Long term side effect studies - SSRI's

[Guest guest]

Does anyone know of official published studies of the side effects

of SSRI's in long term use. By long term I mean 2 to 5 years. I

presume these have been done.

Jane

[Guest guest]

Dear Jane

I recently found this study about the long term consequences of

taking this class of drug.

To my eternal regret I took them for a number of years until as we

say here in Ireland I " wised up " ...........however I certainly have

some serious neurological damage in the form of a peripheral

neuropathy.

Again my pn symptoms cannot be blamed on any other underlying

condition, illness or vit deficiancy ..........I am most certainlt

NOT diabetic.

The consequences of my taking SSRI is that I live in constant pain

24/7 .........pain or should I say P.A.N.E.S

Regards

Persistent adverse neurological effects following SSRI

discontinuation (PANES)

..

Dr Ben Green, MRCPsych, ILTM

Consultant Psychiatrist, Halton Hospital, UK and Hon. Senior

Lecturer, University of Liverpool, UK

These prolonged reactions were first described here in Spring 2000.

No other reports are known of, although this condition may well be

more widespread than is presently recognised.

Selective serotonin reuptake inhibitor (SSRI) discontinuation

syndrome has been described in the literature as a cluster of

symptoms and signs that occur after SSRIs such as paroxetine,

sertraline and fluoxetine have been discontinued Abrupt withdrawal

of antidepressant therapy for 5-8 days is associated with symptoms

such as dizziness, ataxia, paraesthesiae, gastrointestinal and flu-

like symptoms, and other sensory and sleep disturbances. Psychiatric

symptoms include anxiety, agitation, lability of mood,

hypersexuality, crying spells, behaviour change and irritability.

The SSRI discontinuation syndrome appears to be most marked with

paroxetine and to a lesser degree sertraline, with few symptoms seen

with fluoxetine (Rosenbaum et al, 1998). The frequency and severity

of these symptoms appear to vary according to the half-life of the

SSRI (Schatzberg et al, 1997). Schatzberg et al comment that most

discontinuation symptoms rare 'short-lived', but that some effects

may be longer lasting.

Traditional explanations the pharmacology of SSRIs discuss the

effects on the postsynaptic serotonin receptor, but the SSRIs work

at a variety of locations and their effects reverberate through the

nervous and endocrine systems, so that in animal models there may be

altered neuroendocrine function for weeks after ceasing fluoxetine.

Even 60 days after discontinuation of fluoxetine, the oxytocin

response in animals was still significantly reduced by 26% compared

with controls.

Transient dystonias and dyskinesias of the jaw have presviously been

described with SSRIs (Fitzgerald & Healy, 1995). This report

considers four patients on SSRIs who all suffered prolonged

neurological symptoms for months after discontinuing their medication

Mrs A. a 29 year old married lady with a moderate depressive

disorder was switched to paroxetine by her general practitioner

after an initial prescription of dothiepin. She had found the

tricyclic dothiepin too sedating and after a week or so of this

medication requested a change. After two weeks on paroxetine 20 mg

daily she was reviewed by a consultant psychiatrist who increased

the dose to 40 mg daily. The patient suffered a dystonic reaction to

the paroxetine that required physician review and admission, but

apparently responded well to procyclidine. The paroxetine was

discontinued. Unfortunately the dystonic reaction persisted off all

medication and required further medical admission and the re-

prescription of procyclidine. The depression continued unabated and

a tricyclic was started with some improvement in mood. Seven months

after the paroxetine had been stopped the tardive dystonia was noted

to be present and to vary with anxiety levels, body posture,

alertness, and emotional state.

A 35-year-old man (Mr was prescribed paroxetine 30 mg daily for

depression. The depression resolved and the paroxetine was continued

at the same dose for two years. The medication was discontinued in a

staged way, with reductions to 20, then 10 mg, managed over six

weeks or so. Symptoms of withdrawal occurred throughout this period

and comprised vivid nightmares, lability of mood, irritability,

hypersexuality, episodic lightheadedness, episodic electric-shock

like sensations, glove paraesthesiae, and ataxia. These symptoms

ended two weeks after the withdrawal regime was finished.

Nevertheless the patient continued to describe problems of an

episodic nature well after the paroxetine had been discontinued.

These episodes lasting hours to days at a time and comprised

paraesthesiae, dizziness, mild ataxia, and slurred speech. These

episodes have occurred intermittently throughout twelve months of

follow-up during which time the patient has been drug-free. There

are no focal neurological signs or any features suggestive of

progressive neurological disease, nor was there a family history of

neurological disease.

Mrs C., a 29-year-old mother of one, became ill with depression when

her son was aged eight months. She was suicidal and required

hospital admission where she was started on fluoxetine 20 mg daily.

The antidepressant worked well and her mood was restored within four

weeks of admission. She was discharged home, but commented that her

sleep was occasionally disturbed by bad dreams and she was aware of

twitching in the bed. She was kept on the fluoxetine for a further

twelve months and at outpatient reviews mentioned that her sleep was

still occasionally disturbed by nocturnal twitching. She said that

her husband had started to sleep separately, because he was 'tired

of being kicked' in the middle of the night. The fluoxetine was

discontinued eighteen months after the admission. Mrs C described no

worsening of her mood and was euthymic and outpatient review.

However, she was distressed to report that her nocturnal twitching,

which took the form of sudden myoclonic jerks of her limbs, had

actually worsened off fluoxetine. During the day these abnormal

involuntary movements were less marked and more easily disguised,

but nonetheless problematic for the patient. At follow-up eight

months after discontinuation the untoward myoclonic jerks were

continuing. There are no focal neurological signs or any features

suggestive of progressive neurological disease, nor was there a

family history of neurological disease.

Mrs D., a 49 year old health professional was prescribed 20 mg

paroxetine daily in April 2000 for a depressive disorder. This

relieved the depression, but aftr three months the patient started

to develop paresthesiae in the right hand, and some weeks later

experienced her fingers being 'fumbly'. She visited her GP and

complained that although her mood was satisfactory there were

unpleasant side effects. He asked her to reduce the dose to 10 mg

daily. Mrs D began to experience painful, restless legs at night and

vivid dreams. The tingling in her hand spread into her body and

head. After a week of the 10 mg dose the patient discontinued the

paroxetine altogether in the belief that the paroxetine would be out

of her system in a few days and her symptoms would subside. The

symptoms however persisted. She took a week off work, but the

following symptoms persisted for the next three months:

paraesthesiae in hands and feet spreading up arms and legs

intermittently

stiffness in calf muscles

unsteadiness on her feet with wide gait

clumsy fingers

loose bowels

disinhibited mood

These symptoms appeared worst at the end of the day, following heavy

physical work,and with even small amounts of alcohol. By December,

four months after discontinuing the paroxetine most of the symptoms

had reduced in severity to near normal.

Mrs E., a 48 year old woman was prescribed citalopram by her GP for

eleven months. The indication for the prescription was chronic

anxiety. For fifteen months folowing the discontinuation of this

therapy she suffered headaches and dizziness. She also complained of

a fluttering sensation across her scalp. To date there has been

little improvement.

Discussion

These five patients all demonstrated neurological side effects or

withdrawal effects that occurred either during SSRI therapy or in

the discontinuation phase associated with an SSRI. However, these

neurological effects persisted for months after discontinuation and

in most cases persist up until the time of writing. Whether the

association with treatment or discontinuation is causal could be

debated, but the chronological association seems good and three of

the five patients (Mr B, Mrs C and Mrs D) were psychotropic drug-

naïve at the start of the SSRI therapy and wholly drug free

following this.

The three SSRIs prescribed and mentioned above (fluoxetine,

paroxetine and citalopram) differ in terms of structural and

pharmacokinetic properties, but share a relatively selective ability

to affect serotonin re-uptake. Paroxetine and citalopram have a

relatively short half-life and it may be that they are more prone to

association withe discontinuation effects and PANES.

It may be that this common ability of the SSRIs (to affect serotonin

re-uptake), or an indirect consequence of this ability is

responsible for these persistent adverse neurological effects. These

effects appear to have been first described in this report.

There is something of a similarity to the effects seen after

benzodiazepine discontinuation (Ashton, 1987). In benzodiazpine

witrhdrawal the symptoms occur 1-2 weeks after withdrawal and may

persist to some degree. Th mechanism is thought to be related to

GABA-ergic systems.

Further case reports and surveillance data are needed to establish

the significance or otherwise of what we propose to be persistent

adverse neurological effects of SSRIs (PANES).

Contact the author

Dr Ben Green, MRCPsych, ILTM,

Consultant Psychiatrist, Halton Hospital, UK and Hon. Senior

Lecturer, University of Liverpool, UK

References

Ashton, H (1987)Brain systems, disorders and psychotropic drugs.

Oxford, OUP.

Fitzgerald K, Healy, D. (1995) Dystonias and dyskinesias of the jaw

associated with the use of SSRIs. Human Psychopharmacology, 10, 215-

219.

Raap DK; F; Muma Na et al. (1999) Sustained desensitization

of hypothalamic 5-Hydroxytryptamine1A receptors after

discontinuation of fluoxetine: inhibited neuroendocrine responses to

8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in

Gi/o/z proteins. J Pharmacol Exp Ther, Feb, 288:2, 561-7.

Rosenbaum JF; Fava M; Hoog SL; Ascroft RC; Krebs WB (1998) Selective

serotonin reuptake inhibitor discontinuation syndrome: a randomized

clinical trial [see comments] Biol Psychiatry, 1998 Jul, 44:2, 77-

87.

Schatzberg AF; Haddad P; Kaplan EM et al. (1997) Serotonin reuptake

inhibitor discontinuation syndrome: a hypothetical definition.

Discontinuation Consensus panel. J Clin Psychiatry, 1997, 58 Suppl

7:, 5-10

>

>

> Does anyone know of official published studies of the side effects

> of SSRI's in long term use. By long term I mean 2 to 5 years. I

> presume these have been done.

>

> Jane

[Guest guest]

Dear Jane

I recently found this study about the long term consequences of

taking this class of drug.

To my eternal regret I took them for a number of years until as we

say here in Ireland I " wised up " ...........however I certainly have

some serious neurological damage in the form of a peripheral

neuropathy.

Again my pn symptoms cannot be blamed on any other underlying

condition, illness or vit deficiancy ..........I am most certainlt

NOT diabetic.

The consequences of my taking SSRI is that I live in constant pain

24/7 .........pain or should I say P.A.N.E.S

Regards

Persistent adverse neurological effects following SSRI

discontinuation (PANES)

..

Dr Ben Green, MRCPsych, ILTM

Consultant Psychiatrist, Halton Hospital, UK and Hon. Senior

Lecturer, University of Liverpool, UK

These prolonged reactions were first described here in Spring 2000.

No other reports are known of, although this condition may well be

more widespread than is presently recognised.

Selective serotonin reuptake inhibitor (SSRI) discontinuation

syndrome has been described in the literature as a cluster of

symptoms and signs that occur after SSRIs such as paroxetine,

sertraline and fluoxetine have been discontinued Abrupt withdrawal

of antidepressant therapy for 5-8 days is associated with symptoms

such as dizziness, ataxia, paraesthesiae, gastrointestinal and flu-

like symptoms, and other sensory and sleep disturbances. Psychiatric

symptoms include anxiety, agitation, lability of mood,

hypersexuality, crying spells, behaviour change and irritability.

The SSRI discontinuation syndrome appears to be most marked with

paroxetine and to a lesser degree sertraline, with few symptoms seen

with fluoxetine (Rosenbaum et al, 1998). The frequency and severity

of these symptoms appear to vary according to the half-life of the

SSRI (Schatzberg et al, 1997). Schatzberg et al comment that most

discontinuation symptoms rare 'short-lived', but that some effects

may be longer lasting.

Traditional explanations the pharmacology of SSRIs discuss the

effects on the postsynaptic serotonin receptor, but the SSRIs work

at a variety of locations and their effects reverberate through the

nervous and endocrine systems, so that in animal models there may be

altered neuroendocrine function for weeks after ceasing fluoxetine.

Even 60 days after discontinuation of fluoxetine, the oxytocin

response in animals was still significantly reduced by 26% compared

with controls.

Transient dystonias and dyskinesias of the jaw have presviously been

described with SSRIs (Fitzgerald & Healy, 1995). This report

considers four patients on SSRIs who all suffered prolonged

neurological symptoms for months after discontinuing their medication

Mrs A. a 29 year old married lady with a moderate depressive

disorder was switched to paroxetine by her general practitioner

after an initial prescription of dothiepin. She had found the

tricyclic dothiepin too sedating and after a week or so of this

medication requested a change. After two weeks on paroxetine 20 mg

daily she was reviewed by a consultant psychiatrist who increased

the dose to 40 mg daily. The patient suffered a dystonic reaction to

the paroxetine that required physician review and admission, but

apparently responded well to procyclidine. The paroxetine was

discontinued. Unfortunately the dystonic reaction persisted off all

medication and required further medical admission and the re-

prescription of procyclidine. The depression continued unabated and

a tricyclic was started with some improvement in mood. Seven months

after the paroxetine had been stopped the tardive dystonia was noted

to be present and to vary with anxiety levels, body posture,

alertness, and emotional state.

A 35-year-old man (Mr was prescribed paroxetine 30 mg daily for

depression. The depression resolved and the paroxetine was continued

at the same dose for two years. The medication was discontinued in a

staged way, with reductions to 20, then 10 mg, managed over six

weeks or so. Symptoms of withdrawal occurred throughout this period

and comprised vivid nightmares, lability of mood, irritability,

hypersexuality, episodic lightheadedness, episodic electric-shock

like sensations, glove paraesthesiae, and ataxia. These symptoms

ended two weeks after the withdrawal regime was finished.

Nevertheless the patient continued to describe problems of an

episodic nature well after the paroxetine had been discontinued.

These episodes lasting hours to days at a time and comprised

paraesthesiae, dizziness, mild ataxia, and slurred speech. These

episodes have occurred intermittently throughout twelve months of

follow-up during which time the patient has been drug-free. There

are no focal neurological signs or any features suggestive of

progressive neurological disease, nor was there a family history of

neurological disease.

Mrs C., a 29-year-old mother of one, became ill with depression when

her son was aged eight months. She was suicidal and required

hospital admission where she was started on fluoxetine 20 mg daily.

The antidepressant worked well and her mood was restored within four

weeks of admission. She was discharged home, but commented that her

sleep was occasionally disturbed by bad dreams and she was aware of

twitching in the bed. She was kept on the fluoxetine for a further

twelve months and at outpatient reviews mentioned that her sleep was

still occasionally disturbed by nocturnal twitching. She said that

her husband had started to sleep separately, because he was 'tired

of being kicked' in the middle of the night. The fluoxetine was

discontinued eighteen months after the admission. Mrs C described no

worsening of her mood and was euthymic and outpatient review.

However, she was distressed to report that her nocturnal twitching,

which took the form of sudden myoclonic jerks of her limbs, had

actually worsened off fluoxetine. During the day these abnormal

involuntary movements were less marked and more easily disguised,

but nonetheless problematic for the patient. At follow-up eight

months after discontinuation the untoward myoclonic jerks were

continuing. There are no focal neurological signs or any features

suggestive of progressive neurological disease, nor was there a

family history of neurological disease.

Mrs D., a 49 year old health professional was prescribed 20 mg

paroxetine daily in April 2000 for a depressive disorder. This

relieved the depression, but aftr three months the patient started

to develop paresthesiae in the right hand, and some weeks later

experienced her fingers being 'fumbly'. She visited her GP and

complained that although her mood was satisfactory there were

unpleasant side effects. He asked her to reduce the dose to 10 mg

daily. Mrs D began to experience painful, restless legs at night and

vivid dreams. The tingling in her hand spread into her body and

head. After a week of the 10 mg dose the patient discontinued the

paroxetine altogether in the belief that the paroxetine would be out

of her system in a few days and her symptoms would subside. The

symptoms however persisted. She took a week off work, but the

following symptoms persisted for the next three months:

paraesthesiae in hands and feet spreading up arms and legs

intermittently

stiffness in calf muscles

unsteadiness on her feet with wide gait

clumsy fingers

loose bowels

disinhibited mood

These symptoms appeared worst at the end of the day, following heavy

physical work,and with even small amounts of alcohol. By December,

four months after discontinuing the paroxetine most of the symptoms

had reduced in severity to near normal.

Mrs E., a 48 year old woman was prescribed citalopram by her GP for

eleven months. The indication for the prescription was chronic

anxiety. For fifteen months folowing the discontinuation of this

therapy she suffered headaches and dizziness. She also complained of

a fluttering sensation across her scalp. To date there has been

little improvement.

Discussion

These five patients all demonstrated neurological side effects or

withdrawal effects that occurred either during SSRI therapy or in

the discontinuation phase associated with an SSRI. However, these

neurological effects persisted for months after discontinuation and

in most cases persist up until the time of writing. Whether the

association with treatment or discontinuation is causal could be

debated, but the chronological association seems good and three of

the five patients (Mr B, Mrs C and Mrs D) were psychotropic drug-

naïve at the start of the SSRI therapy and wholly drug free

following this.

The three SSRIs prescribed and mentioned above (fluoxetine,

paroxetine and citalopram) differ in terms of structural and

pharmacokinetic properties, but share a relatively selective ability

to affect serotonin re-uptake. Paroxetine and citalopram have a

relatively short half-life and it may be that they are more prone to

association withe discontinuation effects and PANES.

It may be that this common ability of the SSRIs (to affect serotonin

re-uptake), or an indirect consequence of this ability is

responsible for these persistent adverse neurological effects. These

effects appear to have been first described in this report.

There is something of a similarity to the effects seen after

benzodiazepine discontinuation (Ashton, 1987). In benzodiazpine

witrhdrawal the symptoms occur 1-2 weeks after withdrawal and may

persist to some degree. Th mechanism is thought to be related to

GABA-ergic systems.

Further case reports and surveillance data are needed to establish

the significance or otherwise of what we propose to be persistent

adverse neurological effects of SSRIs (PANES).

Contact the author

Dr Ben Green, MRCPsych, ILTM,

Consultant Psychiatrist, Halton Hospital, UK and Hon. Senior

Lecturer, University of Liverpool, UK

References

Ashton, H (1987)Brain systems, disorders and psychotropic drugs.

Oxford, OUP.

Fitzgerald K, Healy, D. (1995) Dystonias and dyskinesias of the jaw

associated with the use of SSRIs. Human Psychopharmacology, 10, 215-

219.

Raap DK; F; Muma Na et al. (1999) Sustained desensitization

of hypothalamic 5-Hydroxytryptamine1A receptors after

discontinuation of fluoxetine: inhibited neuroendocrine responses to

8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in

Gi/o/z proteins. J Pharmacol Exp Ther, Feb, 288:2, 561-7.

Rosenbaum JF; Fava M; Hoog SL; Ascroft RC; Krebs WB (1998) Selective

serotonin reuptake inhibitor discontinuation syndrome: a randomized

clinical trial [see comments] Biol Psychiatry, 1998 Jul, 44:2, 77-

87.

Schatzberg AF; Haddad P; Kaplan EM et al. (1997) Serotonin reuptake

inhibitor discontinuation syndrome: a hypothetical definition.

Discontinuation Consensus panel. J Clin Psychiatry, 1997, 58 Suppl

7:, 5-10

>

>

> Does anyone know of official published studies of the side effects

> of SSRI's in long term use. By long term I mean 2 to 5 years. I

> presume these have been done.

>

> Jane

[Guest guest]

Mo

Good luck researching. This is my two cents worth, divide your

search into two categories, one is the official research which is

not likely to be very personally satisfying in terms of

understanding your own symptoms, and personal accounts from other

people in groups you can find on the net, which will probably get

you saying " yes, thats it exactly " .

Academic research - have you got a university near you? If you are

real keen a librarian in a medical library, if you can get access to

it, might help you look up medical articles. This would take hours

and days. You could always ask your doctor to get his medical reps

to get the articles for him. They will love to do this as it gives

them a reason to have access to him. (been a rep) This might be a

quick way to get the drug companies official research results.

I am new here but I found some posts here which are just as true for

my partner as for Gerties. Look up posts around the topic of SSris

affecting relationships in October I think.

I have lived with someone on ssris in high dose for two years and

you can run your symptoms past me if you like. Ive got good at

recognising them in partner and in other friends on SSRI's. Not sure

how to make direct contact with you, can give you my email if you

like and you think it might not interest others here. The drugs

give " lack of insight " we found so symptoms are less obvious to self

than partners or others.

By the way, I think ssri's can have possibly permanent after effects.

I am quite happy to go on for ages about what symptoms were and I am

quite happy to hear about yours.

Jane

> Snap! I am, as we speak, trying to get this information also. My

angle is to

> try and differentiate between my existing hepatitis c symptoms and

my current

> (tapering) and past use of SSRIs.

> Any help, insight would be greatly appreciated as research is not

my forte

> and I am not terribly computer literate.

>

> Thanks in advance.

>

> Mo

>

>

>

[Guest guest]

Mo

Good luck researching. This is my two cents worth, divide your

search into two categories, one is the official research which is

not likely to be very personally satisfying in terms of

understanding your own symptoms, and personal accounts from other

people in groups you can find on the net, which will probably get

you saying " yes, thats it exactly " .

Academic research - have you got a university near you? If you are

real keen a librarian in a medical library, if you can get access to

it, might help you look up medical articles. This would take hours

and days. You could always ask your doctor to get his medical reps

to get the articles for him. They will love to do this as it gives

them a reason to have access to him. (been a rep) This might be a

quick way to get the drug companies official research results.

I am new here but I found some posts here which are just as true for

my partner as for Gerties. Look up posts around the topic of SSris

affecting relationships in October I think.

I have lived with someone on ssris in high dose for two years and

you can run your symptoms past me if you like. Ive got good at

recognising them in partner and in other friends on SSRI's. Not sure

how to make direct contact with you, can give you my email if you

like and you think it might not interest others here. The drugs

give " lack of insight " we found so symptoms are less obvious to self

than partners or others.

By the way, I think ssri's can have possibly permanent after effects.

I am quite happy to go on for ages about what symptoms were and I am

quite happy to hear about yours.

Jane

> Snap! I am, as we speak, trying to get this information also. My

angle is to

> try and differentiate between my existing hepatitis c symptoms and

my current

> (tapering) and past use of SSRIs.

> Any help, insight would be greatly appreciated as research is not

my forte

> and I am not terribly computer literate.

>

> Thanks in advance.

>

> Mo

>

>

>

[Guest guest]

Mo

Good article. Do you have any legal or insurance consequences of

your side effects or are you only interested for your health sake?

This is a report of problems by a doctor but I wonder if the drug

companies have done clinical trials over years (and then published

them) I guess they wouldnt want to find problems.

Sounds like you have what these others had only you have Pain as

well. Do you mind telling more of your symptoms? How many years

were you on SSRI's ?

We found that even though there seem to be long term consequences

there is nothing to be done about it. But pain is differnt, you

cant just get on with it so easily.

Is anything like this a result of Hep C (which I dont know anything

about, but I guess it is unlikely)

Jane

> >

> >

> > Does anyone know of official published studies of the side

effects

> > of SSRI's in long term use. By long term I mean 2 to 5 years.

I

> > presume these have been done.

> >

> > Jane

[Guest guest]

Mo

Good article. Do you have any legal or insurance consequences of

your side effects or are you only interested for your health sake?

This is a report of problems by a doctor but I wonder if the drug

companies have done clinical trials over years (and then published

them) I guess they wouldnt want to find problems.

Sounds like you have what these others had only you have Pain as

well. Do you mind telling more of your symptoms? How many years

were you on SSRI's ?

We found that even though there seem to be long term consequences

there is nothing to be done about it. But pain is differnt, you

cant just get on with it so easily.

Is anything like this a result of Hep C (which I dont know anything

about, but I guess it is unlikely)

Jane

> >

> >

> > Does anyone know of official published studies of the side

effects

> > of SSRI's in long term use. By long term I mean 2 to 5 years.

I

> > presume these have been done.

> >

> > Jane