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4 … this important class of medicines (SSRIs)

4 Importantly, however, I hope the legacy of the Group will also be in looking forward, to identifying the further work necessary to establish safety, advising on study design and identifying the lessons to be learned.

7 Careful and frequent patient monitoring by healthcare professionals and, where appropriate, other carers, is important in the early stages of treatment, particularly if a patient experiences worsening of symptoms or new symptoms after starting treatment.

7 There is evidence that withdrawal reactions are less severe when the dose is tapered gradually over a period of several weeks, according to the patient’s need. Availability of low dose formulations to allow gradual titration is important.

22 Following legal advice, the meeting in March was cancelled and the group dissolved. It was important that this work was continued, and in May 2003 the CSM established its Expert Working Group on the Safety of SSRIs.

25 In order to have their basic physical and emotional needs met, children are dependent on parents or carers. Therefore, environmental factors are likely to be more important in the development of depression in children compared to adolescents or adults. However, childhood depression does exist.

37 It is important to recognise that (testing for statistical significance) is not a substitute for a detailed review of cases but an aid to identifying promptly those series of cases from a large database which warrant further review.

41 … the following may be important in determining the efficacy and safety of SSRIs and related antidepressants: the different liver enzymes involved in the breakdown of antidepressants and the differing levels of these enzymes between individuals; the time taken for a drug to be cleared from the body – this is likely to be particularly important with regard to the risk of withdrawal reactions occurring on stopping treatment; the extent to which SSRIs and related antidepressants cross the blood brain barrier and enter the central nervous system; the effectiveness of the different SSRIs and other antidepressants in increasing levels of serotonin and other chemicals in the brain, and how this differs between individuals and over time with changing levels of these chemicals in the brain.

42 This is important as the therapeutic effect of antidepressants is delayed suggesting that it cannot be equated with simple transporter inhibition, which occurs almost immediately. It is, however, poorly understood how the observed secondary changes lead to alleviation of depressive symptoms and signs. Together with the pathophysiology of depressive illness, this needs further investigation.

43 Cytochrome P450 2D6 is, for example, responsible for the metabolism of approximately 25% of all drugs; importantly, with respect to psychiatry, it is perhaps the major P450 isoform responsible for the metabolism of many of the antidepressants and antipsychotics used in current clinical practice.

43 Taken together with the fact that CYP2D6 and CYP3A4 will have different affinities for the different antidepressants, and may result in the formation of different metabolites, the balance in the relative activities of CYP2D6 and CYP3A4 in each patient will be important in determining the kinetics of the drugs, and hence the inter-individual variability in kinetics.

44 There seems to be an association between a drug’s half-life and the presence of withdrawal reactions. Drugs such as paroxetine and venlafaxine, which have the shortest half-lives of all the drugs considered in the review, have been most commonly implicated
in studies using spontaneous reports. This may suggest that it is not the actual change that occurs in brain neurochemistry on drug administration that is important, but the rate of that change.

44 Kinetic studies carried out in patients or volunteers, or any studies investigating pharmacokinetic-pharmacodynamic relationships, rely on plasma level measurements. It is important to note that plasma levels give an indication of, but do not truly reflect, levels within the central nervous system, the main site of action of the SSRIs and related antidepressants.

44/45 It is important to note that expression of these transporter proteins also varies amongst the human population. This variation in protein expression may lead to inter-individual variation in the transport of drugs, and thereby may act as a pharmacogenetic determinant of efficacy and toxicity.

45 (2) The SSRIs also have effects on other receptors, as indicated above. This may indeed be important with regard to their efficacy, especially since the reuptake blockade occurs almost immediately while the therapeutic response is not seen for about two weeks. In this respect, receptor desensitisation may be important in determining both efficacy and toxicity. Receptor desensitisation can vary between different individuals and may be genetically determined.

45 It is important to state that any pharmacogenetic studies will require accurate and objective phenotypic characteristisation of all patients and controls included in the study for any results to be interpretable. Initial studies have suggested that the 5HT transporter gene polymorphism may affect tolerability with paroxetine and mirtazapine30, although this needs to be replicated in other cohorts.

57 In the long-term study, the most common adverse event leading to discontinuation was hostility. Clinically important weight loss was also noted.

58 An increased risk of suicidal thoughts and self-harm in the SSRI-treated patients compared with those treated with placebo was seen fairly consistently across products in the trials. There were no suicides in any of the trials. Apart from the issue of suicidal behaviour, increased rates of other adverse events were of concern – particularly hostility, abdominal pain, anorexia, nausea and weight loss, dizziness and insomnia. Withdrawal reactions on stopping treatment were also identified. In weighing the risks and benefits of the SSRIs these other adverse events were considered important, as was the lack of information about the long-term effects of the use of these products in childhood/adolescence.

68 The EWG considered timely and transparent communication with all stakeholders to be of key importance. It also recommended that the clinical trial data on which regulatory decisions were made should be made available to the public. It considered this to be extremely important in relation to the data on the paediatric use of SSRIs where little clinical trial data were in the public domain.

88 It is known that depression is a major risk factor for suicidal thoughts and self-harm. Therefore, when considering the balance of benefits and harms for any antidepressant, it is important to consider the evidence for benefit of the antidepressant in relieving the symptoms of depression and thereby reducing the risk of suicidal thoughts or self-harm as well as the evidence for harm.

96 A logistic regression analysis performed by the MA holder suggests that prescribing indication is an important predictor of the occurrence of a suicide-related event. Patients with panic disorder are less likely to experience a suicide-related event compared with patients with depressive illness

104 It is also important to balance any possible increase in the risk of suicide-related events against the evidence for a reduction in the symptoms of depression for patients treated with antidepressants compared with placebo, because treating depression is a major factor in reducing the risk of suicide-related events.

111 It is important to note that in none of these studies were patients treated with antidepressants compared with non treated patients with similar conditions because of concerns about confounding by indication whereby patients with more severe depression are more likely to be treated and likely to be at higher risk of suicidal behaviour.

111 A further limitation of spontaneous reporting from health professionals is that they may act as a ‘filter’, reporting only those details considered by them to be important rather than providing a direct account of the experiences of the patient.

118 Careful and frequent patient monitoring by healthcare professionals and, where appropriate, other carers, is important in the early stages of treatment, particularly if a patient experiences a worsening of symptoms or new symptoms after starting treatment.

123 It may sometimes be difficult to distinguish symptoms which reflect a return of the original illness because the treatment had been helpful but is now being withdrawn (ie a relapse), and symptoms which occur because the body is adjusting to the change as the drug is withdrawn. It is also important to note that withdrawal-like reactions are seen to occur on discontinuation of placebos where patients are not made aware whether they are taking a placebo or an active SSRI drug.

124 A further limitation of spontaneous reporting from health professionals is that they may act as a ‘filter’, reporting only those details considered by them to be important rather than providing a direct account of the experiences of the patient. Therefore, these data cannot be used to establish a causal association or to quantify an adverse effect.

146 On the other hand, post-marketing data do reflect real life, and reactions which are recorded and reported are likely to be considered clinically important. However, spontaneous reporting data can only give a limited indication of frequency because of the problem of under-reporting and under-recognition because patients do not complain or doctors do not correctly attribute or record such symptoms.

154 (2) In a prospective, controlled cohort study, Costei et al investigated whether there was a clinically important withdrawal syndrome in neonates exposed in utero to paroxetine … The authors concluded that when paroxetine is used near term, it is associated with a high rate of neonatal complications, possibly caused by its withdrawal reactions. The study has some limitations. It relied on information collected directly from the mother by telephone interview without any validation from medical records, and severity of depression may have been an important confounder (patients in the cohort exposed to paroxetine in the third trimester were more likely to have had more severe depression or anxiety than women in the control group). Severe maternal depression is a risk factor for poor perinatal outcomes.

156 There is evidence that withdrawal reactions are less severe when the dose is tapered gradually over a period of several weeks according to the patient’s need. Availability of low dose formulations to allow gradual titration is important.

175 It is important that patients and prescribers are aware, as appropriate, that clinical trials have not shown any additional benefit associated with increasing the dose.

177 As described in chapters 7 and 8, the EWG reviewed data on patients’ experiences from two sources: the Panorama/Mind Yellow Cards and a questionnaire sent out to individuals who contacted the MHRA about the safety of the SSRIs. As well as capturing information on withdrawal reactions and suicidal behaviour (data reviewed in chapters 7 and 8, respectively), these questionnaires also invited people to provide any additional information that they considered important about their experience.

179 Recommended change to patient information leaflet: consolidated and clarified information on how to stop; all important information on stopping Seroxat was consolidated in a dedicated section which simplified the explanation of possible effects;

180 The focus group raised many valid and important points in relation to the Seroxat PIL. The focus group also raised general concerns about accessibility and readability of the PIL. This is a matter that is currently being considered in detail by the CSM’s Working Group on Patient Information.

182 Careful and frequent patient monitoring by healthcare professionals and, where appropriate, other carers, is important in the early stages of treatment, particularly if a patient experiences worsening of symptoms or new symptoms after starting treatment.

186 Whilst placebo-controlled trials provide important information on efficacy, studies against an active comparator should be a requirement for all new antidepressants. The clinical trial protocol must have an appropriate and relevant comparator for the indication prescribed at an appropriate dose; it would be preferable if clinical experts could design a set of standard protocols which could be used in clinical trial design.

CLICK HERE TO RETURN TO THE MAIN ANALYSIS AND REVIEW OF
THE CSM EXPERT WORKING GROUP ON SSRI ANTIDEPRESSANTS

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Search Ref	SIGNIFICANT REFERENCES TO "IMPORTANT" POINTS
4	… this important class of medicines (SSRIs)
4	Importantly, however, I hope the legacy of the Group will also be in looking forward, to identifying the further work necessary to establish safety, advising on study design and identifying the lessons to be learned.
7	Careful and frequent patient monitoring by healthcare professionals and, where appropriate, other carers, is important in the early stages of treatment, particularly if a patient experiences worsening of symptoms or new symptoms after starting treatment.
7	There is evidence that withdrawal reactions are less severe when the dose is tapered gradually over a period of several weeks, according to the patient’s need. Availability of low dose formulations to allow gradual titration is important.
22	Following legal advice, the meeting in March was cancelled and the group dissolved. It was important that this work was continued, and in May 2003 the CSM established its Expert Working Group on the Safety of SSRIs.
25	In order to have their basic physical and emotional needs met, children are dependent on parents or carers. Therefore, environmental factors are likely to be more important in the development of depression in children compared to adolescents or adults. However, childhood depression does exist.
37	It is important to recognise that (testing for statistical significance) is not a substitute for a detailed review of cases but an aid to identifying promptly those series of cases from a large database which warrant further review.
41	… the following may be important in determining the efficacy and safety of SSRIs and related antidepressants: the different liver enzymes involved in the breakdown of antidepressants and the differing levels of these enzymes between individuals; the time taken for a drug to be cleared from the body – this is likely to be particularly important with regard to the risk of withdrawal reactions occurring on stopping treatment; the extent to which SSRIs and related antidepressants cross the blood brain barrier and enter the central nervous system; the effectiveness of the different SSRIs and other antidepressants in increasing levels of serotonin and other chemicals in the brain, and how this differs between individuals and over time with changing levels of these chemicals in the brain.
42	This is important as the therapeutic effect of antidepressants is delayed suggesting that it cannot be equated with simple transporter inhibition, which occurs almost immediately. It is, however, poorly understood how the observed secondary changes lead to alleviation of depressive symptoms and signs. Together with the pathophysiology of depressive illness, this needs further investigation.
43	Cytochrome P450 2D6 is, for example, responsible for the metabolism of approximately 25% of all drugs; importantly, with respect to psychiatry, it is perhaps the major P450 isoform responsible for the metabolism of many of the antidepressants and antipsychotics used in current clinical practice.
43	Taken together with the fact that CYP2D6 and CYP3A4 will have different affinities for the different antidepressants, and may result in the formation of different metabolites, the balance in the relative activities of CYP2D6 and CYP3A4 in each patient will be important in determining the kinetics of the drugs, and hence the inter-individual variability in kinetics.
44	There seems to be an association between a drug’s half-life and the presence of withdrawal reactions. Drugs such as paroxetine and venlafaxine, which have the shortest half-lives of all the drugs considered in the review, have been most commonly implicated in studies using spontaneous reports. This may suggest that it is not the actual change that occurs in brain neurochemistry on drug administration that is important, but the rate of that change.
44	Kinetic studies carried out in patients or volunteers, or any studies investigating pharmacokinetic-pharmacodynamic relationships, rely on plasma level measurements. It is important to note that plasma levels give an indication of, but do not truly reflect, levels within the central nervous system, the main site of action of the SSRIs and related antidepressants.
44/45	It is important to note that expression of these transporter proteins also varies amongst the human population. This variation in protein expression may lead to inter-individual variation in the transport of drugs, and thereby may act as a pharmacogenetic determinant of efficacy and toxicity.
45 (2)	The SSRIs also have effects on other receptors, as indicated above. This may indeed be important with regard to their efficacy, especially since the reuptake blockade occurs almost immediately while the therapeutic response is not seen for about two weeks. In this respect, receptor desensitisation may be important in determining both efficacy and toxicity. Receptor desensitisation can vary between different individuals and may be genetically determined.
45	It is important to state that any pharmacogenetic studies will require accurate and objective phenotypic characteristisation of all patients and controls included in the study for any results to be interpretable. Initial studies have suggested that the 5HT transporter gene polymorphism may affect tolerability with paroxetine and mirtazapine30, although this needs to be replicated in other cohorts.
57	In the long-term study, the most common adverse event leading to discontinuation was hostility. Clinically important weight loss was also noted.
58	An increased risk of suicidal thoughts and self-harm in the SSRI-treated patients compared with those treated with placebo was seen fairly consistently across products in the trials. There were no suicides in any of the trials. Apart from the issue of suicidal behaviour, increased rates of other adverse events were of concern – particularly hostility, abdominal pain, anorexia, nausea and weight loss, dizziness and insomnia. Withdrawal reactions on stopping treatment were also identified. In weighing the risks and benefits of the SSRIs these other adverse events were considered important, as was the lack of information about the long-term effects of the use of these products in childhood/adolescence.
68	The EWG considered timely and transparent communication with all stakeholders to be of key importance. It also recommended that the clinical trial data on which regulatory decisions were made should be made available to the public. It considered this to be extremely important in relation to the data on the paediatric use of SSRIs where little clinical trial data were in the public domain.
88	It is known that depression is a major risk factor for suicidal thoughts and self-harm. Therefore, when considering the balance of benefits and harms for any antidepressant, it is important to consider the evidence for benefit of the antidepressant in relieving the symptoms of depression and thereby reducing the risk of suicidal thoughts or self-harm as well as the evidence for harm.
96	A logistic regression analysis performed by the MA holder suggests that prescribing indication is an important predictor of the occurrence of a suicide-related event. Patients with panic disorder are less likely to experience a suicide-related event compared with patients with depressive illness
104	It is also important to balance any possible increase in the risk of suicide-related events against the evidence for a reduction in the symptoms of depression for patients treated with antidepressants compared with placebo, because treating depression is a major factor in reducing the risk of suicide-related events.
111	It is important to note that in none of these studies were patients treated with antidepressants compared with non treated patients with similar conditions because of concerns about confounding by indication whereby patients with more severe depression are more likely to be treated and likely to be at higher risk of suicidal behaviour.
111	A further limitation of spontaneous reporting from health professionals is that they may act as a ‘filter’, reporting only those details considered by them to be important rather than providing a direct account of the experiences of the patient.
118	Careful and frequent patient monitoring by healthcare professionals and, where appropriate, other carers, is important in the early stages of treatment, particularly if a patient experiences a worsening of symptoms or new symptoms after starting treatment.
123	It may sometimes be difficult to distinguish symptoms which reflect a return of the original illness because the treatment had been helpful but is now being withdrawn (ie a relapse), and symptoms which occur because the body is adjusting to the change as the drug is withdrawn. It is also important to note that withdrawal-like reactions are seen to occur on discontinuation of placebos where patients are not made aware whether they are taking a placebo or an active SSRI drug.
124	A further limitation of spontaneous reporting from health professionals is that they may act as a ‘filter’, reporting only those details considered by them to be important rather than providing a direct account of the experiences of the patient. Therefore, these data cannot be used to establish a causal association or to quantify an adverse effect.
146	On the other hand, post-marketing data do reflect real life, and reactions which are recorded and reported are likely to be considered clinically important. However, spontaneous reporting data can only give a limited indication of frequency because of the problem of under-reporting and under-recognition because patients do not complain or doctors do not correctly attribute or record such symptoms.
154 (2)	In a prospective, controlled cohort study, Costei et al investigated whether there was a clinically important withdrawal syndrome in neonates exposed in utero to paroxetine … The authors concluded that when paroxetine is used near term, it is associated with a high rate of neonatal complications, possibly caused by its withdrawal reactions. The study has some limitations. It relied on information collected directly from the mother by telephone interview without any validation from medical records, and severity of depression may have been an important confounder (patients in the cohort exposed to paroxetine in the third trimester were more likely to have had more severe depression or anxiety than women in the control group). Severe maternal depression is a risk factor for poor perinatal outcomes.
156	There is evidence that withdrawal reactions are less severe when the dose is tapered gradually over a period of several weeks according to the patient’s need. Availability of low dose formulations to allow gradual titration is important.
175	It is important that patients and prescribers are aware, as appropriate, that clinical trials have not shown any additional benefit associated with increasing the dose.
177	As described in chapters 7 and 8, the EWG reviewed data on patients’ experiences from two sources: the Panorama/Mind Yellow Cards and a questionnaire sent out to individuals who contacted the MHRA about the safety of the SSRIs. As well as capturing information on withdrawal reactions and suicidal behaviour (data reviewed in chapters 7 and 8, respectively), these questionnaires also invited people to provide any additional information that they considered important about their experience.
179	Recommended change to patient information leaflet: consolidated and clarified information on how to stop; all important information on stopping Seroxat was consolidated in a dedicated section which simplified the explanation of possible effects;
180	The focus group raised many valid and important points in relation to the Seroxat PIL. The focus group also raised general concerns about accessibility and readability of the PIL. This is a matter that is currently being considered in detail by the CSM’s Working Group on Patient Information.
182	Careful and frequent patient monitoring by healthcare professionals and, where appropriate, other carers, is important in the early stages of treatment, particularly if a patient experiences worsening of symptoms or new symptoms after starting treatment.
186	Whilst placebo-controlled trials provide important information on efficacy, studies against an active comparator should be a requirement for all new antidepressants. The clinical trial protocol must have an appropriate and relevant comparator for the indication prescribed at an appropriate dose; it would be preferable if clinical experts could design a set of standard protocols which could be used in clinical trial design.