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Selective Serotonin Re-uptake Inhibitors (SSRI)

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    Selective Serotonin Re-uptake Inhibitors

    International Programme on Chemical Safety
    Poisons Information Monograph G011
    Pharmaceutical

    This Monograph contains the following sections:
    1. Name, 2. Summary, 3. Physico-chemical properties ,
    7.1 Mode of Action, 9.Clinical Effects, 10.Management,
    11.1 Case reports from the literature, 12.2 Other.

    See also individual Monographs on Fluoxetine (PIM651) and Sertraline
    (PIM177) for further information.

    1.  NAME

        1.1  Substance

             Selective Serotonin Re-uptake Inhibitors

        1.2  Group

             The members of this group contain:

             alaproclate; citalopram;
             fluoxetine; fluvoxamine;
             paroxetine; sertraline;
             zimeldine

        1.3  Synonyms

             SSRI

             Citalopram:     nitalapram
             Zimeldine:      zimelidine

        1.4  Identification numbers

             1.4.1  CAS number

                    Alaproclate hydrochloride     60719-83-7
                    Citalopram                    59729-33-8
                    Citalopram hydrobromide       59729-32-7
                    Fluoxetine                    54910-89-3
                    Fluoxetine hydrochloride      59333-67-4
                    Fluvoxamine                   54739-18-3
                    Fluvoxamine maleate           61718-82-9
                    Paroxetine                    61869-08-7
                    Paroxetine hydrochloride      78246-49-8
                    Sertraline                    79617-96-2
                    Sertraline hydrochloride      79559-97-0
                    Zimeldine                     56775-88-3
                    Anhydrous zimeldine dihydrochloride     60525-15-7
                    Zimeldine dihydrochloride monohydrate   61129-30-4

             1.4.2  Other numbers

                    ATC Classification:
                    Psychoanaleptic, antidepressant, selective
                    serotonin reuptake inhibitor: N06AB


        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             When taken alone Selective Serotonin Re-uptake
             Inhibitors (SSRIs) appear safer in overdose than most other
             classes of antidepressants.
             They are potent inhibitors of serotonin re-uptake by central
             nervous system neurones and may interact with other drugs or
             circumstances which cause serotonin release. The enhancement
             of the serotonergic effects may produce a life-threatening
             serotonin syndrome.
             Drugs which can increase the serotonin level when taken in
             combination with SSRIs include: tricyclic antidepressants,
             monoamine oxidase inhibitors (MAOIs), carbamazepine, lithium
             or serotonergic substances.

        2.2  Summary of clinical effects

             Drowsiness, tremor in upper extremities, lightheadness,
             nausea, vomiting are the most common symptoms. Other symptoms
             include: tachycardia (occasionally bradycardia),
             hypo/hypertension, dilated pupils, agitation, dry mouth and
             sweating.
             Coma and convulsions may occur in large overdoses.
             They are much less cardiotoxic than the conventional
             antidepressants, though citalopram has caused nodal rhythm,
             QT and QRS prolongation.
    
             The combination of SSRIs with agents that increase serotonin
             availability in the central nervous system can cause the
             serotonin syndrome which is characterised by the presence of
             at least 3 of the following symptoms: mental status changes
             (confusion, hypomania), agitation, myoclonus, hyperreflexia,
             sweating, shivering, tremor, diarrhoea, motor incoordination,
             muscle rigidity and fever. Severe complications may occur,
             including: severe hyperthermia, rhabdomyolysis, disseminated
             intravascular coagulation (DIC), convulsions, respiratory
             arrest and death.

        2.3  Diagnosis

             Diagnosis of SSRIs poisoning is clinical and based on
             history of overdosssive supportive care including diazepam,
             mechanical ventilation, external cooling and if necessary,
             curarization.


        2.4  First aid measures and management principles

             Treatment is symptomatic and supportive, with diazepam
             for sedation if necessary. Cardiac monitoring is recommended
             in symptomatic cases.
             If the patient presents within 2 hours, a dose of activated
             charcoal should be given (50g in adults; 1g/kg in children).
             Observation for 6 hours is recommended.
             Treatment of the serotonin syndrome in more severe
             intoxications or where there is a co-ingestion may require
             more aggressive measures such as establishment of an airway,
             ventilation, administration of intravenous fluids, control of
             seizures, and control of hyperthermia may be necessary.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

        3.2  Chemical structure

             See individual Monographs for Fluoxetine and Sertraline.
    
             Citalopram

             Chemical names:
             1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-
             isobenzofurancarbonitrile;
             1-[3-(dimethylamino)propyl]-1-(4- fluorophenyl)- 5-
             phthalancarbonitrile;
    
             Molecular formula Citalopram: C20H21FN2O
             Molecular  weight Citalopram: 324.40.
             Molecular formula Citalopram Hydrobromide: C20H21FN2O.HBr
    
             Fluvoxamine
    
             Chemical names:
             (E)-5-Methoxy-1-[4-(trifluoromethyl)phenyl]-1-pentanone O-(2-
             aminoethyl)oxime;
             5-methoxy-4'-(trifluoromethyl)valerophenone (E)-O-(2-
             aminoethyl)oxime
    
             Molecular formula Fluvoxamine: C15H21F3N2O2
             Molecular  weight Fluvoxamine:  318.34
             Molecular Fluvoxamine Maleate C15H21F3N2O2.C4H4O4,
    
             Paroxetine
    
             Chemical names:
             (3S-trans)-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-
             fluorophenyl) piperidine;
             (-)-trans-4-(p-fluorophenyl)-3-[[3,4 (methylenedioxy)
             phenoxy] methyl]piperidine;
    

             Molecular formula Paroxetine: C19H20FNO3;
             Molecular  weight Paroxetine: 329.37.
             Molecular formula Paroxetine Hydrochloride: C19H20FNO3.HCl
             Molecular formula Paroxetine Hydrochloride hemihydrate:
                                            C19H20FNO3.HCl. 1/2 H2O
    
             Zimeldine
    
             Chemical names:
             (Z)-3-(4-Bromophenyl)-N,N-dimethyl-3-(3-pyridinyl)-2-propen-
             1-amine;
             (Z)-3-(4'-bromophenyl)-3-(3''-pyridyl)dimethylallylamine;
    
             Molecular formula Zimeldine: C16H17BrN2;
             Molecular  weight Zimeldine: 317.23.
             Molecular formula Zimeldine dihydrochloride monohydrate:
                    C16H17BrN2.2HCl.H2O

        3.3  Physical properties

             3.3.1  Colour

             3.3.2  State/Form

             3.3.3  Description

                    Citalopram hydrobromide
                    Melting point: 182 to 183C
    
                    Fluvoxamine Maleate
                    Melting point 120 to 121.5C
    
                    Paroxetine Hydrochloride
                    Melting point 118C
    
                    Paroxetine Hydrochloride hemihydrate
                    melting point 129 to 131C
    
                    Zimeldine dihydrochloride monohydrate
                    melting point 193C
    
                    (Budavari, 1996)

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions


    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    SSRIs are used in the treatment of depression.
                    They are also used in panic disorder, obsessive
                    compulsive disorder and bulimia nervosa.

        4.2  Therapeutic dosage

             4.2.1  Adults

             4.2.2  Children

        4.3  Contraindications

    5.  ROUTES OF EXPOSURE

        5.1  Oral

        5.2  Inhalation

        5.3  Dermal

        5.4  Eye

        5.5  Parenteral

        5.6  Other

    6.  KINETICS

        6.1  Absorption by route of exposure

        6.2  Distribution by route of exposure

        6.3  Biological half-life by route of exposure

        6.4  Metabolism

        6.5  Elimination and excretion



    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    SSRIs are potent inhibitors of serotonin
                    re-uptake by central nervous system neurones and may
                    interact with other drugs or circumstances which cause
                    serotonin release. The enhancement of the serotonergic
                    effects may produce a life-threatening serotonin
                    syndrome.
                    SSRIs can inhibit in vitro and in vivo the hepatic
                    isoenzyme 2D6 of the cytochrome P450 system (CYP2D6),
                    which is involved in the oxidative metabolism of
                    numerous drugs. Caution should be used when combining
                    a SSRI with CYP2D6 substrates (desipramine,
                    nortriptyline, haloperidol, thioridazine, flecainide, 
                    codeine, propranolol, metoprolol), as the SSRI can
                    cause a significant increase in the serum
                    concentrations of these drugs.

             7.1.2  Pharmacodynamics

                    SSRIs specifically inhibit central nervous
                    system neuronal re-uptake of serotonin, thus
                    increasing the concentration of the serotonin at the
                    synapse and enhancing of serotonergic neuronal
                    transmission. A deficiency of serotonin is thought to
                    play a major role in depression, therefore increasing
                    the availability of serotonin would be expected to
                    improve the clinical signs of depression.
                    SSRIs have no direct effect on the re-uptake of
                    noradrenaline, dopamine or GABA. Unlike tricyclic
                    antidepressants, they have no significant affinity for
                    alpha1-adrenergic, H1-histamine, and muscarinic
                    receptors. The selectivity of SSRIs may account for
                    the lower incidence of some adverse effects such as
                    sedation, orthostatic hypotension, and anticholinergic
                    effects.

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                    7.2.1.2  Children

             7.2.2  Relevant animal data


             7.2.3  Relevant in vitro data

        7.3  Carcinogenicity

        7.4  Teratogenicity

        7.5  Mutagenicity

        7.6  Interactions

             Co-administration of drugs increasing the level of
             serotonin: tricyclic antidepressants, MAOIs, reversible
             inhibitors of monoamine oxidase, lithium, may cause a
             serotonin syndrome.
             A minimum 2 week wash-out period should be observed between
             stopping a monoamine oxidase inhibitor (MAOI) and starting a
             SSRI. Conversely, a MAOI should not be started for at least a
             week after a SSRI has been stopped (at least 5 weeks for
             fluoxetine; at least 2 weeks for paroxetine and
             sertraline.

        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses


             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine
                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"


                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses
                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their 
             interpretation

        8.5  Overall interpretation of all toxicological analyses and 
             toxicological investigations

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Nausea, vomiting, abdominal pain, diarrhea,
                    tremor, confusion, agitation, drowsiness, blurred
                    vision, and in rare cases, seizures and coma.
                    Significant cardiovascular toxicity is unusual (except
                    citalopram). Effects have included mild hypo or
                    hypertension, tachycardia and ventricular
                    dysrrhythmia.
                    More serious toxicity may be expected with the
                    co-ingestion of tricyclic antidepressants and/or MAOIs
                    and may result in a life-threatening serotonin
                    syndrome.

             9.1.2  Inhalation

                    Not relevant

             9.1.3  Skin exposure

                    Not relevant

             9.1.4  Eye contact

                    No data

             9.1.5  Parenteral exposure

                    No data


             9.1.6  Other

                    No data

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    A case of sertraline abuse has been reported
                    with high doses, almost daily, for a period of 6
                    months. Effects include: relaxation, euphoria, then
                    intense excitement, marked tremor and visual and
                    auditory hallucinations.

             9.2.2  Inhalation

                    Not relevant

             9.2.3  Skin exposure

                    Not relevant

             9.2.4  Eye contact

                    Not relevant

             9.2.5  Parenteral exposure

                    Not relevant

             9.2.6  Other

                    Not relevant

        9.3  Course, prognosis, cause of death

             Pure SSRIs overdoses usually have a fairly benign
             course. However, a few deaths are reported in the literature,
             most involving a co-ingestion and/or very high doses.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Significant cardiovascular toxicity is unusual.
                    Effects have included mild hypo or hypertension,
                    tachycardia and ventricular dysrrhythmia (citalopram).

             9.4.2  Respiratory

                    No data


             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Drowsiness, headache, restlessness,
                             delirium, insomnia, ataxia, extrapyramidal
                             syndrome, coma and convulsions.

                    9.4.3.2  Peripheral nervous system

                             Blurred vision.

                    9.4.3.3  Autonomic nervous system

                             Hypotension, hypertension,
                             tachycardia, profuse sweating.

                    9.4.3.4  Skeletal and smooth muscle

                             Myoclonus, hyperreflexia.

             9.4.4  Gastrointestinal

                    Nausea, vomiting, diarrhea

             9.4.5  Hepatic

                    Mild liver enzyme disturbances.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data

                    9.4.6.2  Other

                             No data

             9.4.7  Endocrine and reproductive systems

                    Hyperglycemia

             9.4.8  Dermatological

                    Pruritus, rashes, urticaria have been reported

             9.4.9  Eye, ear, nose, throat: local effects

             9.4.10 Haematological

                    No data

             9.4.11 Immunological

                    Skin rashes have been reported

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data

                    9.4.12.3 Others

                             No data

             9.4.13 Allergic reactions

                    No dara

             9.4.14 Other clinical effects

                    No data

             9.4.15 Special risks

        9.5  Other

             SSRI can cause adverse effects after withdrawal, either
             from a reduction in dosage or from the abrupt cessation of
             the drug. The most frequent symptoms include vertigo,
             dizzines, paresthesia (shock-like sensations, tingling and
             burning sensations); less frequent symptoms include
             irritability, anxiety, headache, orthostatic hypotension,
             sleep disturbances. The symptoms usually occur within 48
             hours after stopping the SSRI and they last about 2 weeks.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The primary management of SSRI overdose consists of the
             institution of careful observation of vital signs and
             neurological status and supportive care until signs and
             symptoms resolve.

             In more severe intoxications or where there is a
             co-ingestion, more aggressive measures such as establishment
             of an airway, ventilation, administration of intravenous
             fluids, control of seizures, and control of hyperthermia may
             be necessary.

        10.2 Life supportive procedures and symptomatic/specific 
             treatment

             In pure SSRI overdoses, intensive supportive care is
             rarely required. Measures that may be required based on the
             clinical presentation include: endotracheal intubation and
             assisted ventilation if coma is present, intravenous fluid
             resuscitation if hypotension is present, pharmacological
             control of seizures, cooling if hypirthermia is
             present.

        10.3 Decontamination

             Gastrointestinal decontamination by administration of a
             single oral dose of activated charcoal may be indicated.
             Gastric lavage followed by activated charcoal should be
             advocated in patients who have ingested large doses and/or
             when there has been a significant co-ingestion.

        10.4 Enhanced elimination

             There are no effective method known to enhance elimination.

        10.5 Antidote treatment

             10.5.1 Adults

                    There is no antidote

             10.5.2 Children

                    There is no antidote

        10.6 Management discussion

             No prospective studies have been performed to evaluate
             the treatment of the serotonin syndrome, and treatment
             strategies are primarily based on case reports. Non specific
             serotonin receptor antagonists such as methysergide and
             cyproheptadine have been used successfully. Propranolol which
             blocks serotonin 1A receptors has also been used.
             Benzodiazepines can reduce the muscular rigidity. Dantrolene
             which is a direct skeletal muscle relaxant has also been
             found to be useful. The efficacy of these agents has yet to
             be evaluated.


    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             In 12 patients taking 10 to 100mg fluoxetine a day with
             either phenelzine (30 to 60mg) or tranylcypromine (10 to
             140mg), there was a high incidence (25 to 50%) of adverse
             effects.  These included hypomania, racing thoughts,
             agitation, restlessness, confusion, myoclonus, hypertension,
             tremor and diarrhoea (Feighner et al., 1990).
    
             3 male patients aged 29, 34 and 41 died after taking
             overdoses of moclobemide and citalopram concomitantly
             (Neuvonen et al., 1993).

    12. Additional information

        12.1 Specific preventive measures

             No data

        12.2 Other

             Useful references on the SSRIs:
    
             Alderman CP & Cheum Lee P (1996) Serotonin syndrome
             associated with combined sertraline-amitriptyline therapy.
             Ann Pharmacother, 30: 1499-1500
    
             Amsden GW & Georgian F (1996) Orthostatic hypotension induced
             by sertraline withdrawal. Pharmacotherapy, 16 (4): 684-686
    
             Brown DF & Kerr HD (1994) Serttraline overdose. Ann
             Pharmacother, 28: 1307
    
             Caracci G (1994) Unsuccessful suicide attempt by sertraline
             overdose. Am J Psychiatry, 151:147
    
             Coupland NJ, Bell CJ, Potokar JP (1996) Serotonin reuptake
             inhibitor withdrawal. J Clin Pharmacol, 16: 356-362
    
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)

    Author:  Medical Toxicology Unit,
             Guys and St Thomas Trust
             Avonley Road, London SE14 5ER, UK
    
             November, 1997
    
    Reviewers:      R Ferner, A van Heijst, M Mathieu-Nolf, MO Rambourg
                    Schepens (coordinator)
    
                    London, March, 1998
    
    Editor:         Dr M.Ruse, September 1998
    


    See Also:
       Toxicological Abbreviations