Depressed male patients are almost twice as likely to present with erectile dysfunction compared with non-depressed men Furthermore, patients treated with an SSRI may present with sexual dysfunction as an unwanted side effect of therapy. Paroxetine, sertraline and citalopram are reported to cause delayed ejaculation. The SSRIs are reported to cause sexual dysfunction in the following descending order of frequency: paroxetine, fluoxetine, citalopram, sertraline and fluvoxamine The SNRI, venlafaxine, has been associated with impotence, abnormal ejaculation and orgasm, especially at higher doses, and it is reported to have an incidence of sexual side effects at least as high as that seen with paroxetine and sertraline Sexual side effects should be taken into consideration before prescribing a drug treatment for depression, because sexual dysfunction may play an important role in compliance with treatment and can act as an additional stress factor for the patient In contrast to the tricyclic antidepressants, SSRIs at normal clinical doses have little effect on cognitive psychomotor functioning.
However, sertraline, paroxetine and fluoxetine have all shown some alerting effects and excitation 73 , 74 that may be detrimental in elderly patients. Indeed, fluoxetine has been reported to be associated with an increased incidence of nervousness and insomnia compared with the tricyclic antidepressants 75 , Paroxetine has also been shown to impair cognition and vigilance, which may also be particularly problematic in elderly patients Drug-induced behaviour arousal features in activation, over motivation, pathological anxiety, compromised sexual function and cognitive impairment In contrast to sertraline, paroxetine and fluoxetine, fluvoxamine has been shown to have little or no effect on behavioural arousal Indeed, fluvoxamine has no effect on psychomotor speed, cognitive processing or arousal Similarly, fluvoxamine showed no potentiation of alcohol-related cognitive impairment As fluvoxamine 50 mg and mg was found not to impair psychomotor performance or cognitive ability in any relevant tests, including choice reaction time, tracking, critical flicker fusion threshold and memory scanning, it may be of value for use in outpatients who wish to carry out the tasks of everyday life.
In a double-blind study comparing dothiepin and venlafaxine in elderly patients, venlafaxine Evidence suggests that fluvoxamine has beneficial effects on sleep in depressed patients. A recent double-blind study comparing fluvoxamine and fluoxetine showed that depressed patients treated with fluvoxamine improved their sleep quality both significantly more and more rapidly than patients on fluoxetine Another direct comparative study involving fluvoxamine and paroxetine 72 showed that paroxetine caused a greater disruption of sleep patterns than fluvoxamine, and the paroxetine-induced sleep disruption persisted into the withdrawal phase The beneficial effects of fluvoxamine on sleep quality have also been reported in patients with post-traumatic stress disorder PTSD.
Fluvoxamine was effective in reducing all three symptom clusters of PTSD intrusion, avoidance and hyperardusal , including nightmares and insomnia In addition, patients suffering from other anxiety disorders, such as obsessive-compulsive disorder and panic disorder, have been found to experience a significant reduction of insomnia when treated with fluvoxamine It has been suggested that the beneficial effects of fluvoxamine on sleep may be related to its inhibitory effect on melatonin degradation; this effect has not been observed with other SSRIs 85 , In a double-blind placebo-controlled study, venlafaxine was found to decrease sleep continuity, markedly increase the time to rapid eye movement REM sleep and decrease the duration of total REM sleep Other more recent publications confirm that venlafaxine worsens sleep quality 88 — Changes in bodyweight are associated with a low acceptance of treatment and an increased risk of non-compliance during long-term treatment by patients Typically, SSRIs mediate a reduction in food intake, particularly in the initial phase of therapy.
However, weight is frequently regained after 6 months of treatment and can be followed by additional weight gain during long-term treatment Paroxetine, fluoxetine, citalopram and sertraline have been shown to significantly increase bodyweight after 6—12 months of administration Weight gain could be related to carbohydrate craving, as reported for citalopram However, an alteration in metabolic rate may be responsible for the weight changes In this regard, fluvoxamine was reported to promote an increase in resting metabolic rate, resulting in less weight gain Of the SSRIs, paroxetine may be responsible for the highest amounts of weight gain 92 , However, follow-up over 2 years of patients receiving open-label clomipramine, citalopram, fluoxetine, fluvoxamine, paroxetine or sertraline showed that clomipramine was associated with the highest weight increase and fluoxetine and sertraline with the lowest Weight changes observed with SSRIs appear to involve the interaction of 5-HT with multiple mechanisms, with the extent of weight gain being dependent on small, yet pharmacological important differences in this class of antidepressants Venlafaxine, such as fluoxetine, at least in short term, reduces food intake 98 , Patients with cardiovascular impairment.
The SSRIs are more suitable than the tricyclic antidepressants for the treatment of patients with cardiovascular and cerebrovascular diseases both of which are associated with a high incidence of depression due to their superior cardiovascular safety profile. Evidence for the safety of fluoxetine, sertraline and paroxetine has been inferred from cardiac effects in healthy volunteers, while sertraline has also been used safely in patients with recent myocardial infarctions or unstable angina A review of the citalopram database found that the majority of patients with abnormal ECGs had pre-existing cardiac disease or were receiving medication likely to affect the QTc interval Fluvoxamine has been widely studied in patients with cardiovascular impairment, and evidence suggests it has no effect on cardiovascular function in physically healthy patients and is safe in patients with cardiovascular disease — In contrast, venlafaxine causes increases in heart rate and blood pressure in some patients Hypertensive crises have also been reported for venlafaxine Regular blood pressure monitoring is advised in patients receiving venlafaxine while discontinuation is recommended in patients with a sustained elevation.
Indeed, preliminary evidence suggests that venlafaxine may be an effective treatment in patients with severe orthostatic hypotension Elderly patients. The good safety profile of the SSRIs in comparison with the tricyclic antidepressants is particularly important when treating elderly patients.
Differences in the safety and tolerability profile between the SSRIs suggest that some may be more suitable than others for the treatment of elderly patients. Fluoxetine, for example, is associated with nervousness — and insomnia , which suggests that it should be employed with caution in frail, elderly patients. It should also be noted that although considerable interindividual variation exists, higher plasma levels of paroxetine have been observed in elderly patients along with its reduced elimination.
The clearance of citalopram has also been observed to generally decrease with increasing age ; a dose reduction or close monitoring is therefore advised for the elderly patient taking citalopram. The excellent safety profile of fluvoxamine in the elderly, without the need of dose adjustments, was confirmed in an analysis of data from patients mainly depressed aged 65—97 years enrolled in world-wide post-marketing studies conducted over periods of up to 1 year Findings from a study in elderly patients aged between 75 and 97 years mean 81 years , who also had a high incidence of concomitant illnesses and requirement for other medications, have also confirmed the excellent safety of fluvoxamine Discontinuation symptoms upon abrupt withdrawal have been reported for all SSRIs , although it is now evident that they are considerably more common with paroxetine than with the other SSRIs.
An evaluation of the UK post-marketing surveillance database of adverse reactions revealed more reports of discontinuation symptoms with paroxetine 0. In a double-blind, placebo-controlled study specifically designed to assess the effects of interruption of fluoxetine, sertraline or paroxetine treatment, placebo substitution for paroxetine was associated with an increase in the number and severity of adverse events following the second missed dose and increases in functional impairment at 5 days Effects were considerably less marked with the other SSRIs.
Similar findings were reported in another double-blind, placebo-controlled trial in which treatment with paroxetine, fluoxetine, sertraline or citalopram was suddenly interrupted for 4—7 days Interruption of paroxetine was associated with significantly more cognitive problems and poorer quality of sleep.
Neonatal withdrawal syndrome has also been reported after in utero exposure to paroxetine , while high rates of neonatal complications in women exposed to paroxetine during the third trimester of pregnancy have been possibly attributed to the withdrawal syndrome Of the top 20 medicines in UK with reports of symptoms of withdrawal entered on to the British ADROIT database , paroxetine was at the top of the list with reports.
Venlafaxine occupied the second position with reports, while fluoxetine, sertraline and citalopram were fourth, fifth and sixth, respectively. Fluvoxamine was placed 19th Table 1. It appears that a long drug half-life delays the onset of discontinuation symptoms rather than preventing them.
A review of the literature found that the mean length of time for the appearance of discontinuation symptoms was 6. There is controversy about the possibility that SSRI antidepressants might induce suicidality in some patients; the role of antidepressants in suicide prevention has therefore become a major public health question.
In a review of randomised controlled trials, meta-analyses of clinical trials and epidemiological studies, an excess of suicidal acts on active treatments compared with placebo made it difficult to sustain the hypothesis that SSRIs do not cause problems in some individuals A more recent systematic review of randomised controlled trials, which included 87, patients, also found a significant increase in the odds of suicide attempts for patients receiving SSRIs compared with placebo Other studies have failed to support either an overall difference in suicide risk between antidepressant- and placebo-treated depressed individuals or a difference between SSRIs and either other types of antidepressants or placebo.
Similar suicide rates were seen among those randomly assigned to an SSRI, a standard comparison antidepressant, or placebo in a review of 48, depressed patients participating in the Food and Drug Administration FDA reports of controlled clinical trials for modern FDA-approved antidepressants Neither was there evidence that the risk of suicide or non-fatal self-harm in adults prescribed SSRIs was higher than in those prescribed tricyclic antidepressants in a UK study of , individuals with a first prescription of an antidepressant for depression; there was some weak evidence of an increased risk of non-fatal self-harm for current SSRI use among those aged 18 or younger, although none committed suicide Epidemiological studies also have not supported the hypothesis that SSRIs may have a suicide-emergent effect.
Over a period of 9 years — , treatment of depressed individuals with SSRIs was not associated with an increased risk of suicide in adults, children or adolescents in Sweden However, there may be an association between the fall in suicide rate and greater use of non-tricyclic antidepressants. Data from all US individuals who committed suicide between and showed that prescriptions for SSRIs and other new-generation non-SSRI antidepressants were associated with lower suicide rates and that higher suicide rates in rural areas were associated with fewer antidepressant prescriptions This, along with evidence to suggest that most of those who commit suicide and who have major depressive disorder at the time of death are either untreated or receiving subtherapeutic doses of antidepressants , implies that improved treatment delivery of antidepressants may potentially reduce suicide rates.
The SSRIs are considerably safer than tricyclic antidepressants if taken in overdose. However, citalopram may be a possible exception to the overall good safety profile of the SSRIs in overdose. Despite this, all the SSRI were demonstrated to be relatively safe in overdose and only citalopram was significantly associated with QTc prolongation.
The overall incidence of seizures was 1. In contrast, in a retrospective review of patients, citalopram was associated with a significantly longer QT interval on ECG recording, but mean QTc durations were not significantly different between all drugs studied. Only venlafaxine and citalopram caused seizures and were associated with admission to intensive care units In another study in patients hospitalised due to antidepressant overdose, SSRIs were shown to be less likely to cause coma, to require admission to an intensive care unit and prolong the QRS, but were more likely to cause 5-HT toxicity than venlafaxine.
Venlafaxine was comparable with the tricyclics in terms of the risk of seizures and suicide The SSRIs fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram , and also the SNRI venlafaxine, have become a mainstay and first-line treatment for depression. The highly specific actions of the SSRIs involving enhancement of predominantly serotonergic neurotransmission explain their beneficial effects in depressed patients and patients with anxiety disorders, while the lack of direct actions on other neurotransmitter systems is responsible for their superior safety profile as compared with that of tricyclic antidepressants.
As a class, the SSRIs possess the following mild to moderate adverse effects that do not require dose reductions or discontinuation: erectile and ejaculatory dysfunction, decreased libido, jitteriness, sweating, tachycardia, tremors, anorexia, anxiety, diarrhoea, headache, insomnia and nausea. Although a comparison of the adverse effects of SSRIs and venlafaxine reveals little distinction among the agents, certain differences are emerging.
For example, the impact of SSRIs on sexual function is perhaps the most deleterious side effect from the point of view of the patient's quality of life. In contrast to several other SSRIs and also venlafaxine, evidence suggests that fluvoxamine has beneficial effects on sleep in depressed patients and a lower impact on bodyweight. In terms of cardiotoxicity, it is established that the SSRIs are more suitable than the tricyclic antidepressants for the treatment of patients with cardiovascular disease due to a superior cardiovascular safety profile.
Fluvoxamine has been widely studied in this regard, and evidence suggests it has no effect on cardiovascular function in physically healthy patients and is safe in patients with cardiovascular disease. Fluvoxamine also has an excellent safety profile in frail elderly patients. A discontinuation syndrome involving disequilibrium, nausea, vomiting, fatigue, sleep disturbances, lethargy, irritability and agitation may develop upon abrupt cessation of an SSRI.
This syndrome is more common with the SSRIs with shorter half-lives and inactive metabolites. Finally, the SSRIs are considerably more tolerable than tricyclic antidepressants in overdose, and there is no conclusive evidence to suggest that they are associated with an increased risk of suicide. This review therefore suggests that while clinically significant differences in efficacy amongst SSRIs do not exist, treatment decisions need to be based on considerations such as patient acceptability, patient history of prior response, toxicity and cost.
It is noteworthy in this respect that fluvoxamine has a comparatively good profile in terms of adverse events. It has a particularly low impact on sexual function this may therefore reduce patient non-compliance and an excellent safety profile in the elderly.
National Center for Biotechnology Information , U. International Journal of Clinical Practice. Int J Clin Pract. Author information Article notes Copyright and License information Disclaimer. Received Nov; Accepted Jan. This article has been cited by other articles in PMC. Summary Selective serotonin [5-hydroxytryptamine 5-HT ] reuptake inhibitors SSRIs and the 5-HT noradrenaline reuptake inhibitor, venlafaxine, are mainstays in treatment for depression.
Keywords: Antidepressants, selective serotonin reuptake inhibitors, fluvoxamine, tolerability, safety, review. Introduction Over the years, there have been considerable advances in the development of new antidepressants with the emergence of the selective serotonin [5-hydroxytryptamine 5-HT ] reuptake inhibitors SSRIs and 5-HT noradrenaline reuptake inhibitors SNRIs.
Pharmacologic and pharmacokinetic aspects Receptor Binding Most of the effects of antidepressants, whether therapeutic or adverse, can be directly related to their pharmacology. Open in a separate window. Figure 1. Figure 2. Figure 3.
Figure 4. Half-Life and Active Metabolites The half-lives of fluvoxamine, paroxetine, sertraline and citalopram are all approximately 1 day. Tolerability Gastrointestinal Adverse Events The most common adverse event reported during treatment with SSRIs is nausea, which tends to disappear after some days of treatment Sexual Dysfunction Depressed male patients are almost twice as likely to present with erectile dysfunction compared with non-depressed men Central Nervous System Impairment In contrast to the tricyclic antidepressants, SSRIs at normal clinical doses have little effect on cognitive psychomotor functioning.
Sleep Quality Evidence suggests that fluvoxamine has beneficial effects on sleep in depressed patients. Bodyweight Changes in bodyweight are associated with a low acceptance of treatment and an increased risk of non-compliance during long-term treatment by patients Safety Safety in Special Populations Patients with cardiovascular impairment.
Discontinuation Symptoms Discontinuation symptoms upon abrupt withdrawal have been reported for all SSRIs , although it is now evident that they are considerably more common with paroxetine than with the other SSRIs. Suicide Risk There is controversy about the possibility that SSRI antidepressants might induce suicidality in some patients; the role of antidepressants in suicide prevention has therefore become a major public health question.
Conclusion The SSRIs fluoxetine, sertraline, paroxetine, fluvoxamine and citalopram , and also the SNRI venlafaxine, have become a mainstay and first-line treatment for depression. References 1.
Sanchez C, Hyttel J. Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding. Cell Mol Neurobiol. Hyttel J. Leonard B. Pharmacological differences of serotonin reuptake inhibitors and possible clinical relevance. Dechant K, Clissold S. Paroxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in depressive illness.
Affinities of fluoxetine, its enantiomers, and other inhibitors of serotonin uptake for subtypes of serotonin receptors. The pharmacology of citalopram. Rev Contemp Pharmacother. The Pharmacological Basic of Therapeutics. Goodman and Gilman. A review of the neuropsychological effects of commonly used prescription medications. Arch Clin Neuropsychol. Effects of SSRIs on sexual function: a critical review. J Clin Psychopharmacol. Sexual dysfunction with antihypertensive and antipsychotic agents.
For people with history of mania: Fluvoxamine can increase your risk of activating mania. Your doctor should closely monitor you while you use this drug. For people with seizures: Some people who have used this drug have had seizures. If you have unstable epilepsy, you should not take this drug. If you a history of seizures or controlled epilepsy, your doctor should monitor you closely if you take this drug.
If you begin to have seizures or if your seizures happen more often, you should talk to your doctor about stopping this drug. For people with liver disease: If you have a history of liver disease, your body may not clear this drug as quickly as it should. This could lead to a buildup of this drug in your body. To prevent this, your doctor may start you at a lower dosage and carefully monitor you during dose increases.
For pregnant women: Fluvoxamine is a category C pregnancy drug. That means two things:. This drug should only be used if the potential benefit justifies the potential risk. Your doctor may decide that another drug is safer for you during your pregnancy. For women who are breastfeeding: Fluvoxamine is passed into breast milk and may cause side effects in a child who is breastfed.
Talk to your doctor if you breastfeed your child. You may need to decide whether to stop breastfeeding or stop taking this medication. For seniors: Older adults are more likely to be more sensitive to fluvoxamine and may process the drug more slowly. As a result, a higher amount of a drug stays in the body for a longer time. This raises the risk of side effects, especially low sodium levels. For children: The safety and effectiveness of the use of fluvoxamine extended-release capsules has not been established in people younger than 18 years.
All possible dosages and drug forms may not be included here. Your dosage, drug form, and how often you take the drug will depend on:. It has not been confirmed that fluvoxamine is safe and effective for use in people younger than 18 years.
Older adults are more likely to be more sensitive to fluvoxamine and may process the drug more slowly. As a result, a higher amount of a drug stays in your body for a longer time. This raises your risk of side effects. Your doctor may adjust your dosage to keep levels of this drug from building up too much in your body.
However, because drugs affect each person differently, we cannot guarantee that this list includes all possible dosages. Always speak with your doctor or pharmacist about dosages that are right for you. Fluvoxamine oral capsule is used for long-term treatment.
Symptoms also include headache, sweating, nausea, dizziness, tingling sensations, shaking, or confusion. For this drug to work well, a certain amount needs to be in your body at all times. If you take too much: You could have dangerous levels of the drug in your body. Symptoms of an overdose of this drug can include:. But if your symptoms are severe, call or go to the nearest emergency room right away. What to do if you miss a dose: Take your dose as soon as you remember.
But if you remember just a few hours before your next scheduled dose, take only one dose. Never try to catch up by taking two doses at once. This could result in dangerous side effects. How to tell if the drug is working: You should have reduced symptoms of obsessive compulsive disorder. A prescription for this medication is refillable. You should not need a new prescription for this medication to be refilled.
Thus, it seems that the antagonism of sigma-1 receptors by sertraline may be involved in the recurrence of psychotic symptoms in this case, although a further detailed study is necessary. It is suggested that the relative potency of sertraline for dopamine transporter inhibition might differentiate its psychopharmacology from that of other SSRIs [ 29 ].
It is therefore possible that activation of the dopaminergic system by the inhibition of dopamine transporter may be involved in the mechanism of unwanted effects deterioration of psychosis of sertarline in this case, although further study is necessary.
This case suggests that the sigma-1 receptor agonist fluvoxamine could be an alternative approach in treating psychotic major depression. More detailed randomized, double-blind studies should be performed to clarify the role of sigma-1 receptors in the efficacy of fluvoxamine for psychotic major depression.
The treatment of the reported case was made according to standard clinical practice; however written informed consent was obtained from the patient for publication of this case report. Schatzberg AF: New approaches to managing psychotic depression. J Clin Psychiatry. Expert Rev Neurother. Article PubMed Google Scholar. Harv Rev Psychiatry. Am J Psychiatry. Int Clin Psychopharmacol. Furuse T, Hashimoto K: Fluvoxamine monotherapy for psychotic depression: the potential role of sigma-1 receptors.
Ann Gen Psychiatry. Shirayama Y, Hashimoto K: A case of psychotic depression treated with fluvoxamine monotherapy. Clin Psychopharmacol Neurosci. Google Scholar. Stahl SM: Antidepressant treatment of psychotic major depression: potential role of the sigma receptor. CNS Spectr. Psychiatric Times. Ishikawa M, Hashimoto K: The role of sigma-1 receptors in the pathophysiology of neuropsychiatric diseases.
J Receptor Ligand Channel Res. CAS Google Scholar. J Psychopharmacol. Hashimoto K, Ishiwata K: Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Curr Pham Des. Drugs Future. Hashimoto K: Sigma-1 receptors and selective serotonin reuptake inhibitors: clinical implications of their relationship.
Hindmarch I, Hashimoto K: Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered. Hum Psychopharmacol Clin Exp. Eur J Pharmacol. Hashimoto K, Fujita Y, Iyo M: Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors. Nishimura T, Ishima T, Iyo M, Hashimoto K: Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP 3 receptors and cellular signaling pathways.
Open Clin Chem J. Biol Psychiatry. Critical Issues in the Treatment of Affective Disorders. Basic pharmacology. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Akira Kishimoto. KH conceived of the study and participated in its study and coordination.
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