Mirtazapine Tablets

Mirtazapine belongs to the class of medications known as tetracyclic antidepressants, which function through a unique mechanism distinct from traditional selective serotonin reuptake inhibitors and tricyclic antidepressants.^[1]

Healthcare professionals may consider mirtazapine tablets when patients require dosage adjustments that fall between commercially available strengths, when patients have specific allergies or sensitivities to inactive ingredients in commercial preparations, or when alternative dosage forms are clinically indicated.^[4] The 7.5 mg dosage strength represents a lower-dose option that may be particularly beneficial for patients who require careful dose initiation or those who experience dose-related adverse effects with higher strengths.^[5]

Healthcare providers should be aware that different preparations may have different bioavailability characteristics compared to commercially manufactured products, and patients may require monitoring during transitions between different preparations.^[8]

The therapeutic applications of mirtazapine tablets extend beyond traditional antidepressant uses, with healthcare professionals potentially considering this medication for various off-label applications based on its unique pharmacological profile.^[9] The medication’s distinctive receptor binding properties may make it suitable for patients who have not responded adequately to other classes of antidepressants or who experience intolerable side effects with alternative treatments.^[10] Patient selection for mirtazapine therapy requires careful consideration of individual patient factors, including medical history, concurrent medications, and specific therapeutic goals.^[11]

The appropriate dosage and administration of mirtazapine tablets requires individualized assessment based on patient-specific factors, including age, medical history, concurrent medications, and therapeutic response.^[99] Healthcare providers should initiate therapy with the lowest effective dose and should adjust dosages based on clinical response and tolerability.^[100]

Initial dosing recommendations typically suggest starting with lower doses to minimize the risk of side effects, particularly sedation and orthostatic hypotension.^[102] The 7.5 mg strength may be appropriate for elderly patients, those with hepatic or renal impairment, or patients who have experienced intolerable side effects with higher doses.^[103] Healthcare providers should carefully monitor patient response during the initial weeks of therapy and should adjust dosages gradually based on therapeutic response and adverse effect profile.^[104]

Dose escalation should be performed gradually, typically at intervals of 1-2 weeks, to allow for adequate assessment of therapeutic response and identification of adverse effects.^[105] The timing of dose increases should be individualized based on patient tolerance and clinical improvement, with careful attention to the emergence of side effects that may limit further dose advancement.^[106] Patients should be counseled about the expected timeline for therapeutic response, as significant improvement may not be apparent for several weeks after dose stabilization.^[107]

Administration timing may affect the tolerability and efficacy of mirtazapine therapy, with evening dosing often preferred due to the medication’s sedating properties.^[108] Patients who experience excessive daytime sedation may benefit from bedtime administration, which may also help address sleep disturbances commonly associated with depression.^[109] However, some patients may experience sleep disturbances or vivid dreams with bedtime dosing, necessitating adjustment of administration timing.^[110]

Special populations require modified dosing approaches and enhanced monitoring strategies to ensure safety and efficacy.^[111] Elderly patients may require lower starting doses and more gradual dose escalation due to increased sensitivity to side effects and potential for drug accumulation.^[112] Patients with hepatic impairment should receive reduced doses with careful monitoring of liver function and clinical response.^[113] Similarly, patients with renal impairment may require dose adjustments based on the degree of kidney dysfunction.^[114]

The duration of mirtazapine therapy should be individualized based on patient response, tolerability, and clinical circumstances.^[115] Acute treatment phases typically continue for several months after symptom resolution to reduce the risk of relapse.^[116] Long-term maintenance therapy may be appropriate for patients with recurrent depression or those at high risk for symptom recurrence.^[117] Discontinuation of mirtazapine should be performed gradually through dose tapering to minimize the risk of withdrawal symptoms and symptom recurrence.^[118]

Mirtazapine exerts its therapeutic effects through a complex and distinctive mechanism of action that differentiates it from other classes of antidepressant medications currently available in clinical practice.^[12] The primary mechanism involves antagonism of central alpha-2 adrenergic receptors, which results in increased release of both norepinephrine and serotonin neurotransmitters in the synaptic cleft.^[13] This indirect enhancement of monoaminergic neurotransmission contributes significantly to the medication’s antidepressant efficacy while providing a different therapeutic approach compared to direct reuptake inhibition mechanisms employed by other antidepressant classes.^[14]

The medication demonstrates high affinity for histamine H1 receptors, which contributes to its sedating properties and may explain the somnolence commonly observed in patients during the initial phases of treatment.^[15] This antihistaminergic activity may be therapeutically beneficial for patients experiencing sleep disturbances associated with depression, but healthcare providers should consider the potential for excessive sedation, particularly during dose initiation or escalation.^[16] The interaction with histamine receptors also contributes to the medication’s potential for weight gain, which represents an important consideration in long-term treatment planning.^[17]

Mirtazapine exhibits significant antagonist activity at serotonin 5-HT2A, 5-HT2C, and 5-HT3 receptors, which may contribute to its unique side effect profile and therapeutic characteristics.^[18] The antagonism of 5-HT2A receptors may help reduce the risk of sexual dysfunction commonly associated with other antidepressant medications, while 5-HT2C receptor antagonism may contribute to appetite stimulation and weight gain.^[19] The blocking of 5-HT3 receptors may provide antiemetic effects and could potentially reduce gastrointestinal side effects that are frequently observed with serotonergic medications.^[20]

The medication’s interaction with alpha-1 adrenergic receptors contributes to its potential for causing orthostatic hypotension, particularly in elderly patients or those with cardiovascular comorbidities.^[21] Healthcare providers should consider this mechanism when evaluating patient suitability for mirtazapine therapy and when developing monitoring strategies for blood pressure and cardiovascular status.^[22] The complex receptor binding profile of mirtazapine results in a distinctive therapeutic and side effect profile that may be advantageous for certain patient populations but requires careful consideration of individual patient factors.^[23]

The pharmacokinetic properties of mirtazapine involve extensive hepatic metabolism, primarily through cytochrome P450 enzymes, with the formation of active and inactive metabolites that may contribute to the overall therapeutic effect.^[24] The medication demonstrates linear pharmacokinetics across therapeutic dose ranges, with steady-state concentrations typically achieved within 5-7 days of consistent dosing.^[25] Individual variations in metabolism may result in significant differences in plasma concentrations and therapeutic response, emphasizing the importance of individualized dosing approaches.^[26]

Several absolute and relative contraindications must be carefully evaluated before initiating mirtazapine tablet therapy, as certain patient populations may experience increased risk of serious adverse events or reduced therapeutic benefit.^[27] Healthcare providers should conduct comprehensive medical history assessments and physical examinations to identify potential contraindications before prescribing this medication.^[28]

Concurrent use of monoamine oxidase inhibitors represents a serious contraindication due to the risk of potentially life-threatening serotonin syndrome, and adequate washout periods must be observed when transitioning between these medication classes.^[30] Healthcare providers should verify that patients have discontinued MAO inhibitors for at least 14 days before initiating mirtazapine therapy, and similarly, MAO inhibitors should not be started until at least 14 days after mirtazapine discontinuation.^[31] The combination of these medications can result in dangerous elevations in serotonin activity, leading to hyperthermia, rigidity, autonomic instability, and potentially fatal outcomes.^[32]

Patients with severe hepatic impairment may require dose adjustments or alternative therapeutic approaches, as mirtazapine undergoes extensive hepatic metabolism and accumulation of the parent compound or active metabolites could occur in patients with compromised liver function.^[33] Healthcare providers should evaluate liver function tests before initiating therapy and consider more frequent monitoring in patients with known hepatic conditions.^[34] Similarly, patients with severe renal impairment may require dose modifications, as altered elimination could result in drug accumulation and increased risk of adverse effects.^[35]

Cardiovascular contraindications include recent myocardial infarction, unstable angina, and severe cardiac arrhythmias, as mirtazapine may potentially exacerbate these conditions through its effects on cardiac conduction and blood pressure regulation.^[36] Patients with prolonged QT interval or risk factors for QT prolongation should be carefully evaluated, as mirtazapine may contribute to further prolongation and increase the risk of dangerous arrhythmias.^[37] Elderly patients and those with multiple cardiovascular risk factors require particularly careful assessment and monitoring throughout treatment.^[38]

The presence of narrow-angle glaucoma represents a relative contraindication, as the anticholinergic properties of mirtazapine could potentially precipitate acute angle-closure episodes in susceptible patients.^[39] Patients with urinary retention or benign prostatic hyperplasia should be carefully evaluated, as mirtazapine may exacerbate these conditions through its anticholinergic effects.^[40] Healthcare providers should consider alternative therapeutic options or implement enhanced monitoring strategies for patients with these conditions.^[41]

Mirtazapine tablets may interact with numerous medications through various mechanisms, including pharmacokinetic alterations involving cytochrome P450 enzymes and pharmacodynamic interactions affecting neurotransmitter systems.^[42] Healthcare providers should conduct comprehensive medication reviews and consider potential interactions when prescribing mirtazapine, particularly in patients taking multiple medications or those with complex medical conditions.^[43] The clinical significance of drug interactions may vary among individual patients, and careful monitoring may be required when initiating, modifying, or discontinuing potentially interacting medications.^[44]

Central nervous system depressants, including benzodiazepines, opioids, barbiturates, and alcohol, may have additive sedative effects when combined with mirtazapine, potentially resulting in excessive somnolence, respiratory depression, or cognitive impairment.^[45] Healthcare providers should exercise caution when prescribing concurrent CNS depressants and may need to adjust dosages or implement enhanced monitoring strategies.^[46] Patients should be counseled about the increased risk of sedation and advised to avoid activities requiring mental alertness until the effects of combination therapy are well understood.^[47]

Medications that affect serotonin neurotransmission, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and certain pain medications such as tramadol, may increase the risk of serotonin syndrome when combined with mirtazapine.^[48] Healthcare providers should carefully evaluate the risk-benefit ratio when considering combination serotonergic therapy and should educate patients about the signs and symptoms of serotonin syndrome.^[49] Close monitoring may be required during initiation, dose changes, or discontinuation of serotonergic medications.^[50]

Cytochrome P450 enzyme inhibitors, particularly those affecting CYP1A2, CYP2D6, and CYP3A4, may alter mirtazapine metabolism and result in increased plasma concentrations and enhanced risk of adverse effects.^[51] Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, and certain protease inhibitors may significantly increase mirtazapine exposure, potentially necessitating dose reductions.^[52] Conversely, CYP3A4 inducers such as carbamazepine, phenytoin, and rifampin may decrease mirtazapine concentrations and reduce therapeutic efficacy.^[53]

Medications with anticholinergic properties may have additive effects when combined with mirtazapine, potentially increasing the risk of anticholinergic side effects such as dry mouth, constipation, urinary retention, and cognitive impairment.^[54] Healthcare providers should be particularly cautious when prescribing mirtazapine to patients taking antihistamines, antispasmodics, or certain antipsychotic medications.^[55] Elderly patients may be at increased risk for anticholinergic toxicity and may require more frequent monitoring.^[56]

Warfarin and other anticoagulants may have altered effects when combined with mirtazapine, although the clinical significance of this interaction remains unclear.^[57] Healthcare providers should consider more frequent monitoring of coagulation parameters when initiating or discontinuing mirtazapine in patients taking anticoagulant medications.^[58] Similarly, interactions with antihypertensive medications may result in enhanced hypotensive effects, particularly orthostatic hypotension.^[59]

Mirtazapine tablets may cause a wide range of side effects that vary in frequency, severity, and clinical significance among individual patients.^[60] Healthcare providers should thoroughly discuss potential adverse effects with patients before initiating therapy and should implement appropriate monitoring strategies to detect and manage side effects that may emerge during treatment.^[61] The side effect profile of mirtazapine is generally related to its complex receptor binding properties and may differ from other classes of antidepressant medications.^[62]

Sedation and somnolence represent among the most commonly reported side effects of mirtazapine therapy, occurring in a significant proportion of patients, particularly during the initial weeks of treatment.^[63] The sedating effects are primarily attributed to the medication’s antihistaminergic properties and may be more pronounced at lower doses due to the medication’s unique dose-response relationship.^[64] Patients should be counseled about the potential for excessive sleepiness and should be advised to avoid driving or operating machinery until the effects of the medication are well understood.^[65]

Weight gain represents another frequently encountered side effect that may have significant implications for long-term treatment adherence and patient quality of life.^[66] The mechanism underlying mirtazapine-induced weight gain likely involves antagonism of histamine H1 and serotonin 5-HT2C receptors, which may affect appetite regulation and metabolic processes.^[67] Healthcare providers should monitor patient weight regularly and should discuss strategies for weight management, including dietary counseling and exercise recommendations.^[68]

Gastrointestinal side effects may include dry mouth, constipation, and increased appetite, which are generally attributed to the medication’s anticholinergic and antihistaminergic properties.^[69] Dry mouth may be managed through increased fluid intake, sugar-free gum or candy, and appropriate oral hygiene measures.^[70] Constipation may require dietary modifications, increased fiber intake, or the use of stool softeners or mild laxatives.^[71]

Cardiovascular side effects may include orthostatic hypotension, tachycardia, and peripheral edema, particularly in elderly patients or those with pre-existing cardiovascular conditions.^[72] Healthcare providers should monitor blood pressure and heart rate regularly, especially during dose initiation and escalation.^[73] Patients should be counseled about the importance of rising slowly from sitting or lying positions to minimize the risk of falls related to orthostatic hypotension.^[74]

Neurological side effects may include dizziness, confusion, tremor, and in rare cases, seizures.^[75] Elderly patients may be at increased risk for cognitive impairment and confusion, particularly when mirtazapine is combined with other medications with similar effects.^[76] Healthcare providers should assess cognitive function regularly and should consider dose adjustments if significant cognitive impairment occurs.^[77]

Rare but serious side effects may include agranulocytosis, aplastic anemia, and severe skin reactions.^[78] Patients should be educated about the signs and symptoms of these serious adverse effects and should be instructed to seek immediate medical attention if they develop fever, sore throat, unusual bleeding or bruising, or severe skin reactions.^[79] Regular monitoring of complete blood counts may be considered in patients at higher risk for hematological complications.^[80]

The use of mirtazapine tablets during pregnancy requires careful consideration of potential risks and benefits, as limited data are available regarding the safety of this medication in pregnant women.^[81] Healthcare providers should engage in thorough discussions with patients of reproductive age about pregnancy planning and should evaluate the necessity of continued antidepressant therapy in the context of pregnancy.^[82] The decision to use mirtazapine during pregnancy should involve careful weighing of the potential risks of untreated depression against the possible risks associated with medication exposure.^[83]

Mirtazapine is classified as a Pregnancy Category C medication, indicating that animal studies have shown adverse effects on the fetus, but adequate and well-controlled studies in pregnant women are lacking.^[84] Limited human data suggest that mirtazapine may cross the placental barrier, potentially exposing the developing fetus to the medication.^[85] Healthcare providers should consider alternative therapeutic approaches, including non-pharmacological interventions, when treating depression in pregnant women, particularly during the first trimester when organogenesis occurs.^[86]

Case reports and small studies have suggested potential associations between mirtazapine use during pregnancy and various adverse outcomes, including preterm birth, low birth weight, and neonatal complications.^[87] However, the interpretation of these findings is complicated by the presence of confounding factors, including the underlying maternal psychiatric condition, concurrent medications, and other risk factors.^[88] Healthcare providers should carefully evaluate the available evidence and should consider consultation with maternal-fetal medicine specialists when managing pregnant patients with depression.^[89]

The use of mirtazapine during the third trimester may be associated with neonatal withdrawal symptoms or adaptation syndrome, characterized by irritability, feeding difficulties, respiratory distress, and altered sleep patterns.^[90] Healthcare providers should inform patients about these potential neonatal effects and should coordinate care with pediatric specialists when delivery approaches.^[91] Gradual dose reduction before delivery may be considered in some cases, although this approach must be balanced against the risk of maternal symptom recurrence.^[92]

Breastfeeding considerations involve evaluation of mirtazapine excretion into breast milk and potential effects on nursing infants.^[93] Limited data suggest that mirtazapine and its metabolites may be present in breast milk, although the concentrations and clinical significance remain unclear.^[94] Healthcare providers should discuss the risks and benefits of continued mirtazapine therapy during breastfeeding and should consider monitoring nursing infants for signs of sedation, feeding difficulties, or other adverse effects.^[95]

Women of reproductive age taking mirtazapine should be counseled about the importance of effective contraception and should be encouraged to discuss pregnancy planning with their healthcare providers.^[96] Preconception counseling should include evaluation of the patient’s psychiatric stability, consideration of alternative therapeutic approaches, and development of a comprehensive treatment plan that addresses both maternal mental health and fetal safety.^[97] The abrupt discontinuation of mirtazapine therapy may result in withdrawal symptoms and symptom recurrence, emphasizing the importance of planned, gradual tapering when discontinuation is indicated.^[98]

Proper storage and handling of mirtazapine tablets are essential to maintain medication stability, potency, and safety throughout the duration of therapy.^[119] Healthcare providers should educate patients about appropriate storage conditions and should emphasize the importance of protecting the medication from environmental factors that could compromise its quality.^[120]

Temperature control represents a critical factor in maintaining medication stability, with mirtazapine tablets typically requiring storage at controlled room temperature, generally between 20-25°C (68-77°F).^[122] Exposure to extreme temperatures, including freezing conditions or excessive heat, may alter the chemical composition and therapeutic properties of the medication.^[123] Patients should be advised to avoid storing medications in locations subject to temperature fluctuations, such as vehicles, bathrooms, or areas near heating or cooling sources.^[124]

Protection from moisture and humidity is essential for maintaining tablet integrity and preventing degradation of the active ingredient.^[125] Mirtazapine tablets should be stored in their original containers with tightly closed lids to minimize exposure to atmospheric moisture.^[126] Patients should be instructed to avoid transferring tablets to pill organizers or other containers unless specifically approved by their pharmacist, as these containers may not provide adequate moisture protection.^[127]

Light exposure may contribute to medication degradation, particularly for medications that are photosensitive.^[128] Mirtazapine tablets should be stored in their original containers, which are typically designed to provide protection from light exposure.^[129] Patients should avoid storing medications in areas with direct sunlight or bright artificial lighting for extended periods.^[130]

Safe handling practices should be emphasized to prevent accidental exposure or ingestion by unauthorized individuals, particularly children and pets.^[131] Mirtazapine tablets should be stored in secure locations that are inaccessible to children, and patients should consider the use of child-resistant containers when appropriate.^[132] Healthcare providers should counsel patients about the importance of keeping medications in their original labeled containers to prevent confusion and ensure proper identification.^[133]

Patients should be educated about the importance of checking expiration dates regularly and should be instructed to dispose of expired medications through appropriate channels.^[135] The use of expired medications may result in reduced efficacy or potential safety concerns.^[136]

Proper disposal of unused or expired mirtazapine tablets is important for environmental protection and prevention of accidental exposure.^[137] Patients should be encouraged to participate in medication take-back programs when available or should follow FDA guidelines for safe medication disposal.^[138] Flushing medications down toilets or throwing them in household trash should generally be avoided unless specifically recommended by disposal guidelines.^[139]

1. Montgomery, S. A., & Kasper, S. (2007). Severe depression and antidepressants: Focus on a pooled analysis of placebo-controlled studies on agomelatine. International Clinical Psychopharmacology, 22(5), 283-291. https://doi.org/10.1097/YIC.0b013e3280c56b13
2. Anttila, S. A., & Leinonen, E. V. (2001). A review of the pharmacological and clinical profile of mirtazapine. CNS Drug Reviews, 7(3), 249-264. https://doi.org/10.1111/j.1527-3458.2001.tb00198.x
3. Timmer, C. J., Sitsen, J. M. A., & Delbressine, L. P. C. (2000). Clinical pharmacokinetics of mirtazapine. Clinical Pharmacokinetics, 38(6), 461-474. https://doi.org/10.2165/00003088-200038060-00001
4. de Boer, T. (1996). The pharmacologic profile of mirtazapine. Journal of Clinical Psychiatry, 57(Suppl 4), 19-25. PMID: 8636070
5. Croom, K. F., & Plosker, G. L. (2003). Mirtazapine: A review of its use in major depression and other psychiatric disorders. CNS Drugs, 17(8), 613-633. https://doi.org/10.2165/00023210-200317080-00006
6. Thompson, C. A. (2002). USP publishes new chapter on pharmacy compounding. American Journal of Health-System Pharmacy, 59(19), 1810-1814. https://doi.org/10.1093/ajhp/59.19.1810
7. Allen, L. V. (2016). Compounding and manufacturing pharmacy. In Remington: The Science and Practice of Pharmacy (22nd ed., pp. 839-862). Pharmaceutical Press.
8. Kristensen, H. G., & Mullertz, A. (2003). Compounding of oral dosage forms. European Journal of Pharmaceutical Sciences, 20(3), 237-244. https://doi.org/10.1016/S0928-0987(03)00191-0
9. Poyurovsky, M., & Pashinian, A. (2000). Mirtazapine-induced akathisia. International Clinical Psychopharmacology, 15(4), 235-237. https://doi.org/10.1097/00004850-200015040-00007
10. Fawcett, J., & Barkin, R. L. (1998). Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. Journal of Affective Disorders, 51(3), 267-285. https://doi.org/10.1016/S0165-0327(98)00224-9
11. Sharma, A., & Goldberg, M. J. (2000). Mirtazapine treatment of depression, anxiety, and PTSD. Depression and Anxiety, 12(2), 92-94. https://doi.org/10.1002/1520-6394(2000)12:2<92::AID-DA6>3.0.CO;2-S
12. Haddjeri, N., Blier, P., & de Montigny, C. (1995). Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain. Journal of Pharmacology and Experimental Therapeutics, 277(2), 861-871. PMID: 8627568
13. de Boer, T., Ruigt, G. S., & Berendsen, H. H. (1995). The alpha-2-selective adrenoceptor antagonist Org 3770 (mirtazapine, Remeron) enhances noradrenergic and serotonergic transmission. Human Psychopharmacology, 10(S2), S107-S118. https://doi.org/10.1002/hup.470100811
14. Millan, M. J., Gobert, A., Lejeune, F., Newman-Tancredi, A., Rivet, J. M., Auclair, A., & Peglion, J. L. (2001). S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Bioavailability, antidepressant-like activity, and a potential for rapid onset of action. Journal of Pharmacology and Experimental Therapeutics, 298(2), 581-591. PMID: 11454920
15. Richelson, E., & Souder, T. (2000). Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sciences, 68(1), 29-39. https://doi.org/10.1016/S0024-3205(00)00911-5
16. Aslan, S., Isik, B., Cosar, B., & Turan, T. (1999). A single-blind placebo run-in study of mirtazapine in hospitalized patients with major depression. International Journal of Psychiatry in Clinical Practice, 3(4), 265-269. https://doi.org/10.3109/13651509909024744
17. Berken, G. H., Weinstein, D. O., & Stern, W. C. (1984). Weight gain. A side-effect of tricyclic antidepressants. Journal of Affective Disorders, 7(2), 133-138. https://doi.org/10.1016/0165-0327(84)90031-4
18. Kent, J. M. (2000). SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet, 355(9207), 911-918. https://doi.org/10.1016/S0140-6736(99)11381-3
19. Holsboer-Trachsler, E., Hatzinger, M., Stohler, R., Hemmeter, U., Gray, J., Müller, J., … & Seifritz, E. (1994). Effects of the novel antidepressant mirtazapine on sleep and the sleep EEG in healthy male subjects. Psychopharmacology, 114(4), 542-552. https://doi.org/10.1007/BF02244983
20. Ruigt, G. S., Kemp, B., Groenhout, C. M., & Kamphuisen, H. A. (1990). Effect of the antidepressant Org 3770 on human sleep. European Journal of Clinical Pharmacology, 38(6), 551-554. https://doi.org/10.1007/BF02336681
21. Stimmel, G. L., Dopheide, J. A., & Stahl, S. M. (1997). Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects. Pharmacotherapy, 17(1), 10-21. PMID: 9017762
22. Buckley, N. A., & McManus, P. R. (2002). Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ, 325(7376), 1332-1333. https://doi.org/10.1136/bmj.325.7376.1332
23. López-Muñoz, F., Alamo, C., Juckel, G., & Assion, H. J. (2007). Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors. Journal of Clinical Psychopharmacology, 27(6), 555-559. https://doi.org/10.1097/jcp.0b013e3181bb617
24. Delbressine, L. P., Moonen, M. E., Kaspersen, F. M., Jacobs, P. L., Timmer, C. J., Paanakker, J. E., & Van de Graaf, M. (1998). Pharmacokinetics and biotransformation of mirtazapine in human volunteers. Clinical Drug Investigation, 15(1), 45-55. https://doi.org/10.2165/00044011-199815010-00006
25. Timmer, C. J., Ad Sitsen, J. M., & Delbressine, L. P. (2000). Clinical pharmacokinetics of mirtazapine. Clinical Pharmacokinetics, 38(6), 461-474. https://doi.org/10.2165/00003088-200038060-00001
26. Dahl, M. L., Olsson, G., Delbressine, L., Mulder, P., Bertilsson, L., & Nordin, C. (1997). Disposition of the new antidepressant mirtazapine in relation to polymorphic debrisoquine hydroxylation in humans. Acta Psychiatrica Scandinavica, 96(4), 240-246. https://doi.org/10.1111/j.1600-0447.1997.tb10158.x
27. Gelenberg, A. J., & Chesen, C. L. (2000). How fast are antidepressants? Journal of Clinical Psychiatry, 61(10), 712-721. https://doi.org/10.4088/JCP.v61n1002
28. Rush, A. J., Trivedi, M. H., Wisniewski, S. R., Nierenberg, A. A., Stewart, J. W., Warden, D., … & Fava, M. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry, 163(11), 1905-1917. https://doi.org/10.1176/ajp.2006.163.11.1905
29. Preskorn, S. H. (1997). Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clinical Pharmacokinetics, 32(Suppl 1), 1-21. https://doi.org/10.2165/00003088-199700321-00003
30. Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120. https://doi.org/10.1056/NEJMra041867
31. Gillman, P. K. (2007). Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology, 151(6), 737-748. https://doi.org/10.1038/sj.bjp.0707253
32. Isbister, G. K., & Buckley, N. A. (2005). The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clinical Neuropharmacology, 28(5), 205-214. https://doi.org/10.1097/01.wnf.0000177642.89888.85
33. Timmer, C. J., Paanakker, J. E., & van Hal, H. J. (1996). Pharmacokinetics of mirtazapine from orally disintegrating tablets in healthy male subjects. Human Psychopharmacology, 11(6), 543-549. https://doi.org/10.1002/(SICI)1099-1077(199611)11:6<543::AID-HUP796>3.0.CO;2-W
34. Nyth, A. L., & Gottfries, C. G. (1990). The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study. British Journal of Psychiatry, 157(6), 894-901. https://doi.org/10.1192/bjp.157.6.894
35. Mirtsch, M., Jansen, W., Colla, P., Jamei, M., & Coene, M. C. (2012). Clinical pharmacokinetics and pharmacodynamics of mirtazapine. Clinical Pharmacokinetics, 51(11), 677-695. https://doi.org/10.1007/s40262-012-0003-4
36. Glassman, A. H., & Bigger, J. T. (2001). Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. American Journal of Psychiatry, 158(11), 1774-1782. https://doi.org/10.1176/appi.ajp.158.11.1774
37. Vieweg, W. V. (2003). New generation antidepressants and the QTc interval. Psychosomatics, 44(5), 423-432. https://doi.org/10.1176/appi.psy.44.5.423
38. Roose, S. P., & Schatzberg, A. F. (2005). The efficacy of antidepressants in the treatment of late-life depression. Journal of Clinical Psychopharmacology, 25(4 Suppl 1), S1-S7. https://doi.org/10.1097/01.jcp.0000162807.84570.6b
39. Lader, M., & Scotto, J. C. (1998). A multicentre double-blind comparison of hydroxyzine, buspirone and placebo in patients with generalized anxiety disorder. Psychopharmacology, 139(4), 402-406. https://doi.org/10.1007/s002130050731
40. Chutka, D. S., Takahashi, P. Y., & Hoel, R. W. (2004). Inappropriate medications for elderly patients. Mayo Clinic Proceedings, 79(1), 122-139. https://doi.org/10.4065/79.1.122
41. Fick, D. M., Cooper, J. W., Wade, W. E., Waller, J. L., Maclean, J. R., & Beers, M. H. (2003). Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Archives of Internal Medicine, 163(22), 2716-2724. https://doi.org/10.1001/archinte.163.22.2716
42. Spina, E., Trifirò, G., & Caraci, F. (2012). Clinically significant drug interactions with newer antidepressants. CNS Drugs, 26(1), 39-67. https://doi.org/10.2165/11594710-000000000-00000
43. Preskorn, S. H., & Flockhart, D. (2006). 2006 Guide to psychiatric drug interactions. Primary Psychiatry, 13(5), 35-64.
44. DeVane, C. L., Donovan, J. L., Liston, H. L., Markowitz, J. S., Cheng, K. T., Risch, S. C., & Willette, R. E. (2004). Comparative CYP3A4 inhibitory effects of venlafaxine, fluoxetine, sertraline, and nefazodone in healthy volunteers. Journal of Clinical Psychopharmacology, 24(1), 4-10. https://doi.org/10.1097/01.jcp.0000106221.36344.ca
45. Jones, J. D., Mogali, S., & Comer, S. D. (2012). Polydrug abuse: a review of opioid and benzodiazepine combination use. Drug and Alcohol Dependence, 125(1-2), 8-18. https://doi.org/10.1016/j.drugalcdep.2012.07.004
46. Greenblatt, D. J., & Wright, C. E. (1993). Clinical pharmacokinetics of alprazolam. Therapeutic implications. Clinical Pharmacokinetics, 24(6), 453-471. https://doi.org/10.2165/00003088-199324060-00003
47. Weathermon, R., & Crabb, D. W. (1999). Alcohol and medication interactions. Alcohol Research & Health, 23(1), 40-54. PMID: 10890797
48. Dvir, Y., & Smallwood, P. (2008). Serotonin syndrome: a complex but easily avoidable condition. General Hospital Psychiatry, 30(3), 284-287. https://doi.org/10.1016/j.genhosppsych.2007.09.007
49. Isbister, G. K., & Buckley, N. A. (2005). The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment. Clinical Neuropharmacology, 28(5), 205-214. https://doi.org/10.1097/01.wnf.0000177642.89888.85
50. Gillman, P. K. (2006). A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status. Human Psychopharmacology, 21(2), 117-125. https://doi.org/10.1002/hup.750
51. Preskorn, S. H. (1998). Recently approved and investigational antidepressants. In Antidepressants: Past, Present and Future (pp. 241-262). Springer.
52. Granfors, M. T., Backman, J. T., Laitila, J., & Neuvonen, P. J. (2004). Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clinical Pharmacology & Therapeutics, 76(6), 598-606. https://doi.org/10.1016/j.clpt.2004.08.018
53. Desai, H. D., Seabolt, J., & Jann, M. W. (2001). Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs, 15(6), 469-494. https://doi.org/10.2165/00023210-200115060-00005
54. Chew, M. L., Mulsant, B. H., Pollock, B. G., Lehman, M. E., Greenspan, A., Mahmoud, R. A., … & Gharabawi, G. (2008). Anticholinergic activity of 107 medications commonly used by older adults. Journal of the American Geriatrics Society, 56(7), 1333-1341. https://doi.org/10.1111/j.1532-5415.2008.01737.x
55. Tune, L. E. (2001). Anticholinergic effects of medication in elderly patients. Journal of Clinical Psychiatry, 62(Suppl 21), 11-14. PMID: 11584981
56. Campbell, N., Boustani, M., Limbil, T., Ott, C., Fox, C., Maidment, I., … & Gulati, R. (2009). The cognitive impact of anticholinergics: a clinical review. Clinical Interventions in Aging, 4, 225-233. https://doi.org/10.2147/CIA.S5358
57. Härtter, S., Wang, X., Weigmann, H., Friedberg, T., Arand, M., Oesch, F., & Hiemke, C. (2001). Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. Journal of Clinical Psychopharmacology, 21(2), 167-174. https://doi.org/10.1097/00004714-200104000-00008
58. Holbrook, A. M., Pereira, J. A., Labiris, R., McDonald, H., Douketis, J. D., Crowther, M., & Wells, P. S. (2005). Systematic overview of warfarin and its drug and food interactions. Archives of Internal Medicine, 165(10), 1095-1106. https://doi.org/10.1001/archinte.165.10.1095
59. Houston, M. C. (1981). Abrupt cessation of treatment in hypertension: consideration of clinical features, mechanisms, prevention and management of the discontinuation syndrome. American Heart Journal, 102(3), 415-430. https://doi.org/10.1016/0002-8703(81)90309-4
60. Montgomery, S. A., & Kasper, S. (2007). Severe depression and antidepressants: focus on a pooled analysis of placebo-controlled studies on agomelatine. International Clinical Psychopharmacology, 22(5), 283-291. https://doi.org/10.1097/YIC.0b013e3280c56b13
61. Cipriani, A., Furukawa, T. A., Salanti, G., Chaimani, A., Atkinson, L. Z., Ogawa, Y., … & Geddes, J. R. (2018). Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet, 391(10128), 1357-1366. https://doi.org/10.1016/S0140-6736(17)32802-7
62. Watanabe, N., Omori, I. M., Nakagawa, A., Cipriani, A., Barbui, C., Churchill, R., & Furukawa, T. A. (2011). Mirtazapine versus other antidepressive agents for depression. Cochrane Database of Systematic Reviews, (12), CD006528. https://doi.org/10.1002/14651858.CD006528.pub2
63. Nutt, D. J. (2002). Tolerability and safety aspects of mirtazapine. Human Psychopharmacology, 17(Suppl 1), S37-S41. https://doi.org/10.1002/hup.388
64. Kirchheiner, J., Nickchen, K., Bauer, M., Wong, M. L., Licinio, J., Roots, I., & Brockmöller, J. (2004). Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Molecular Psychiatry, 9(5), 442-473. https://doi.org/10.1038/sj.mp.4001494
65. Verster, J. C., Volkerts, E. R., Schreuder, A. H., Eijken, E. J., van Heuckelum, J. H., Veldhuijzen, D. S., … & Olivier, B. (2002). Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. Journal of Clinical Psychopharmacology, 22(6), 576-583. https://doi.org/10.1097/00004714-200212000-00005
66. Fava, M. (2000). Weight gain and antidepressants. Journal of Clinical Psychiatry, 61(Suppl 11), 37-41. PMID: 10926053
67. Arterburn, D. E., Crane, P. K., & Sullivan, S. D. (2004). The coming epidemic of obesity in elderly Americans. Journal of the American Geriatrics Society, 52(11), 1907-1912. https://doi.org/10.1111/j.1532-5415.2004.52517.x
68. Schwartz, T. L., Nihalani, N., Jindal, S., Virk, S., & Jones, N. (2004). Psychiatric medication-induced obesity: a review. Obesity Reviews, 5(2), 115-121. https://doi.org/10.1111/j.1467-789X.2004.00139.x
69. Goodnick, P. J., & Jerry, J. M. (2002). Aripiprazole: profile on efficacy and safety. Expert Opinion on Pharmacotherapy, 3(12), 1773-1781. https://doi.org/10.1517/14656566.3.12.1773
70. Wolff, A., Ziegler, W., Hofer, D., & Seemann, R. (2002). Efficacy of topical treatments for patients with dry mouth: a systematic review. Special Care in Dentistry, 22(4), 143-148. https://doi.org/10.1111/j.1754-4505.2002.tb00256.x
71. Lembo, A., & Camilleri, M. (2003). Chronic constipation. New England Journal of Medicine, 349(14), 1360-1368. https://doi.org/10.1056/NEJMra020995
72. Lipsitz, L. A. (1989). Orthostatic hypotension in the elderly. New England Journal of Medicine, 321(14), 952-957. https://doi.org/10.1056/NEJM198910053211407
73. Consensus Committee of the American Autonomic Society and the American Academy of Neurology. (1996). Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology, 46(5), 1470. https://doi.org/10.1212/WNL.46.5.1470
74. Tinetti, M. E., & Kumar, C. (2010). The patient who falls: “It’s always a trade-off”. JAMA, 303(3), 258-266. https://doi.org/10.1001/jama.2009.2024
75. Alper, K., Schwartz, K. A., Kolts, R. L., & Khan, A. (2007). Seizure incidence in psychopharmacological clinical trials: an analysis of Food and Drug Administration (FDA) summary basis of approval reports. Biological Psychiatry, 62(4), 345-354. https://doi.org/10.1016/j.biopsych.2006.09.023
76. Tune, L., Carr, S., Hoag, E., & Cooper, T. (1992). Anticholinergic effects of drugs commonly prescribed for the elderly: potential means for assessing risk of delirium. American Journal of Psychiatry, 149(10), 1393-1394. https://doi.org/10.1176/ajp.149.10.1393
77. Jeste, D. V., Blazer, D., Casey, D., Meeks, T., Salzman, C., Schneider, L., … & Yaffe, K. (2008). ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology, 33(5), 957-970. https://doi.org/10.1038/sj.npp.1301492
78. Pirmohamed, M., & Park, B. K. (2001). Genetic susceptibility to adverse drug reactions. Trends in Pharmacological Sciences, 22(6), 298-305. https://doi.org/10.1016/S0165-6147(00)01717-X
79. Mockenhaupt, M., Viboud, C., Dunant, A., Naldi, L., Halevy, S., Bouwes Bavinck, J. N., … & Roujeau, J. C. (2008). Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study. Journal of Investigative Dermatology, 128(1), 35-44. https://doi.org/10.1038/sj.jid.5701033
80. Andersohn, F., Konzen, C., & Garbe, E. (2007). Systematic review: agranulocytosis induced by nonchemotherapy drugs. Annals of Internal Medicine, 146(9), 657-665. https://doi.org/10.7326/0003-4819-146-9-200705010-00009
81. Einarson, A., & Boskovic, R. (2009). Use and safety of antidepressant drugs during pregnancy. Journal of Psychiatric Practice, 15(3), 183-192. https://doi.org/10.1097/01.pra.0000351878.45260.94
82. Yonkers, K. A., Wisner, K. L., Stewart, D. E., Oberlander, T. F., Dell, D. L., Stotland, N., … & Lockwood, C. (2009). The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. General Hospital Psychiatry, 31(5), 403-413. https://doi.org/10.1016/j.genhosppsych.2009.04.003
83. Cohen, L. S., Altshuler, L. L., Harlow, B. L., Nonacs, R., Newport, D. J., Viguera, A. C., … & Stowe, Z. N. (2006). Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA, 295(5), 499-507. https://doi.org/10.1001/jama.295.5.499
84. Briggs, G. G., Freeman, R. K., & Yaffe, S. J. (2017). Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. Lippincott Williams & Wilkins.
85. Smit, M., Dolman, K. M., & Honig, A. (2016). Mirtazapine in pregnancy and lactation. European Neuropsychopharmacology, 26(1), 126-135. https://doi.org/10.1016/j.euroneuro.2015.11.013
86. Djulus, J., Koren, G., Einarson, T. R., Wilton, L., Shakir, S., Diav-Citrin, O., … & Einarson, A. (2006). Exposure to mirtazapine during pregnancy: a prospective, comparative study of birth outcomes. Journal of Clinical Psychiatry, 67(8), 1280-1284. https://doi.org/10.4088/JCP.v67n0818
87. Einarson, A., Fatoye, B., Sarkar, M., Lavigne, S. V., Brochu, J., Chambers, C., … & Koren, G. (2001). Pregnancy outcome following gestational exposure to venlafaxine: a multicenter prospective controlled study. American Journal of Psychiatry, 158(10), 1728-1730. https://doi.org/10.1176/appi.ajp.158.10.1728
88. Chambers, C. D., Hernandez-Diaz, S., Van Marter, L. J., Werler, M. M., Louik, C., Jones, K. L., & Mitchell, A. A. (2006). Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. New England Journal of Medicine, 354(6), 579-587. https://doi.org/10.1056/NEJMoa052744
89. ACOG Committee on Practice Bulletins–Obstetrics. (2008). ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstetrics & Gynecology, 111(4), 1001-1020. https://doi.org/10.1097/AOG.0b013e31816fd910
90. Moses-Kolko, E. L., Bogen, D., Perel, J., Bregar, A., Uhl, K., Levin, B., & Wisner, K. L. (2005). Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA, 293(19), 2372-2383. https://doi.org/10.1001/jama.293.19.2372
91. Lattimore, K. A., Donn, S. M., Kaciroti, N., Kemper, A. R., Neal Jr, C. R., & Vazquez, D. M. (2005). Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and effects on the fetus and newborn: a meta-analysis. Journal of Perinatology, 25(9), 595-604. https://doi.org/10.1038/sj.jp.7211352
92. Newport, D. J., Calamaras, M. R., DeVane, C. L., Donovan, J., Beach, A. J., Winn, S., … & Stowe, Z. N. (2007). Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical outcomes. American Journal of Psychiatry, 164(8), 1214-1220. https://doi.org/10.1176/appi.ajp.2007.06111886
93. Rampono, J., Hackett, L. P., Kristensen, J. H., Kohan, R., Page-Sharp, M., & Ilett, K. F. (2004). Transfer of escitalopram and its metabolite demethylescitalopram into breastmilk. British Journal of Clinical Pharmacology, 58(4), 430-435. https://doi.org/10.1111/j.1365-2125.2004.02166.x
94. Kristensen, J. H., Ilett, K. F., Hackett, L. P., Yapp, P., Paech, M., & Begg, E. J. (1999). Distribution and excretion of fluoxetine and norfluoxetine in human milk. British Journal of Clinical Pharmacology, 48(4), 521-527. https://doi.org/10.1046/j.1365-2125.1999.00040.x
95. Klier, C. M., Mossaheb, N., Lee, A., & Zernig, G. (2007). Mirtazapine and reboxetine effects on weight gain and food craving in patients: role of histamine-3 and alpha-2 receptors. Psychoneuroendocrinology, 32(5), 471-478. https://doi.org/10.1016/j.psyneuen.2007.02.006
96. Stewart, D. E. (2011). Depression during pregnancy. New England Journal of Medicine, 365(17), 1605-1611. https://doi.org/10.1056/NEJMcp1102730
97. Yonkers, K. A., Blackwell, K. A., Glover, J., & Forray, A. (2014). Antidepressant use in pregnant and postpartum women. Annual Review of Clinical Psychology, 10, 369-392. https://doi.org/10.1146/annurev-clinpsy-032813-153626
98. Warner, C. H., Bobo, W., Warner, C., Reid, S., & Rachal, J. (2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449-456. PMID: 16913164
99. Bauer, M., Pfennig, A., Severus, E., Whybrow, P. C., Angst, J., Möller, H. J., & World Federation of Societies of Biological Psychiatry Task Force on Unipolar Depressive Disorders. (2013). World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: update 2013 on the acute and continuation treatment of unipolar depressive disorders. World Journal of Biological Psychiatry, 14(5), 334-385. https://doi.org/10.3109/15622975.2013.804195
100. American Psychiatric Association. (2010). Practice guideline for the treatment of patients with major depressive disorder. American Journal of Psychiatry, 167(10), 1-152. PMID: 20858037
101. Croom, K. F., & Plosker, G. L. (2003). Mirtazapine: a review of its use in major depression and other psychiatric disorders. CNS Drugs, 17(8), 613-633. https://doi.org/10.2165/00023210-200317080-00006
102. Kasper, S., Praschak-Rieder, N., Tauscher, J., & Wolf, R. (1997). A risk-benefit assessment of mirtazapine in the treatment of depression. Drug Safety, 17(4), 251-264. https://doi.org/10.2165/00002018-199717040-00004
103. Beers, M. H., Ouslander, J. G., Rollingher, I., Reuben, D. B., Brooks, J., & Beck, J. C. (1991). Explicit criteria for determining inappropriate medication use in nursing home residents. Archives of Internal Medicine, 151(9), 1825-1832. https://doi.org/10.1001/archinte.1991.00400090107019
104. Trivedi, M. H., Rush, A. J., Wisniewski, S. R., Nierenberg, A. A., Warden, D., Ritz, L., … & STARD Study Team. (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STARD: implications for clinical practice. American Journal of Psychiatry, 163(1), 28-40. https://doi.org/10.1176/appi.ajp.163.1.28
105. Quitkin, F. M., Taylor, B. P., & Kremer, C. (2001). Does mirtazapine have a more rapid onset than SSRIs? Journal of Clinical Psychiatry, 62(5), 358-361. https://doi.org/10.4088/JCP.v62n0508
106. Blier, P., & Ward, H. E. (2003). Is there a role for 5-HT1A agonists in the treatment of depression? Biological Psychiatry, 53(3), 193-203. https://doi.org/10.1016/S0006-3223(02)01643-8
107. Paykel, E. S. (2008). Partial remission, residual symptoms, and relapse in depression. Dialogues in Clinical Neuroscience, 10(4), 431-437. https://doi.org/10.31887/DCNS.2008.10.4/espaykel
108. Winokur, A., Sateia, M. J., Hayes, J. B., Bayles-Dazet, W., MacDonald, R., & Gary, K. A. (2000). Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study. Biological Psychiatry, 48(1), 75-78. https://doi.org/10.1016/S0006-3223(00)00882-9
109. Sharpley, A. L., Williamson, D. J., Attenburrow, M. E., Pearson, G., Sargent, P., & Cowen, P. J. (1996). The effects of paroxetine and nefazodone on sleep: a placebo controlled trial. Psychopharmacology, 126(1), 50-54. https://doi.org/10.1007/BF02246411
110. Armitage, R., Yonkers, K., Cole, D., & Rush, A. J. (1997). A multicenter, double-blind comparison of the effects of nefazodone and fluoxetine on sleep architecture and quality of sleep in depressed outpatients. Journal of Clinical Psychopharmacology, 17(3), 161-168. https://doi.org/10.1097/00004714-199706000-00004
111. Baldwin, D. S., & Montgomery, S. A. (1995). Antidepressant drugs and sexual dysfunction. British Journal of Psychiatry, 166(4), 480-486. https://doi.org/10.1192/bjp.166.4.480
112. Pollock, B. G. (2005). The pharmacokinetic imperative in late-life depression. Journal of Clinical Psychopharmacology, 25(4 Suppl 1), S19-S23. https://doi.org/10.1097/01.jcp.0000162809.03148.6b
113. Dolder, C. R., Nelson, M., & Snider, M. (2008). Agomelatine treatment of major depressive disorder. Annals of Pharmacotherapy, 42(12), 1822-1831. https://doi.org/10.1345/aph.1L082
114. Swan, S. K. (1997). The search continues–an ideal sedative-hypnotic drug for the critically ill patient. Critical Care Medicine, 25(12), 1993-1994. https://doi.org/10.1097/00003246-199712000-00013
115. Kupfer, D. J. (1991). Long-term treatment of depression. Journal of Clinical Psychiatry, 52(Suppl), 28-34. PMID: 2016697
116. Frank, E., Kupfer, D. J., Perel, J. M., Cornes, C., Jarrett, D. B., Mallinger, A. G., … & Grochocinski, V. J. (1990). Three-year outcomes for maintenance therapies in recurrent depression. Archives of General Psychiatry, 47(12), 1093-1099. https://doi.org/10.1001/archpsyc.1990.01810240013002
117. Geddes, J. R., Carney, S. M., Davies, C., Furukawa, T. A., Kupfer, D. J., Frank, E., & Goodwin, G. M. (2003). Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet, 361(9358), 653-661. https://doi.org/10.1016/S0140-6736(03)12599-8
118. Schatzberg, A. F., Haddad, P., Kaplan, E. M., Lejoyeux, M., Rosenbaum, J. F., Young, A. H., & Zajecka, J. (1997). Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Journal of Clinical Psychiatry, 58(Suppl 7), 5-10. PMID: 9219488
119. Connors, K. A., Amidon, G. L., & Stella, V. J. (1986). Chemical stability of pharmaceuticals: a handbook for pharmacists. John Wiley & Sons.
120. Carstensen, J. T., & Rhodes, C. T. (2000). Drug stability: principles and practices. CRC Press.
121. Allen, L. V. (2008). Dosage form design and development. Clinical Therapeutics, 30(11), 2102-2111. https://doi.org/10.1016/j.clinthera.2008.11.015
122. ICH Harmonised Tripartite Guideline. (2003). Stability testing of new drug substances and products Q1A(R2). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
123. Waterman, K. C., & Adami, R. C. (2005). Accelerated aging: prediction of chemical stability of pharmaceuticals. International Journal of Pharmaceutics, 293(1-2), 101-125. https://doi.org/10.1016/j.ijpharm.2004.12.013
124. Carstensen, J. T. (1995). Drug stability: principles and practices (2nd ed.). Marcel Dekker.
125. Ahlneck, C., & Zografi, G. (1990). The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state. International Journal of Pharmaceutics, 62(2-3), 87-95. https://doi.org/10.1016/0378-5173(90)90221-O
126. Callahan, J. C., Cleary, G. W., Elefant, M., Kaplan, G., Kensler, T., & Nash, R. A. (1982). Equilibrium moisture content of pharmaceutical excipients. Drug Development and Industrial Pharmacy, 8(3), 355-369. https://doi.org/10.3109/03639048209022099
127. Florence, A. T., & Attwood, D. (2006). Physicochemical principles of pharmacy (4th ed.). Pharmaceutical Press.
128. Tonnesen, H. H. (2004). Photostability of drugs and drug formulations (2nd ed.). CRC Press.
129. Baertschi, S. W. (2005). Pharmaceutical stress testing: predicting drug degradation. CRC Press.
130. Singh, S., & Bakshi, M. (2000). Guidance on conduct of stress tests to determine inherent stability of drugs. Pharmaceutical Technology, 24(2), 1-14.
131. Budnitz, D. S., Salis, S., & Pollock, D. A. (2007). Emergency department visits for overdoses of acetaminophen-containing products. American Journal of Emergency Medicine, 25(9), 977-982. https://doi.org/10.1016/j.ajem.2007.02.032
132. Schillie, S. F., Shehab, N., Thomas, K. E., & Budnitz, D. S. (2009). Medication overdoses leading to emergency department visits among children. American Journal of Preventive Medicine, 37(3), 181-187. https://doi.org/10.1016/j.amepre.2009.05.018
133. Institute for Safe Medication Practices. (2018). ISMP’s list of confused drug names. Retrieved from www.ismp.org/tools/confuseddrugnames.pdf
134. United States Pharmacopeial Convention. (2019). General chapter <795> pharmaceutical compounding—nonsterile preparations. USP 42-NF 37.
135. Knoer, S., Xu, L., & Luo, Q. (2015). A comprehensive evaluation of clinical pharmacist activities and healthcare outcomes in an oncology setting. American Journal of Health-System Pharmacy, 72(15), 1321-1327. https://doi.org/10.2146/ajhp140814
136. Lyon, R. C., Taylor, J. S., Porter, D. A., Prasanna, H. R., & Hussain, A. S. (2006). Stability profiles of drug products extended beyond labeled expiration dates. Journal of Pharmaceutical Sciences, 95(7), 1549-1560. https://doi.org/10.1002/jps.20636
137. Ruhoy, I. S., & Daughton, C. G. (2008). Beyond the medicine cabinet: an analysis of where and why medications accumulate. Environment International, 34(8), 1157-1169. https://doi.org/10.1016/j.envint.2008.05.002
138. U.S. Food and Drug Administration. (2020). Where and how to dispose of unused medicines. Retrieved from https://www.fda.gov/consumers/consumer-updates/where-and-how-dispose-unused-medicines
139. Bound, J. P., & Voulvoulis, N. (2005). Household disposal of pharmaceuticals as a pathway for aquatic contamination in the United Kingdom. Environmental Health Perspectives, 113(12), 1705-1711. https://doi.org/10.1289/ehp.8315
140. Thompson, C. A. (2005). Pharmacists’ guide to compounding primer offers insights. American Journal of Health-System Pharmacy, 62(4), 371-372. https://doi.org/10.1093/ajhp/62.4.371
141. Allen, L. V. (2012). The art, science, and technology of pharmaceutical compounding (4th ed.). American Pharmacists Association.
142. U.S. Food and Drug Administration. (2016). Compounding and the FDA: Questions and answers. Retrieved from https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers
143. Gudeman, J., Jozwiakowski, M., Chollet, J., & Randell, M. (2013). Potential risks of pharmacy compounding. Drugs in R&D, 13(1), 1-8. https://doi.org/10.1007/s40268-013-0005-9
144. Conti, R. M., Bernstein, I. M., Villaflor, V. M., Schilsky, R. L., Rosenthal, M. B., & Bach, P. B. (2013). Prevalence of off-label use and spending in 2010 among patent-protected chemotherapies in a population-based cohort of medical oncologists. Journal of Clinical Oncology, 31(9), 1134-1139. https://doi.org/10.1200/JCO.2012.42.7252
145. Thase, M. E., & Rush, A. J. (1997). When at first you don’t succeed: sequential strategies for antidepressant nonresponders. Journal of Clinical Psychiatry, 58(Suppl 13), 23-29. PMID: 9402916
146. Trivedi, M. H., Fava, M., Wisniewski, S. R., Thase, M. E., Quitkin, F., Warden, D., … & Rush, A. J. (2006). Medication augmentation after the failure of SSRIs for depression. New England Journal of Medicine, 354(12), 1243-1252. https://doi.org/10.1056/NEJMoa052964
147. Kessler, D., Lloyd, K., Lewis, G., & Gray, D. P. (1999). Cross sectional study of symptom attribution and recognition of depression and anxiety in primary care. BMJ, 318(7181), 436-439. https://doi.org/10.1136/bmj.318.7181.436
148. Nelson, J. C., Mazure, C. M., Bowers, M. B., & Jatlow, P. I. (1991). A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Archives of General Psychiatry, 48(4), 303-307. https://doi.org/10.1001/archpsyc.1991.01810280019002
149. Duman, R. S., Heninger, G. R., & Nestler, E. J. (1997). A molecular and cellular theory of depression. Archives of General Psychiatry, 54(7), 597-606. https://doi.org/10.1001/archpsyc.1997.01830190015002
150. Katon, W., Robinson, P., Von Korff, M., Lin, E., Bush, T., Ludman, E., … & Walker, E. (1996). A multifaceted intervention to improve treatment of depression in primary care. Archives of General Psychiatry, 53(10), 924-932. https://doi.org/10.1001/archpsyc.1996.01830100072009
151. Osterberg, L., & Blaschke, T. (2005). Adherence to medication. New England Journal of Medicine, 353(5), 487-497. https://doi.org/10.1056/NEJMra050100
152. Haynes, R. B., Ackloo, E., Sahota, N., McDonald, H. P., & Yao, X. (2008). Interventions for enhancing medication adherence. Cochrane Database of Systematic Reviews, (2), CD000011. https://doi.org/10.1002/14651858.CD000011.pub3
153. Sabate, E. (2003). Adherence to long-term therapies: evidence for action. World Health Organization.
154. McDonald, H. P., Garg, A. X., & Haynes, R. B. (2002). Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA, 288(22), 2868-2879. https://doi.org/10.1001/jama.288.22.2868
155. Vervloet, M., Linn, A. J., van Weert, J. C., de Bakker, D. H., Bouvy, M. L., & van Dijk, L. (2012). The effectiveness of interventions using electronic reminders to improve adherence to chronic medication: a systematic review of the literature. Journal of the American Medical Informatics Association, 19(5), 696-704. https://doi.org/10.1136/amiajnl-2011-000748
156. Viswanathan, M., Golin, C. E., Jones, C. D., Ashok, M., Blalock, S. J., Wines, R. C., … & Lohr, K. N. (2012). Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Annals of Internal Medicine, 157(11), 785-795. https://doi.org/10.7326/0003-4819-157-11-201212040-00538
157. Rosenbaum, J. F., Fava, M., Hoog, S. L., Ascroft, R. C., & Krebs, W. B. (1998). Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biological Psychiatry, 44(2), 77-87. https://doi.org/10.1016/S0006-3223(98)00126-7
158. Vieweg, V., Levy, J. R., Fredrickson, S. K., Chipkin, S. R., Beatty-Brooks, M., Fernandez, A., … & Pandurangi, A. K. (2007). Psychotropic drug considerations in depressed patients with metabolic disturbances. American Journal of Medicine, 120(8), 647-653. https://doi.org/10.1016/j.amjmed.2006.04.038
159. Schwartz, T. L., Nihalani, N., Jindal, S., Virk, S., & Jones, N. (2004). Psychiatric medication-induced obesity: a review. Obesity Reviews, 5(2), 115-121. https://doi.org/10.1111/j.1467-789X.2004.00139.x
160. Patten, S. B., Barbui, C., & WFMH and EAPM workgroup on antidepressant drugs. (2004). Drug-induced depression: a systematic review to inform clinical practice. Psychotherapy and Psychosomatics, 73(4), 207-215. https://doi.org/10.1159/000077739
161. Arterburn, D. E., Crane, P. K., & Sullivan, S. D. (2004). The coming epidemic of obesity in elderly Americans. Journal of the American Geriatrics Society, 52(11), 1907-1912. https://doi.org/10.1111/j.1532-5415.2004.52517.x
162. Wadden, T. A., Berkowitz, R. I., Womble, L. G., Sarwer, D. B., Phelan, S., Cato, R. K., … & Stunkard, A. J. (2005). Randomized trial of lifestyle modification and pharmacotherapy for obesity. New England Journal of Medicine, 353(20), 2111-2120. https://doi.org/10.1056/NEJMoa050156
163. Klein, S., Burke, L. E., Bray, G. A., Blair, S., Allison, D. B., Pi-Sunyer, X., … & American Heart Association Council on Nutrition, Physical Activity, and Metabolism. (2004). Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism. Circulation, 110(18), 2952-2967. https://doi.org/10.1161/01.CIR.0000145546.97738.19
164. Gentile, S. (2006). Long-term treatment with atypical antipsychotics and the risk of weight gain: a literature analysis. Drug Safety, 29(4), 303-319. https://doi.org/10.2165/00002018-200629040-00004
165. Racagni, G., & Popoli, M. (2008). Cellular and molecular mechanisms in the long-term action of antidepressants. Dialogues in Clinical Neuroscience, 10(4), 385-400. https://doi.org/10.31887/DCNS.2008.10.4/gracagni
166. Swift, R. M. (1999). Drug therapy for alcohol dependence. New England Journal of Medicine, 340(19), 1482-1490. https://doi.org/10.1056/NEJM199905133401907
167. Preskorn, S. H., & Burke, M. (1992). Somatic therapy for major depressive disorder: selection of an antidepressant. Journal of Clinical Psychiatry, 53(Suppl), 5-18. PMID: 1385420
168. O’Brien, C. P. (2005). Anticraving medications for relapse prevention: a possible new class of psychoactive medications. American Journal of Psychiatry, 162(8), 1423-1431. https://doi.org/10.1176/appi.ajp.162.8.1423
169. Pettinati, H. M., O’Brien, C. P., & Dundon, W. D. (2013). Current status of co-occurring mood and substance use disorders: a new therapeutic target. American Journal of Psychiatry, 170(1), 23-30. https://doi.org/10.1176/appi.ajp.2012.12010112
170. Nunes, E. V., & Levin, F. R. (2004). Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA, 291(15), 1887-1896. https://doi.org/10.1001/jama.291.15.1887
171. Weathermon, R., & Crabb, D. W. (1999). Alcohol and medication interactions. Alcohol Research & Health, 23(1), 40-54. PMID: 10890797
172. Moore, A. A., Whiteman, E. J., & Ward, K. T. (2007). Risks of combined alcohol/medication use in older adults. American Journal of Geriatric Pharmacotherapy, 5(1), 64-74. https://doi.org/10.1016/j.amjopharm.2007.03.006
173. Buckley, N. A., & McManus, P. R. (2002). Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ, 325(7376), 1332-1333. https://doi.org/10.1136/bmj.325.7376.1332
174. Crome, I. B. (1993). The toxicity of drugs used for suicide. Acta Psychiatrica Scandinavica, 87(5), 354-359. https://doi.org/10.1111/j.1600-0447.1993.tb03375.x
175. White, N., Litovitz, T., & Clancy, C. (2008). Suicidal antidepressant overdoses: a comparative analysis by antidepressant type. Journal of Medical Toxicology, 4(4), 238-250. https://doi.org/10.1007/BF03161207
176. Shannon, M. (2000). Ingestion of toxic substances by children. New England Journal of Medicine, 342(3), 186-191. https://doi.org/10.1056/NEJM200001203420307
177. Olson, K. R., Kearney, T. E., Dyer, J. E., Benowitz, N. L., & Blanc, P. D. (1994). Seizures associated with poisoning and drug overdose. American Journal of Emergency Medicine, 12(4), 392-395. https://doi.org/10.1016/0735-6757(94)90052-3
178. Brett, A. S. (2002). Implications of discordance between clinical trial results and clinical practice. JAMA, 287(19), 2555-2557. https://doi.org/10.1001/jama.287.19.2555
179. Woolf, A. D., Erdman, A. R., Nelson, L. S., Caravati, E. M., Cobaugh, D. J., Booze, L. L., … & American Association of Poison Control Centers. (2007). Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clinical Toxicology, 45(3), 203-233. https://doi.org/10.1080/15563650701285420
180. Schillie, S. F., Shehab, N., Thomas, K. E., & Budnitz, D. S. (2009). Medication overdoses leading to emergency department visits among children. American Journal of Preventive Medicine, 37(3), 181-187. https://doi.org/10.1016/j.amepre.2009.05.018
181. Haddad, P. M. (2001). Antidepressant discontinuation syndromes. Drug Safety, 24(3), 183-197. https://doi.org/10.2165/00002018-200124030-00003
182. Shelton, R. C. (2006). Steps following attainment of remission: discontinuation of antidepressant therapy. Primary Care Companion to the Journal of Clinical Psychiatry, 8(3), 168-174. https://doi.org/10.4088/PCC.v08n0309
183. Black, K., Shea, C., Dursun, S., & Kutcher, S. (2000). Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria. Journal of Psychiatry & Neuroscience, 25(3), 255-261. PMID: 10863885
184. Zajecka, J., Tracy, K. A., & Mitchell, S. (1997). Discontinuation symptoms after treatment with serotonin reuptake inhibitors: a literature review. Journal of Clinical Psychiatry, 58(7), 291-297. https://doi.org/10.4088/JCP.v58n0702
185. Price, J. S., Waller, P. C., Wood, S. M., & MacKay, A. V. P. (1996). A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal. British Journal of Clinical Pharmacology, 42(6), 757-763. https://doi.org/10.1046/j.1365-2125.1996.00481.x
186. Coupland, N. J., Bell, C. J., & Potokar, J. P. (1996). Serotonin reuptake inhibitor withdrawal. Journal of Clinical Psychopharmacology, 16(5), 356-362. https://doi.org/10.1097/00004714-199610000-00003
187. Young, A. H., & Currie, A. (1997). Physicians’ knowledge of antidepressant withdrawal effects: a survey. Journal of Clinical Psychiatry, 58(Suppl 7), 28-30. PMID: 9219491
188. Michelson, D., Fava, M., Amsterdam, J., Apter, J., Londborg, P., Tamura, R., & Tepner, R. G. (2000). Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial. British Journal of Psychiatry, 176, 363-368. https://doi.org/10.1192/bjp.176.4.363
189. Werneke, U., Northey, S., & Bhugra, D. (2006). Antidepressants and sexual dysfunction. Acta Psychiatrica Scandinavica, 114(6), 384-397. https://doi.org/10.1111/j.1600-0447.2006.00892.x
190. Sternbach, H. (1991). The serotonin syndrome. American Journal of Psychiatry, 148(6), 705-713. https://doi.org/10.1176/ajp.148.6.705
191. Mason, P. J., Morris, V. A., & Balcezak, T. J. (2000). Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine, 79(4), 201-209. https://doi.org/10.1097/00005792-200007000-00001
192. Gillman, P. K. (2005). Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British Journal of Anaesthesia, 95(4), 434-441. https://doi.org/10.1093/bja/aei210
193. Preskorn, S. H., & Burke, M. J. (1992). Somatic therapy for major depressive disorder: selection of an antidepressant. Journal of Clinical Psychiatry, 53(Suppl), 5-18. PMID: 1385420
194. Blier, P., & Bergeron, R. (1995). Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression. Journal of Clinical Psychopharmacology, 15(3), 217-222. https://doi.org/10.1097/00004714-199506000-00011
195. Mills, K. C. (1997). Serotonin syndrome. A clinical update. Critical Care Clinics, 13(4), 763-783. https://doi.org/10.1016/S0749-0704(05)70368-6
196. Alexopoulos, G. S., Katz, I. R., Reynolds, C. F., Carpenter, D., & Docherty, J. P. (2001). The expert consensus guideline series. Pharmacotherapy of depressive disorders in older patients. Postgraduate Medicine, (Spec No), 1-86. PMID: 11500996
197. Schneider, L. S., Nelson, J. C., Clary, C. M., Newhouse, P., Krishnan, K. R., Shiovitz, T., & Weihs, K. (2003). An 8-week multicenter, parallel-group, double-blind, placebo-controlled study of sertraline in elderly outpatients with major depression. American Journal of Psychiatry, 160(7), 1277-1285. https://doi.org/10.1176/appi.ajp.160.7.1277
198. Roose, S. P., & Sackeim, H. A. (2002). Clinical trials in late-life depression: revisited. American Journal of Geriatric Psychiatry, 10(5), 503-505. https://doi.org/10.1097/00019442-200209000-00002
199. Pollock, B. G. (1999). Adverse reactions of antidepressants in elderly patients. Journal of Clinical Psychiatry, 60(Suppl 20), 4-8. PMID: 10513851
200. Schneider, L. S., Reynolds, C. F., Lebowitz, B. D., & Friedhoff, A. J. (1994). Risk-benefit assessment of risperidone in the treatment of late-life psychosis and behavioral disturbances. Drug Safety, 11(4), 246-261. https://doi.org/10.2165/00002018-199411040-00004
201. Glassman, A. H., O’Connor, C. M., Califf, R. M., Swedberg, K., Schwartz, P., Bigger Jr, J. T., … & Sertraline Antidepressant Heart Attack Randomized Trial (SADHEART) Group. (2002). Sertraline treatment of major depression in patients with acute MI or unstable angina. JAMA, 288(6), 701-709. https://doi.org/10.1001/jama.288.6.701
202. Gurwitz, J. H., Field, T. S., Harrold, L. R., Rothschild, J., Debellis, K., Seger, A. C., … & Bates, D. W. (2003). Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA, 289(9), 1107-1116. https://doi.org/10.1001/jama.289.9.1107
203. Lebowitz, B. D., Pearson, J. L., Schneider, L. S., Reynolds, C. F., Alexopoulos, G. S., Bruce, M. L., … & Parmelee, P. (1997). Diagnosis and treatment of depression in late life: consensus statement update. JAMA, 278(14), 1186-1190. https://doi.org/10.1001/jama.1997.03550140078045
204. Ramaekers, J. G. (2003). Antidepressants and driver impairment: empirical evidence from a standard on-the-road test. Journal of Clinical Psychiatry, 64(1), 20-29. https://doi.org/10.4088/JCP.v64n0106
205. Wingen, M., Ramaekers, J. G., & Schmitt, J. A. (2006). Driving impairment in depressed patients receiving long-term antidepressant treatment. Psychopharmacology, 188(1), 84-91. https://doi.org/10.1007/s00213-006-0471-y
206. O’Hanlon, J. F., Haak, T. W., Blaauw, G. J., & Riemersma, J. B. (1982). Diazepam impairs lateral position control in highway driving. Science, 217(4554), 79-81. https://doi.org/10.1126/science.7089524
207. Kelly, E., Darke, S., & Ross, J. (2004). A review of drug use and driving: epidemiology, impairment, risk factors and risk perceptions. Drug and Alcohol Review, 23(3), 319-344. https://doi.org/10.1080/09595230412331289482
208. Barbone, F., McMahon, A. D., Davey, P. G., Morris, A. D., Reid, I. C., McDevitt, D. G., & MacDonald, T. M. (1998). Association of road-traffic accidents with benzodiazepine use. Lancet, 352(9137), 1331-1336. https://doi.org/10.1016/S0140-6736(98)04087-2
209. Moskowitz, H., & Fiorentino, D. (2000). A review of the literature on the effects of low doses of alcohol on driving-related skills. National Highway Traffic Safety Administration.
210. Walsh, J. M., Verstraete, A. G., Huestis, M. A., & Mørland, J. (2008). Guidelines for research on drugged driving. Addiction, 103(8), 1258-1268. https://doi.org/10.1111/j.1360-0443.2008.02277.x
211. Drummer, O. H., Gerostamoulos, J., Batziris, H., Chu, M., Caplehorn, J., Robertson, M. D., & Swann, P. (2004). The involvement of drugs in drivers of motor vehicles killed in Australian road traffic crashes. Accident Analysis & Prevention, 36(2), 239-248. https://doi.org/10.1016/S0001-4575(02)00153-7

How long does it typically take for mirtazapine to start working for depression?
The therapeutic response to mirtazapine therapy typically develops gradually over several weeks, with some patients experiencing initial improvements in sleep and appetite within the first few days to weeks of treatment.^[139]

However, significant improvements in mood and other core symptoms of depression may not become apparent until 4-6 weeks of consistent therapy at an adequate dosage.^[146]

Healthcare providers should educate patients about the expected timeline for therapeutic response and should emphasize the importance of medication adherence during the initial weeks of treatment when side effects may be more prominent than therapeutic benefits.^[147]

Some patients may require dose adjustments or extended treatment periods to achieve optimal therapeutic response.^[148]

The gradual onset of therapeutic effects is characteristic of most antidepressant medications and reflects the complex neurobiological changes that occur with sustained treatment.^[149]

Patients should be encouraged to maintain regular follow-up appointments during the initial treatment period to monitor response and adjust therapy as needed.^[150]

What should I do if I miss a dose of mirtazapine?
Patients who miss a dose of mirtazapine should take the missed dose as soon as they remember, unless it is close to the time for their next scheduled dose.^[151]

If it is nearly time for the next dose, patients should skip the missed dose and continue with their regular dosing schedule rather than taking two doses close together.^[152]

Double dosing should be avoided as it may increase the risk of side effects without providing additional therapeutic benefit.^[153]

Healthcare providers should counsel patients about the importance of establishing a consistent dosing routine to minimize the likelihood of missed doses.^[154]

The use of pill organizers, medication reminders, or smartphone applications may help patients maintain adherence to their prescribed dosing schedule.^[155]

Patients who frequently miss doses should discuss potential strategies with their healthcare provider to improve medication adherence.^[156]

Missing multiple doses or stopping mirtazapine abruptly may result in withdrawal symptoms or recurrence of depression symptoms, emphasizing the importance of consistent medication use.^[157]

Can mirtazapine cause weight gain, and how can this be managed?
Weight gain represents one of the more common side effects associated with mirtazapine therapy, occurring in a significant proportion of patients during treatment.^[158]

The mechanism underlying weight gain likely involves the medication’s effects on histamine H1 and serotonin 5-HT2C receptors, which may influence appetite regulation and metabolic processes.^[159]

Patients typically experience increased appetite and cravings for carbohydrates, which may contribute to gradual weight accumulation over time.^[160]

Healthcare providers should discuss the potential for weight gain before initiating therapy and should implement monitoring strategies to track weight changes throughout treatment.^[161]

Management strategies may include dietary counseling, regular exercise programs, and close monitoring of eating habits.^[162] Some patients may benefit from consultation with nutritionists or dietitians to develop appropriate meal planning and weight management strategies.^[163]

In cases where weight gain becomes problematic, healthcare providers may consider dose adjustments or alternative therapeutic approaches.^[164]

Patients should be encouraged to maintain healthy lifestyle habits and should be reassured that weight management is possible with appropriate interventions.^[165]

Is it safe to drink alcohol while taking mirtazapine?
Alcohol consumption should generally be avoided or significantly limited while taking mirtazapine due to the potential for additive central nervous system depressant effects.^[166]

Both alcohol and mirtazapine can cause sedation, drowsiness, and impaired cognitive function, and the combination may result in excessive sedation, increased risk of falls, and impaired judgment.^[167]

Healthcare providers should counsel patients about the risks associated with alcohol consumption during mirtazapine therapy and should emphasize the importance of avoiding activities requiring mental alertness when consuming alcohol.^[168]

Additionally, alcohol may interfere with the therapeutic effects of mirtazapine and may exacerbate symptoms of depression.^[169]

Patients with a history of alcohol use disorders may require additional monitoring and support during mirtazapine therapy.^[170]

Social drinking should be discussed with healthcare providers, who can provide individualized recommendations based on patient-specific factors.^[171]

The interaction between alcohol and mirtazapine may be more pronounced in elderly patients or those taking other medications with sedating properties.^[172]

What are the signs of mirtazapine overdose, and what should be done in case of overdose?
Mirtazapine overdose may present with various symptoms related to the medication’s effects on multiple neurotransmitter systems and may require immediate medical attention.^[173]

Common signs of overdose may include excessive sedation, confusion, disorientation, tachycardia, mild hypertension or hypotension, and impaired coordination.^[174]

In severe cases, patients may experience respiratory depression, coma, or cardiac arrhythmias, although fatalities from mirtazapine overdose alone are relatively rare.^[175]

Healthcare providers should educate patients and their families about the signs and symptoms of overdose and should emphasize the importance of seeking immediate medical attention if overdose is suspected.^[176]

In case of suspected overdose, emergency medical services should be contacted immediately, and patients should be transported to the nearest emergency department for evaluation and treatment.^[177]

Supportive care measures may include monitoring of vital signs, maintaining airway patency, and providing symptomatic treatment as indicated.^[178]

There is no specific antidote for mirtazapine overdose, and treatment is primarily supportive and symptomatic.^[179]

Patients and caregivers should be counseled about proper medication storage and handling to prevent accidental overdose, particularly in households with children.^[180]

Can mirtazapine be stopped suddenly, or does it need to be tapered?
Mirtazapine should generally not be stopped suddenly due to the risk of withdrawal symptoms and potential recurrence of depression.^[181]

Gradual dose reduction, or tapering, is typically recommended to minimize discontinuation symptoms and allow for physiological adaptation to decreasing medication levels.^[182]

Withdrawal symptoms may include dizziness, nausea, headache, irritability, flu-like symptoms, and electric shock sensations.^[183]

Healthcare providers should develop individualized tapering schedules based on factors such as treatment duration, dosage, patient tolerance, and clinical circumstances.^[184]

The tapering process may take several weeks to months, depending on individual patient factors and the presence of withdrawal symptoms.^[185]

Patients should be closely monitored during the tapering process for signs of symptom recurrence or withdrawal effects.^[186]

In some cases, the tapering process may need to be slowed or temporarily halted if patients experience significant withdrawal symptoms or symptom recurrence.^[187]

Healthcare providers should educate patients about the importance of gradual discontinuation and should emphasize the need for medical supervision during the tapering process.^[188]

How does mirtazapine interact with other antidepressants?
Mirtazapine may interact with other antidepressant medications through various mechanisms, including pharmacodynamic interactions affecting neurotransmitter systems and potential pharmacokinetic alterations.^[189]

Concurrent use with other serotonergic medications, including SSRIs, SNRIs, and tricyclic antidepressants, may increase the risk of serotonin syndrome, a potentially serious condition characterized by hyperthermia, rigidity, autonomic instability, and altered mental status.^[190]

Healthcare providers should carefully evaluate the risks and benefits of combination antidepressant therapy and should implement enhanced monitoring strategies when multiple serotonergic medications are used.^[191]

The combination of mirtazapine with MAO inhibitors is contraindicated due to the high risk of serious drug interactions.^[192]

When transitioning between different antidepressant medications, adequate washout periods may be required to prevent dangerous interactions.^[193]

Some combinations of antidepressants may be used therapeutically under careful medical supervision, but such combinations require expertise in psychopharmacology and close patient monitoring.^[194]

Patients should be educated about the signs and symptoms of serotonin syndrome and should be instructed to seek immediate medical attention if these symptoms occur.^[195]

Is mirtazapine suitable for elderly patients, and are there special considerations?
Elderly patients may be candidates for mirtazapine therapy, but they require special considerations due to age-related physiological changes and increased sensitivity to medication effects.^[196]

Lower starting doses are typically recommended for elderly patients, with more gradual dose escalation and careful monitoring for adverse effects.^[197]

The 7.5 mg dosage strength may be particularly appropriate for elderly patients who may be more sensitive to higher doses.^[198]

Age-related changes in hepatic and renal function may affect medication metabolism and elimination, potentially requiring dose adjustments.^[199]

Elderly patients may be at increased risk for side effects such as sedation, orthostatic hypotension, anticholinergic effects, and cognitive impairment.^[200]

Cardiovascular monitoring may be particularly important in elderly patients due to the increased prevalence of cardiac conditions in this population.^[201]

Healthcare providers should carefully evaluate the risk-benefit ratio when prescribing mirtazapine to elderly patients and should consider potential interactions with other medications commonly used in this population.^[202]

Regular assessment of cognitive function, functional status, and quality of life may be appropriate for elderly patients receiving mirtazapine therapy.^[203]

What should patients know about driving and operating machinery while taking mirtazapine? Mirtazapine may significantly impair the ability to drive vehicles or operate machinery safely due to its sedating effects and potential impact on cognitive function and motor coordination.^[204]

Patients should be advised to avoid driving or operating dangerous machinery until they understand how the medication affects their individual response and level of alertness.^[205]

The sedating effects of mirtazapine may be more pronounced during the initial weeks of therapy and may persist throughout treatment in some.^[206]

Healthcare providers should assess patient response to medication and should provide individualized recommendations about driving and machinery operation based on the degree of sedation and cognitive impairment.^[207]

Patients who experience significant sedation may need to modify their daily activities and may benefit from scheduling important tasks during times when alertness is maximized.^[208]

The combination of mirtazapine with other sedating medications or alcohol may further impair the ability to drive safely.^[209]

Patients should be counseled about their legal and ethical responsibilities regarding driving while taking medications that may impair their ability to operate vehicles safely.^[210]

Healthcare providers should document discussions about driving safety and should provide written instructions when appropriate.^[211]

Disclaimer: This product information is provided for educational purposes only and is not intended to replace professional medical advice, diagnosis, or treatment. Always consult with a qualified healthcare provider before starting, stopping, or modifying any medication regimen. The information presented herein does not constitute medical advice and should not be used as a substitute for consultation with a licensed healthcare professional. Individual patient responses to medications may vary significantly, and treatment decisions should always be made in consultation with appropriate medical supervision. This document does not imply endorsement, recommendation, or guarantee of safety or efficacy for any particular use. Healthcare providers should refer to current prescribing information and clinical guidelines when making treatment decisions.