Problems associated with long term treatment with selective serotonin reuptake inhibitors
Chantal Moret* and Mike Isaac**
Although the selective serotonin reuptake inhibitors (SSRIs) are now used as a first-line treatment for depression, they are not devoid of side effects. Most short-term treatment-related side effects of SSRIs are transient and disappear after a few days or weeks. However, following long-term treatment with the SSRIs some adverse events may occur. They are often difficult to recognise since they often resemble residual symptoms of the depression. They have a clear negative influence on the patient's quality of life and are one of the main reasons for a lack of long-term compliance with the associated increased risk of recurrence of a depressive episode. This article is an overview of some of the more common long-term adverse events seen with SSRIs.
note: Clicking on a reference, for example
and Nemeroff, 2000)
The discovery of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) in the 1950s revolutionised the treatment of depression. Although these compounds can bring profound benefit and relief from suffering they are associated with considerable side effects and even toxicity (Gumnick and Nemeroff, 2000; Pacher et al., 2001; Martinez and Marangell, 2004; Pacher and Kecskemeti, 2004). The introduction in the mid-1980s of more selective and better tolerated drugs, the selective serotonin reuptake inhibitors (SSRIs), has enabled many patients to benefit from effective antidepressant therapy without uncomfortable, distressing and often dangerous adverse effects.
SSRIs are now used as a first-line treatment for depression, in part because of their relatively benign adverse effect profile and safety in overdose, especially compared with the older TCAs and MAOIs. However, their efficacy in depression is no greater and their onset of action is no more rapid than that of the MAOIs or TCAs. In addition, they are not completely devoid of side effects (Mourilhe and Stokes, 1998). Sexual dysfunction, weight gain and sleep disturbance are the most troubling adverse events seen during long-term SSRI therapy (Ferguson, 2001). SSRIs are devoid of receptor interactions and their associated side effects which characterise MAOIs and TCAs (Richelson, 1996), and their only apparent pharmacological activity is the inhibition of the reuptake of serotonin. Most of side effects result from an over-stimulation of various serotonin receptors in both the brain and the periphery (Lieberman, 2003). The most common side effects associated with SSRIs such as nausea and headache, nervousness, insomnia and sexual dysfunction (Kelsey, 2001) are related to the stimulation of 5-HT2 and 5-HT3 receptors.
Many of the side effects of SSRIs are transient and subside over time, and can be minimized by having patients take the drug with meals and starting treatment with low doses followed by a slow titration to recommended doses (Kelsey, 2001).
Overall, compared to the old generations of antidepressants, the SSRIs present a therapeutic option that is attractive to the majority of primary care physicians, psychiatrists and patients. However, with the passage of time certain problems are emerging in relation to long term treatment with the SSRIs.
Cases of arrhythmias, prolonged QTc interval on electrocardiogram (Isbister et al., 2004; Odar-Cederlöf et al., 2006) and orthostatic hypotension (Pacher and Ungvari, 2001) have been reported with SSRIs in patients with no previous history of cardiovascular disorders suggesting possible exceptions to the cardiovascular safety of these compounds. Experimentally, in different mammalian animal and human cardiovascular preparations, SSRIs have been shown to elicit strong cardiovascular depressant effects by inhibiting cardiac and vascular Na+, Ca2+ and K+ channels, providing possible mechanistic explanations of the clinical reports (see the review by Pacher and Kecskemeti, 2004). Although rare, the existence of clinically important cardiac and vascular effects shows the need for vigilance especially when prescribing SSRIs to patients with cardiovascular disorders.
Cases of SSRI-induced suicidality (suicide attempts and suicidal ideation) have been reported both in adults (Teicher et al., 1990; Rothschild and Locke 1991; Hawthorne and Lacey 1992) and in adolescents and children. It is worth noting, however, that in spite of a certain risk of suicidality with SSRIs (and probably with all antidepressants) a recent study demonstrated that continued antidepressant treatment is associated with overall reduced risk of suicide (Sondergard et al., 2007).
- Paediatric and adolescent patients
Recent attention has focused on the possible risks of antidepressant treatment in children and adolescents. The US Food and Drug Administration (FDA) reviewed 24 placebo-controlled trials of antidepressants in paediatric and adolescent patients with depression and found that they cause a 2-fold (4% v 2%) increased risk for suicidal behaviour/ideation. Thus in 2004 the FDA warned the public about the risks of these drugs in children and adolescents (under 18 years) but did not prohibit their use. In 2005, FDA asked manufacturers of SSRIs to include a black box warning statement in product labelling recommending monitoring in young patients for the occurrence of suicidality. Following the FDA warnings, families and clinicians have become increasingly reluctant to use antidepressants in children and adolescents and prescriptions numbers have reduced dramatically with a disconcerting parallel increase in adolescent suicide (Lineberry et al., 2007).
A meta-analysis in patients younger than 19 years with major depressive disorder showed that the benefits of second-generation antidepressants (SSRIs, nefazodone, venlafaxine, and mirtazapine) was significantly greater than the risks of suicidal ideation and suicide attempts which supports the careful, well-monitored use of these agents (Bridge et al., 2007).
In May 2007 the FDA proposed that makers of all antidepressant medications extend the existing black box suicidality warning to young adults aged 18 to 24. The new proposed warning emphasizes, however, that depression itself may lead to suicide and that antidepressant medications benefits most patients. The FDA advises that patients of all ages who are started on antidepressants should be monitored for worsening depressive symptoms, especially suicidal thoughts or behaviours or unusual changes in behaviour.
For more details on these findings and decisions, see Controversy section.
- Elderly patients
Despite the frequent use of antidepressants in elderly patients (Mamdani et al., 2000; Sambamoorthi et al., 2003) only two studies have addressed the risk of suicidality in this population. One study found a substantial increase in the relative risk of suicide following the initiation of SSRI treatment in older patients (Juurlink et al., 2006), while the other (Barak et al., 2006) has shown that elderly depressed patients treated with SSRIs may be at reduced risk of attempting suicide.
Sexual dysfunction is common among both men and women with major depressive disorder. A study revealed that of 134 patients with major depression surveyed, 40% of men and 50% of women reported decreased sexual interest (Kennedy et al., 1999), while 40% to 50% of the sample also reported reduced levels of arousal. Sexual dysfunction is also a common side effect of SSRIs (Balon, 2006). The assessment of SSRI-induced sexual dysfunction is thus complicated by the fact that such effects may result from the depressed state. It is clear, however, that SSRIs may negatively influence any or all phases of the sexual cycle with decreased or absent libido, impairment of arousal and erectile dysfunction but delayed ejaculation and absent or delayed orgasm are their most common effects (Rosen et al., 1999). A European survey (Williams et al., 2006) estimated the prevalence of SSRI-induced sexual dysfunction to be 26.6% of a French sample and 39.2% of a British sample. Patients reported that experiencing these sexual impairments negatively affected their quality of life, self-esteem, mood and relationships with sexual partners.
If ignored, sexual dysfunction can maintain the depression, compromise treatment outcome and lead to non-compliance. This may be a particular problem for patients on maintenance therapy since treatment interruption may trigger recurrence of depression (Werneke et al., 2006; Cohen et al., 2007). Consequently, patients should be monitored early in the treatment with SSRIs for adverse sexual effects.
Up to 20% of pregnant women suffer from depression (Patkar et al., 2004; Ryan et al., 2005) and pharmacotherapy for depression is often necessary during pregnancy (Ryan et al., 2005). In a study of 201 women with a history of major depressive disorder before pregnancy, 68% of those who discontinued treatment relapsed during pregnancy compared with only 26% of those who continued treatment (Cohen et al., 2006), indicating the importance of treating depressed pregnant women. The question remains as to whether infants of women taking antidepressants have worse birth outcomes and, if so, whether the risks are due to the medication or to the psychiatric condition. SSRIs cross freely the placental barrier and are thus transferred to foetus as well as to the newborn during lactation (Lattimore et al., 2005; Austin, 2006). Therefore both the foetus and the newborn can suffer from the adverse effects of the SSRIs, including long-term neurodevelopmental disturbances. There is an increased risk for neonatal adaptation problems in offspring exposed to SSRIs in late (third trimester) pregnancy, which may cause irritability, constant crying, eating and sleeping difficulties, and even seizures in newborns (Laine et al., 2003). It has been suggested that the symptoms were related to central nervous system serotonergic over stimulation.
The main effects of SSRIs during pregnancy are the following:
In general SSRIs are not major teratogenic compounds. However, some recent studies have shown that the use of SSRIs, particularly paroxetine, early in pregnancy is related to a moderately increased risk of congenital malformations in offspring (Wogelius et al., 2006; Donnelly and Paton, 2007). Increased risk of having an infant with major congenital malformations (adjusted OR = 2.23), or major cardiac malformations (adjusted OR = 3.07) was found in women exposed to > 25 mg/day of paroxetine during the first trimester of pregnancy (Berard et al., 2007). Another recent study (Louik et al., 2007) did not find any significantly increased risks of defects associated with SSRI use overall. Specific SSRIs, notably paroxetine and sertraline; may confer increased risks for some specific defects. These defects are rare, however, and the absolute risks are small.
Persistent pulmonary hypertension
When taken during late (after the 20th week of gestation) pregnancy SSRIs can be associated with the development of persistent pulmonary hypertension in the newborn, according to the results of a recent case-control study (Chambers et al., 2006).
Neonatal withdrawal syndrome
A database analysis has found that SSRIs given during pregnancy may lead to withdrawal symptoms in the neonate characterised by convulsions, irritability, abnormal crying, and tremor (Sanz et al., 2005). A review by Thormahlen (2006) has concluded that SSRIs are associated with neonatal withdrawal symptoms such as respiratory distress, irritability, lethargy, and tremors. Paroxetine is more commonly associated with neonatal withdrawal than other SSRIs. In a cohort study, 30% of infants exposed to SSRIs had poor neonatal adaptation, compared with 9% of drug-free controls (p = 0.018) (Oberlander et al., 2004).
In 2006, the American College of Obstetricians and Gynaecologists (ACOG ) has recommended against the use of SSRIs during pregnancy, unless treatment is absolutely required and no other options exist. The ACOG proposes that clinicians and patients should decide on an individual basis whether the benefits of SSRI therapy outweigh the associated risks.
Hyponatremia (serum sodium concentrations below 130 mEq/l) can lead to disturbing symptoms (Table 1) which can cause serious morbidity and even death (Guay, 2000).
Hyponatremia is associated with SSRI use, with an incidence which varies from 0.5% to 32% (Jacob and Spinler, 2006). The condition develops within the first few weeks of treatment and resolves within 2 weeks of therapy discontinuation. SSRI-induced hyponatremia is probably secondary to development of a syndrome of inappropriate secretion of antidiuretic hormone (Romero et al., 2007; Rottmann, 2007). Risk factors for developing SSRI-induced hyponatremia are advanced age, female gender and the concomitant use of diuretics. This potentially life-threatening adverse event should be taken seriously particularly in the fragile population of elderly who often are polymedicated and take diuretics.
Release of serotonin from platelets facilitates platelet aggregation. Platelets do not synthesize serotonin and are dependent on the reuptake process for their serotonin content. SSRIs, by inhibiting the reuptake of serotonin into the platelet, cause a decrease in platelet serotonin, leading to a decrease in serotonin release, resulting in reduced platelet aggregation and prolonged bleeding (Dalton et al., 2003). The few epidemiology studies that have investigated the association between SSRIs and upper gastrointestinal tract bleeding provide only weak evidence to support a link (Yuan et al., 2006). In general the risk of bleeding with SSRI treatment is low (Serebruany, 2006; Reeves et al., 2007). However, the risk of bleeding is increased with concomitant use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) (Yuan et al., 2006; Turner et al., 2007 ). Two studies found that the risk for an upper gastrointestinal bleed from the concurrent use of NSAIDs or low-dose aspirin with a SSRI exceeded the additive risk of the agents alone (Mort et al., 2006). A multicentre retrospective analysis (Wessinger et al., 2006) concluded that it is highly recommendable to avoid the combination of SSRIs with any medication that increase bleeding risk.
SSRI use in older adults (over 50 years) is associated with increased risk of incident clinical fragility fracture, increased odds of falling and lower bone mineral density at the hip (Richards et al., 2007). Another study in men over 65 has also reported significantly lower bone mineral density in SSRI users but not in those taking other antidepressants (Haney et al., 2007). Since depression and bone fragility are both common in the elderly, it is highly recommendable to avoid the SSRI therapy in this age group. Osteoblasts and osteoclasts possess both 5-HT receptors and 5-HT transporters which probably explains the action of SSRIs in osteoporosis and skeletal fractures (Lerner, 2005).
Extrapyramidal symptoms (EPS) are rare adverse drug reactions to SSRIs. The risk of EPS seems to increase with advanced age (> 65 years) and with the presence of the A1 allele of D2 dopamine receptor gene Taq1A polymorphism (Hedenmalm et al., 2006a). The mechanism involved in SSRI-induced extrapyramidal symptoms has been suggested to be the inhibitory influence of serotonin on dopaminergic neurotransmission (Arya, 1994). This same mechanism is thought to be involved in other rare dopaminergic adverse events seen with SSRIs namely hyperprolactinemia, galactorrhea, mammary hypertrophy, and gynaecomastia (Damsa et al., 2004).
Rare cases of apathy, lack of motivation and frontal lobe syndrome have been reported in adults, adolescents and children treated with SSRIs (Hoehn-Saric et al., 1990, 1991; George and Trimble, 1992; Garland and Baerg, 2001). A recent case control study in elderly depressed patients also showed that apathy occurred more frequently in those receiving SSRIs than non-SSRI antidepressants (Wongpakaran et al., 2007). A comparison of SSRIs and selective noradrenaline reuptake inhibitors in depression (Dubini et al., 1997) concluded that, while both classes were similarly active on most depressive symptoms, serotonergic drugs produce less improvement in motivation than the noradrenergic agents. This is consistent with a more widespread negative effect on motivation by SSRIs.
When used for 6 months or less, SSRIs are not likely to cause weight gain and opinions vary as to whether they cause weight gain when used for one year or longer (Deshmukh and Franco, 2003). Paroxetine may be more likely than other SSRIs to cause weight gain during both short-term or long-term treatment (Pae and Patkar, 2007). However this adverse event induced by the SSRIs is less of a problem than that caused by other recent antidepressants such as mirtazapine (Laimer et al., 2006) and many older antidepressants (tricyclics and monoamine oxidase inhibitors) (Cassano and Fava, 2004).
SSRIs interfere with sleep architecture. Fluoxetine, paroxetine and sertraline delay REM sleep onset, while fluoxetine and paroxetine increase awakenings and reduce REM sleep, slow-wave sleep, total sleep time and sleep efficiency. In contrast sertraline tends to reduce nocturnal wakening (Ferguson, 2001). In a naturalistic setting, drowsiness was reported by 17% of patients receiving SSRIs (Hu et al., 2004) The acute adverse effects of SSRIs on sleep persist with long-term treatment (Ferguson, 2001; Silvestri et al., 2001). SSRI use by older women, including those with no depressive symptoms, is associated with sleep disturbance, including poor sleep efficiency, long sleep latency, and sleep fragmentation, manifested by multiple long wake episodes (Ensrud et al., 2006).
Cases of alopecia associated with SSRIs have been reported, notably with sertraline administered for one year at 50 mg per day (Hedenmalm et al. 2006b). Hair loss improved after a dose reduction to 25 mg per day(Hedenmalm et al. 2006b). However this adverse event is rare and appears to be more common in women. Although SSRIs do not increase road accident risk in depressed patients (Barbone et al., 1998), a controlled study assessing actual driving performance has found that depressed patients receiving long-term treatment with SSRI antidepressants showed impaired driving performance, without deficits in memory, psychomotor and attention functions (Wingen et al., 2006). The impairment observed following the acute administration of the SSRIs persisted with time for up to a year.
When SSRIs are discontinued, adverse effects such as nausea, irritability, anxiety, and muscular aches can also occur (Himei and Okamura, 2006). These effects can be minimized by gradually tapering the dose when discontinuing an SSRI (Martinez and Marangell, 2004). The discontinuation syndrome is most commonly associated with the use of paroxetine and is more likely to occur in patients who experienced adverse reactions in the early phase of treatment (Himei and Okamura, 2006). Persistent sexual side effects after SSRI discontinuation have been observed (Csoka and Shipko, 2006).
Depression is a highly prevalent, chronic and recurrent disorder. Long-term treatment of depression consolidates the improvement obtained during the acute phase of the treatment and prevents relapses and recurrences of the disorder. Many early-onset side effects of the SSRIs such as nausea, diarrhoea, headache and agitation, disappear within 2-3 weeks. Long-term side effects may, however, be more important in terms of patient compliance and quality of life. Adverse events that persist as long as the patient takes the medication such as those described here represent a knottier problem. Unfortunately many of them are not as well described as those in the drug package insert, which are based on short-term studies. In addition many of the long-term adverse effects such as sexual dysfunction, weight changes and sleep disorders can be confused with depressive symptoms making it difficult to distinguish them from residual depressive symptoms (Wingen et al., 2006).
ACOG Committee on Obstetric Practice (2006). ACOG Committee Opinion No. 354: Treatment with selective serotonin reuptake inhibitors during pregnancy. Obstet Gynecol 108:1601-3.
Arya DK (1994). Extrapyramidal symptoms with selective serotonin reuptake inhibitors. Br J Psychiatry 165:728-33.
Austin MP (2006). To treat or not to treat: maternal depression, SSRI use in pregnancy and adverse neonatal effects. Psychol Med 36:1663-70.
Balon R (2006). SSRI-associated sexual dysfunction. Am J Psychiatry 163:1504-964.
Barak Y, Olmer A, Aizenberg D (2006). Antidepressants reduce the risk of suicide among elderly depressed patients. Neuropsychopharmacology 31:178-81.
Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, MacDonald TM (1998). Association of road-traffic accidents with benzodiazepine use. Lancet 352:1331-6.
Berard A, Ramos E, Rey E, Blais L, St-Andre M, Oraichi D (2007). First trimester exposure to paroxetine and risk of cardiac malformations in infants: the importance of dosage. Birth Defects Res B Dev Reprod Toxicol 80:18-27.
Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, Pincus HA, Ren L, Brent DA (2007). Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. J Am Med Assoc 297:1683-96.
Cassano P, Fava M (2004). Tolerability issues during long-term treatment with antidepressants. Ann Clin Psychiatry 16:15-25.
Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA (2006). Selective serotonin-reuptake inhibitors and risk of persistent pulmonary hypertension of the newborn. N Engl J Med 354:2188-90.
Cohen LS, Altshuler LL, Harlow BL, Nonacs R, Newport DJ, Viguera AC, Suri R, Burt VK, Hendrick V, Reminick AM, Loughead A, Vitonis AF, Stowe ZN (2006). Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA 295: 499-507.
Cohen S, Kühn KU, Bender S, Erfurth A, Gastpar M, Murafi A, Rothermundt M, Signerski J, Sträter B, Teusch L, Weig W, Welling A, Westheide J, Huber TJ (2007). Sexual impairment in psychiatric inpatients: focus on depression. Pharmacopsychiatry 40:58-63.
Csoka AB, Shipko S (2006). Persistent sexual side effects after SSRI discontinuation. Psychother Psychosom 75:187-8.
Dalton SO, Johansen C, Mellemkjaer L, Nørgård B, Sørensen HT, Olsen JH (2003). Use of selective serotonin reuptake inhibitors and risk of upper gastrointestinal tract bleeding: a population-based cohort study. Arch Intern Med 163:59-64.
Damsa C, Bumb A, Bianchi-Demicheli F, Vidailhet P, Sterck R, Andreoli A, Beyenburg S (2004). "Dopamine-dependent" side effects of selective serotonin reuptake inhibitors: a clinical review. J Clin Psychiatry 65:1064-8.
Deshmukh R, Franco K (2003). Managing weight gain as a side effect of antidepressant therapy. Cleve Clin J Med 70:614, 616, 618, passim.
Donnelly A, Paton C (2007). Safety of selective serotonin reuptake inhibitors in pregnancy. Psychiatric Bulletin 31: 183-186.
Dubini A, Bosc M, Polin V (1997). Do noradrenaline and serotonin differentially affect social motivation and behaviour? Eur Neuropsychopharmacol 7 (Suppl 1):S49-55.
Ensrud KE, Blackwell TL, Ancoli-Israel S, Redline S, Yaffe K, Diem S, Claman D, Stone KL (2006). Use of selective serotonin reuptake inhibitors and sleep disturbances in community-dwelling older women. J Am Geriatr Soc. 54:1508-15.
Ferguson JM (2001). SSRI Antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry 3:22-27.
Garland EJ, Baerg EA (2001). Amotivational syndrome associated with selective serotonin reuptake inhibitors in children and adolescents. J Child Adolesc Psychopharmacol 11:181-6.
George MS, Trimble MR (1992). A fluvoxamine-induced frontal lobe syndrome in a patient with comorbid Gilles de la Tourette's syndrome and obsessive-compulsive disorder. Clin Psychiatry. 53:379-80.
Guay D (2000). Hyponatremia associated with selective serotonin reuptake inhibitors: clinical review. Consult Pharmacist 15:160-77.
Gumnick JF, Nemeroff CB (2000). Problems with currently available antidepressants. J Clin Psychiat 61(Suppl 10): 5-15.
Haney EM, Chan BK, Diem SJ, Ensrud KE, Cauley JA, Barrett-Connor E, Orwoll E, Bliziotes MM; for the Osteoporotic Fractures in Men Study Group. (2007) Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men. Arch Intern Med. 167:1246-51.
Hawthorne ME, Lacey JH (1992). Severe disturbance occurring during treatment for depression of a bulimic patient with fluoxetine. J Affect Disord 26:205-7.
Hedenmalm K, Güzey C, Dahl ML, Yue QY, Spigset O (2006a). Risk factors for extrapyramidal symptoms during treatment with selective serotonin reuptake inhibitors, including cytochrome P-450 enzyme, and serotonin and dopamine transporter and receptor polymorphisms. J Clin Psychopharmacol 26:192-7.
Hedenmalm K, Sundström A, Spigset O (2006b). Alopecia associated with treatment with selective serotonin reuptake inhibitors (SSRIs). Pharmacoepidemiol Drug Saf 15:719-25.
Himei A, Okamura T (2006). Discontinuation syndrome associated with paroxetine in depressed patients: a retrospective analysis of factors involved in the occurrence of the syndrome. CNS Drugs 20:665-72.
Hoehn-Saric R, Harris CJ, Pearlson GD, Cox CS, Machlin SR, Camargo EE (1991). A fluoxetine-induced frontal lobe syndrome in an obsessive-compulsive patient. J Clin Psychiatry 52:131-3.
Hoehn-Saric R, Lipsey JR, McLeod DD (1990). Apathy and indifference in patients on fluvoxamine and fluoxetine. J Clin Psychopharmacol 10:343-5.
Hu XH, Bull SA, Hunkeler EM, Ming E, Lee JY, Fireman B, Markson LE (2004). Incidence and duration of side effects and those rated as bothersome with selective serotonin reuptake inhibitor treatment for depression: patient report versus physician estimate. J Clin Psychiatry 65:959-65.
Isbister GK, Bowe SJ, Dawson A, Whyte IM (2004). Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose. J Toxicol Clin Toxicol 42:277-85.
Jacob S, Spinler SA (2006). Hyponatremia associated with selective serotonin-reuptake inhibitors in older adults. Ann Pharmacother 40:1618-22.
Juurlink DN, Mamdani MM, Kopp A, Redelmeier DA (2006). The risk of suicide with selective serotonin reuptake inhibitors in the elderly. Am J Psychiatry 163:813-21.
Kelsey JE (2001). Mood disorders. In Rakel RE and Bope ET (Eds.) Conn's Current Therapy (pp. 1147-54). Philadelphia: WB Saunders Company.
Kennedy SH, Dickens SE, Eisfeld BS, Bagby RM (1999). Sexual dysfunction before antidepressant therapy in major depression. J Affect Disord 56:201-8.
Laimer M, Kramer-Reinstadler K, Rauchenzauner M, Lechner-Schoner T, Strauss R, Engl J, Deisenhammer EA, Hinterhuber H, Patsch JR, Ebenbichler CF (2006). Effect of mirtazapine treatment on body composition and metabolism. J Clin Psychiatry 67:421-4.
Laine K, Heikkinen T, Ekblad U, Kero P (2003). Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 60(7):720-6.
Lattimore KA, Donn SM, Kaciroti N, Kemper AR, Neal CR Jr, Vazquez DM (2005). Selective serotonin reuptake inhibitor (SSRI) use during pregnancy and effects on the fetus and newborn: a meta-analysis. J Perinatol 25:595-604.
Lerner UH (2005). Serotonin reuptake inhibitors may increase the risk of osteoporosis. Lakartidningen 102:2746-9 (Article in Swedish).
Lieberman JA (2003). History of the use of antidepressants in primary care. Primary Care Companion to the Journal of Clinical Psychiatry 5 (Suppl 7): 6-10.
Lineberry TW, Bostwick JM, Beebe TJ, Decker PA (2007). Impact of the FDA black box warning on physician antidepressant prescribing and practice patterns: opening Pandora's suicide box. Mayo Clin Proc 82:518-20.
Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA (2007) First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 356:2675-83.
Mamdani MM, Parikh SV, Austin PC, Upshur RE (2000). Use of antidepressants among elderly subjects: trends and contributing factors. Am J Psychiatry 157:360-7.
Martinez JM, Marangell LB (2004). Mood disorders. In Rakel, RE and Bope ET (Eds.), Conn's current therapy, 2004 (pp. 1161-9). Philadelphia: WB Saunders Company.
Mort JR, Aparasu RR, Baer RK (2006). Interaction between selective serotonin reuptake inhibitors and nonsteroidal antiinflammatory drugs: review of the literature. Pharmacotherapy 26:1307-13.
Mourilhe P, Stokes PE (1998). Risks and benefits of selective serotonin reuptake inhibitors in the treatment of depression. Drug Safety 18:57-82.
Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W (2004). Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure. J Clin Psychiatry 65:230-7.
Odar-Cederlöf I, Hjelmström P, Jersenius I, Andersson M, Rasmanis G, Bergman U (2006). Citalopram is not safe from the cardiac point of view - SSRI preparations can cause prolonged QTc time. Lakartidningen 103:1112-4
Pacher P, Kecskemeti V (2004). Trends in the development of new antidepressants. Is there a light at the end of the tunnel? Curr Med Chem 11: 925-43.
Pacher P, Kohegyi E, Kecskemeti V, Furst S (2001). Current trends in the treatment of new antidepressants. Curr Med Chem 8: 89-100.
Pacher P, Ungvari Z (2001). Selective serotonin-reuptake inhibitor antidepressants increase the risk of falls and hip fractures in elderly people by inhibiting cardiovascular ion channels. Med Hypotheses 57:469-71.
Pae CU, Patkar AA (2007). Paroxetine: current status in psychiatry. Expert Rev Neurother 7:107-20.
Patkar AA, Bilal L, Masan PS (2004). Pharmacotherapy of anti-depressants in pregnancy. Ann Clin Psychiatry 16:87-100.
Reeves RR, Wise PM, Cox SK (2007). SSRIs and the risk of abnormal bleeding. J Psychosoc Nurs Ment Health Serv 45:15-21.
Richards JB, Papaioannou A, Adachi JD, Joseph L, Whitson HE, Prior JC, Goltzman D; Canadian Multicentre Osteoporosis Study Research Group (2007). Effect of selective serotonin reuptake inhibitors on the risk of fracture. Arch Intern Med 167:188-94.
Richelson E (1996). Synaptic effects of antidepressants. J. Clin Psychiat 16(Suppl 2): 1S-9S.
Romero S, Pintor L, Serra M, Plana T, Navarro V, Gasto C, Goldstein B (2007).
Syndrome of inappropriate secretion of antidiuretic hormone due to citalopram and venlafaxine. Gen Hosp Psychiatry 29:81-4.
Rosen RC, Lane RM, Menza M (1999). Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol 19:67-85.
Rottmann CN (2007). SSRIs and the syndrome of inappropriate antidiuretic hormone secretion. Am J Nurs 107:51-8.
Rothschild AJ, Locke CA (1991). Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 52:491-3.
Ryan D, Milis L, Misri N (2005). Depression during pregnancy. Can Fam Physician 51:1087-93.
Sambamoorthi U, Olfson M, Walkup JT, Crystal S (2003). Diffusion of new generation antidepressant treatment among elderly diagnosed with depression. Med Care 41:180-94.
Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R (2005). Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 365:482-7.
Serebruany VL (2006). Selective serotonin reuptake inhibitors and increased bleeding risk: are we missing something? Am J Med 119:113-6.
Silvestri R, Pace-Schott EF, Gersh T, Stickgold R, Salzman C, Hobson JA (2001). Effects of fluvoxamine and paroxetine on sleep structure in normal subjects: a home-based Nightcap evaluation during drug administration and withdrawal. J Clin Psychiatry 62:642-52.
Sondergard L, Lopez AG, Andersen PK, Kessing LV (2007). Continued antidepressant treatment and suicide in patients with depressive disorder. Arch Suicide Res 11:163-75.
Teicher MH, Glod C, Cole JO (1990). Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 147:207-10.
Thormahlen GM (2006). Paroxetine use during pregnancy: is it safe? Ann Pharmacother 40:1834-7.
Turner MS, May DB, Arthur RR, Xiong GL (2007). Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks. J Intern Med 261:205-13.
Werneke U, Northey S, Bhugra D (2006). Antidepressants and sexual dysfunction. Acta Psychiatr Scand 114:384-97.
Wessinger S, Kaplan M, Choi L, Williams M, Lau C, Sharp L, Crowell MD, Keshavarzian A, Jones MP (2006). Increased use of selective serotonin reuptake inhibitors in patients admitted with gastrointestinal haemorrhage: a multicentre retrospective analysis. Aliment Pharmacol Ther 23:937-44.
Williams VS, Baldwin DS, Hogue SL, Fehnel SE, Hollis KA, Edin HM (2006). Estimating the prevalence and impact of antidepressant-induced sexual dysfunction in 2 European countries: a cross-sectional patient survey. J Clin Psychiatry 67:204-10.
Wingen M, Ramaekers JG, Schmitt JA (2006). Driving impairment in depressed patients receiving long-term antidepressant treatment. Psychopharmacology 188:84-91.
Wogelius P, Norgaard M, Gislum M, Pedersen L, Munk E, Mortensen PB, Lipworth L, Sorensen HT (2006). Maternal use of selective serotonin reuptake inhibitors and risk of congenital malformations. Epidemiology 17:701-4.
Wongpakaran N, van Reekum R, Wongpakaran T, Clarke D (2007). Selective serotonin reuptake inhibitor use associates with apathy among depressed elderly: a case-control study. Ann Gen Psychiatry 6:7.
Yuan Y, Tsoi K, Hunt RH (2006). Selective serotonin reuptake inhibitors and risk of upper GI bleeding: confusion or confounding? Am J Med 119:719-27.
last updated August 2007