus, they were generally symptoms of another disorder rather than discrete disorders in their own right. Therefore, addressing the underlying physical or psychological illness would often lead to relief of the insomnia. In contrast, primary insomnias were sleep disturbances not associated with known psychological or physical disabilities. Primary insomnias were more difficult to treat and usually require the use of pharmacologic sleep aids. Incorporation of effective sleep hygiene was important to all forms of insomnia.

Depression has been shown to increase sleep latency (time required to fall asleep), increase waking after sleep onset and increase early-morning awakenings. Thus, treatments that restore sleep architecture in depressed patients can be presumed effective in nondepressed patients with insomnia. (Gursky and krahn, 2000)

The most frequently used antidepressants for sleep were the tricyclic antidepressants (TCAs) and selective serotonin-reuptake inhibitors (SSRIs) as recognized by Winokur et al., (2001). Although the monoamine-oxidase inhibitors (MAOIs) have been shown to suppress REM sleep (a positive effect against depression and insomnia-enlarged REM density), their requisite dietary restrictions and drug interaction profiles made them a poor choice for insomnia treatment. The MAOIs were also associated with increased awakenings after sleep onset, a substantial negativity for sleep efficiency.

6 Monti, (1989) discovered that the MAOIs had a historically prominent place in the early pharmacotherapy of depression. Clinical populations for whom MAOIs were thought to hold particular promise included patients with: (1) atypical depression characterized by symptoms as hypersomnolence, lethargy, apathy, carbohydrate craving , reverse diurnal mood patterns and heightened rejection sensitivity; (2) bipolar patients with depression; (3) patients with panic disorder (with or without coexisting depression) and (4) as an alternative option for treatment refractory depressed patients.

Clinicians have long recognized that specific TCAs demonstrated wide intraclass variability with respect to effects on nocturnal sleep and daytime sleepiness. Based on clinical observations and patient self-report data, several TCAs (e.g., amitriptyline and trimipramine) were viewed as predominately sedating drugs, most likely due to their potent antihistaminic properties. This sedating effect had led some to speculate that the TCAs might be of particular value in treating depressed patients who also manifested problems with insomnia. Conversely, clinical experience suggested that these TCAs should be avoided in depressed patients sensitive to daytime sedating effects or presenting with a history of intolerance to other sedating compounds, e.g., cold preparations with prominent antihistaminic properties. (Ware et al., 1989)

Consistent with clinical experience, certain TCAs, including amitriptyline , trimipramine and doxepin were effective in treating insomnia. More specifically, both amitriptyline and doxepin improved sleep architecture by shortening sleep latency, increasing total sleep time, decreasing awakening after sleep onset, suppressing REM sleep and improving overall sleep efficiency. Other TCAs, such as desipramine or

7 protriptyline prolonged sleep onset latency, reduced sleep efficiency and increased WASO or awakenings/arousals after sleep onset. (Vogel et al.,1990 )& (Gursky & Krahn, 2000).

Many studies carried by(Goodnick and Goldstein, 1998) have demonstrated that the SSRIs were as effective as the TCAs in the treatment of depression, but better tolerated and had superior safety profile in overdose for most patients. Although SSRIs differ in chemical structure and pharmacokinetic characteristics, all are extensively biotransformed before excretion, initially through oxidative pathways. Fluvoxamine is metabolised by oxidation, oxidative deamination and hydrolysis to several metabolites. The selective serotonin reuptake inhibitors (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram) were the most widely utilized class of antidepressants in clinical practice.

SSRIs were associated with increased awakenings after sleep onset, decreased REM time and sleep percentage, increased sleep latency and increased REM latency. Escitalopram appeared to be the exception to the SSRI rule. Data suggest that escitalopram’s high affinity for the serotonin transportation might make it the one SSRI that improves sleep architecture. (Wade 2006).

Lehne (2007) noted that SSRIs were the most widely prescribed antidepressants in the United States. They were indicated for the treatment of depression, and several were also co-indicated for the treatment of panic, social phobia and obsessive–compulsive disorder.

Serotonin-2 receptor antagonist/ serotonin reuptake inhibitors (SARIS) were reported by DeMartinis and Winokur, (2007) as another

8 class of antidepressants that modulate serotonin activity and has a pronounced effect on the regulation of sleep. Among SARIs, trazodone is the second most commonly prescribed drug for insomnia. It has been shown to improve sleep quality, increase sleep time and enhance slow- wave sleep (deep sleep) which occurs while preserving normal sleep architecture. Trazodone can also repair the sleep disturbances associated with SSRIs and is frequently employed as adjunctive therapy to SSRI treatment.

Another SARI, nefazodone, improves sleep efficiency, decreases awakenings and enhances REM sleep. It serves as an alternative treatment for insomnia but should be used with caution. Nefazodone is associated with a rare, but dangerous liver toxicity and can raise the blood levels of many other concomitant medications. ( Winokur et al., 2001 & Lehne, 2007).

Nofzinger et al., (1995) found that bupropion was the sole representative of the antidepressant category referred to as the norepinephrine and dopamine reuptake inhibitors (NE/DARI). The primary effects of bupropion treatment on sleep architecture were related to changes in REM parameters, including a tendency towards shortened REM latency and an increase in REM time and REM percent. The majority of antidepressant drugs produced a decrease in REM (i.e., REM suppression) associated with a prolongation of REM latency. Thus, bupriopion represented one of the few antidepressant drugs that did not suppress REM sleep, and similar to nefazodone, it increased REM and shortened REM latency.

9 Adverse drug reactions

Exanthematous reactions are the most common type of Adverse Cutaneous Drug Reactions (ACDRs) and can occur with any of the antidepressants. Symptoms may include a cutaneous eruption that mimics a measles-like viral exanthem with erythematous macules and papules distributed symmetrically. The pathogenesis in still unknown, but this type of ACDR is believed to be a delayed type IV hypersensitivity reaction. The initial eruption usually occurs within the first 2 weeks of administration. In some cases the eruption may subside without discontinuation of the offending agent and will not recur on readministration of the drug. Therefore, continuation of the drug is permissible if ongoing treatment with a particular agent is necessary and if there is no evidence of a more serious Adverse Cutaneous Reactions Kimyai - Asadi et al., 1991.

Urticaria, the second most common cutaneous adverse effect, can occur with any of the antidepressants. Urticaria may occur with or without angioedema, whereas angioedema alone is rare. Lesions generally do not last more than 24 hours, but are constantly being replaced by new eruptions. Lesions may appear several hours after re- challenge. Angioedema affects the face, tongue and extremities and involves a larger edematous area including the dermis and subcutaneous tissue. Also angioedema has been specifically associated with TCAs, fluoxetine , and trazodone. Urticaria and angioedema are believed to be type I hypersensitivity reactions. Lesions generally resolve promptly after drug discontinuation. (Fisher et al., 1993).

10 Fixed drug eruptions are among the most common ACDR and may be found in association with any of the antidepressants, but notably with nefazodone. Lesions may occur on the mucocutaneous sites (lips, genitalia), and have histopathologic findings consistent with an erythema multiforme–like eruption. Fixed drug eruptions typically resolve within several weeks of drug discontinuation, leaving a dark-brown to violet post-inflammatory hyperpigmentation. Re-introduction of the offending agent, or in some instances a similar medication, generally results in a recurrence of the lesion at the previous location, ultimately causing increased hyperpigmentation. (Fitzpatrick et al., 2001).

Donoghue, 1995 & Leonard, (1995) estimated that SSRIs had more benign tolerability profile with fewer adverse events; most of those which did occur were mild and transient in nature. They were easily administered; require minimal titration compared with older antidepressant drugs and could also be routinely given once daily. All SSRIs were well absorbed after oral administration and this was not diminished by concomitant food intake, thus providing excellent bioavailability.

Antidepressant drugs can induce altered taste perception including dysgeusia (distortion of taste), hypogeusia (diminished sensitivity of taste), and ageusia (absence of taste). Both first-generation tricyclic antidepressants and later developed SSRIs have been reported clinically to cause chemosensory complaints. (Ackerman and Kasbekar , 1997 & Mourad et al.,1998).

(Steele and Ashby, 1993 & Ming et al., 1999) reported that pigmentary changes have been associated with amitriptyline, imipramine, desipramine, and clomipramine. Leukoderma has been detected with

11 venlafaxine and melanosis with citalopram and clomipramine. Reports of general discoloration have been noted during treatment with all the SSRIs. Photodistributed slate-gray or blue-gray pigmentary changes generally occur after long-term exposure and typically resolve months or years after drug discontinuation. Hair and nail color changes may also be involved.

Sertraline

Sertraline is one of the SSRIs. Its history dates back to the early 1970s, when Pfizer chemist "Reinhard Sarges" invented a novel series of psychoactive compounds based on the structures of neuroleptics chlorprothixene and thiothixene (Welch 1995).

Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. A few years later, in 1977, pharmacologist "Kenneth Koe" asked another Pfizer chemist, "Willard Welch" to synthesize some previously unexplored tametraline derivatives. Welch generated a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo . The most potent and selective isomer was taken into further development and eventually named "sertraline". (Mullin 2006).

12 Fabre et al., (1995) explained that sertraline was only approved for use in adults ages 18 and over. That year, it was approved by the food and drug administration (FDA) for use in treating children aged 6 or older with severe obsessive-compulsive disorder (OCD). Sertraline has been approved for the following indications: major depression, (OCD), post traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder and social phobia (social anxiety disorder). Similarly studies via Kobak et al., (1998) revealed the effectiveness of sertraline for the treatment of OCD in adults and children. It was better tolerated and performed better than the gold standard of OCD treatment clomipramine.

Sertraline was approved by FDA in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committe. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. (David, 1999).

Lydiard et al., (1997) found that sertraline treatment of depressed patients with personality disorders improved their personality traits, and this improvement was almost independent from the improvement of their depression. Furthermore, Ravindran et al., (1999) found that sertraline is effective for both severe depression and dysthymia, a milder and more chronic variety of depression.

13 On the other hand, sertraline resulted in a much lower rate of side effects than amitriptyline (49%, vs. 72% for amitriptyline and 32% for placebo), particularly dry mouth, constipation and increased appetite. However, there were more cases of nausea and sexual dysfunction in the sertraline group. Participants taking sertraline showed a greater improvement of the subjective quality of life on such measures as work satisfaction, subjective feeling, perceptions of health and cognitive function. (Reimherr et al., 1990 & Lydiard et al., 1997).

According to Keller et al., (1998) & Miller et al., (1998), Only 11% of patients on sertraline suffered from severe side effects vs. 24% on imipramine. Constipation, dizziness, tremor, dry mouth, micturition disorder and sweating were observed more often with imipramine, and diarrhea and insomnia with sertraline. Patients on sertraline also reported significantly better social and physical functioning. They did not differ from the healthy population on the measures of marital, parental, physical and work functioning and were close to normal on social adjustment and other measures of interpersonal functioning.

Sertraline used for the treatment of depression in elderly (older than 60) patients was superior to SSRI fluoxetine (Prozac), and TCAs amitriptyline, nortriptyline (Pamelor) and imipramine. Sertraline had much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurred more frequently with sertraline. Muijsers et al., (2002).

14 Sertraline has been successfully used for the treatment of social phobia (social anxiety disorder). In addition to psychological components of social phobia, such as fear and avoidance, sertraline also ameliorated some physiological components, such as blushing and palpitations, but not sweating and trembling. It appeared that a higher dose range was needed for adequate response. Furthermore, improvement was achieved slowly. The response was higher among the patients with later onset, especially adult onset of the disorder. The greatest improvement of quality of life was observed among the most impaired patients. (Liebowitz et al., 2003 & Davidson et al., 2006).

Though the original pre-marketing clinical trials demonstrated only weak-to-moderate efficacy of sertraline for depression; many later research established it as one of the most effective drugs in the treatment of depression. (Schramm et al., 2007 & Turner et al., 2008).

Several studies proved that sertraline produced mild side-effects. These included, insomnia, agitation or nervousness, nausea, diarrhea or loose stools, dyspepsia and dry mouth. Sertraline appeared to be associated with microscopic colitis, a rare condition of unknown etiology. As well as akathisia that is, "inner tension, restlessness, and the inability to stay still". Akathisia begian soon after the initiation of treatment or a dose increase; often, several hours after taking the medication. However, it disappeared within several days after sertraline was stopped or its dose was decreased. In some cases, clinicians confused akathisia with anxiety and increased the dose of sertraline, causing further worsening of the

15 patients' symptoms. (Devane, 1992, Olivera, 1997, Lauterbach et al., 1997 & Fernández et al.,2007).

Bergeron et al, (2002) & Blier et al, (2006) revealed that the sertraline dosages necessary for the effective treatment of OCD were higher than the usual dosage for depression. The onset of action was also slower for OCD than for depression. The treatment recommendation was to start treatment with a half of maximal recommended dose for at least two months. After that, the dose could be raised to the maximal recommended in the cases of unsatisfactory response.

According to a meta-analysis of 12 new-generation antidepressants, sertraline and escitalopram were the best in terms of efficacy and acceptability in the acute-phase treatment of adults with unipolar major depression. (Cipriani et al., 2009).

The recent trial findings indicated that continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) might both afford the highest effectiveness and minimize the side effects. (Kornstein et al., 2006)

When taken by moth sertraline is absorbed slowly, achieving its maximal concentration in the plasma 4–6 hours after ingestion. In the blood, it is 98.5% bound to plasma proteins. Its half-life in the body is

16 13–45 hours and, on average, is about 1.5 times longer in women (32 hours) than in men (22 hours), leading to a 1.5-times-higher exposure in women. (Devane et al., 2002).

Comparing the levels of sertraline and its principal metabolite, desmethylsertraline, in mother's blood to their concentration in umbilical cord blood at the time of delivery, Hendrick et al., (2003) indicated that fetal exposure to sertraline and its metabolite was approximately a third of the maternal exposure.

Moreover, Epperson et al., (2001) & Stowe et al., (2003) found that the concentration of sertraline and desmethylsertraline in breast milk was highly variable and, on average, was of the same order of magnitude as their concentration in the blood plasma of the mother. As a result, more than half of breast-fed babies received less than 2 mg/day of sertraline and desmethylsertraline combined, and in most cases these substances were undetectable in their blood. No changes in serotonin uptake by the platelets of breast-fed infants were found, as measured by their blood serotonin levels before and after their mothers began sertraline treatment.

Antidepressants and salivary glands

The primary function of salivary glands is to secrete saliva, a fluid composed of water, electrolytes and various multifunctional proteins. The autonomic sympathetic and parasympathetic receptor

17 systems regulate salivary gland secretion via a co-ordinated sequence of signal transduction and intracellular signalling events (Looms et al., 1998).

Three major salivary glands (the parotid, the sublingual, and the submandibular) produce about 90% of the total salivary output. Minor salivary glands are located throughout the buccal mucosa and palate, and they account for the remainder of the secretory output. When a person is awake, the parotid glands secrete up to 50% of the saliva output. However, when a person is asleep, the parotid contributes almost no saliva and most of the nocturnal output is provided by the submandibular glands. The parotid gland secretes mostly serous fluid that makes for the watery characteristics of saliva, while the sublingual glands produce mucin. The submandibular gland secretes a mixture of serous and mucin. The function of saliva is as diverse as it is critical. Water and mucin in addition to enzymes such as amylase, ribonuclease, and lipase initiate the digestion of food by lubricating it and dissolving it into particles. Saliva also maintain proper oral and upper gastrointestinal pH levels and it modulates the oral flora (many glycoproteins and enzymes contain antibacterial, antifungal, and antiviral properties). Saliva is also considered a part of the mucosal immune system, because plasma cells within the salivary glands produce immunoglobulin A antibodies. The buffering capacity of saliva protects tooth enamel and contributes to dental health (Atkinson and Wu, 1994).

Guggenheimer & Moore (2003) reported that saliva has an important protective effect for the dentition because of its remineralization, antibacterial, and buffering actions.

18 Lying superior to the digastric muscles, each submandibular gland is divided into superficial and deep lobes, which are separated by the mylohyoid muscle, the superficial portion is larger. The mylohyoid muscle runs below it. Secretions are delivered into "Wharton's ducts" on the superficial portion after which they hook around the posterior edge of the mylohyoid muscle and proceed on the superior surface laterally. The ducts are then crossed by the lingual nerve and ultimately drain into the sublingual caruncles on either side of the lingual frenulum along with the major sublingual duct "Bartholin" .(Ten Cate 1998).

Many studies have shown a strong relation between salivary hypofunction and antidepressant drugs Frank et al., (1999) demonstrated that antidepressant medications were the most common cause of oral dryness.. Because the production of saliva is controlled by cholinergic innervation, it is reasonable to assume that anticholinergic drugs like antidepressants will prevent salivary flow.

Oral dryness can induce lower pH values, alter the electrolyte balance, and decrease secretory IgA, thereby weakening the dentition's defense against caries. Patients often present with mouth or tongue burning, bacterial or fungal infections of oral mucosa and teeth, glossitis with fissuring of the tongue, cracked lips, halitosis, parotitis, gingivitis, and difficulty swallowing and speaking. Poor oral health can lead to tooth loss and malnutrition (Papas et al., 1993).

Hunter & Wilson (1995) reported that 63% of patients on TCAS complained of dry mouth (xerostomia) and that 35% of the patient on

19 (SSRIs), had a similar complaint and that the xerostomia will subside gradually after few weeks of stopping the treatment.

Trepenning et al., (1993) explained that salivary hypofunction could alter the oral flora and contribute to plaque formation, thereby increasing the risk for opportunistic infections (e.g., Candida albicans infection) and prolifetration of cariogenic microorganisms (e.g.,Streptococcus mutans).

Since the treatment of psychiatric disorders and affective disturbances mainly involves antidepressant, antipsychotic and anxiolytic drugs, patients with psychiatric alterations that make use of these drugs usually complain of dry mouth (Thomsom et al., 2000).

Rat dentition

Rats are monophyodont, which means that they have one set of teeth during their lifetime. In contrast, humans have both deciduous and permanent dentitions. Rats have only two types of teeth in their mouth which are molars and incisors. They lack the pointed canines, which function to tear food. The growth of incisors is continuous and fast during the entire life-time of the rat, so clinical dental caries does not occur in incisors. Rats have 12 molars, 3 in each quadrant which are very similar to human molars, although their tips lack enamel. They begin to erupt around 16 days after birth. The crown of the rat molar is multi-cuspal and multi-fissural, and the morphological development stages are very similar to humans (Lange & Hammarström 1984).