Annotation
British Journal of Psychiatry (1992), 161, 735—741
Fluoxetine and Suicidal Behaviour Some Clinical and Theoretical
Aspects of a Controversy
A. C. POWER and P. J. COWEN
“¿In the practical decisions of life it will scarcely ever be possible to go through all the arguments in favour of or against one possible decision, and one will therefore always have to act on insufficient evidence― Werner Heisenberg (1962).
The development of selective serotonin (5-hydroxy tryptamine, 5-HT) reuptake inhibitors (SSRIs) has added a new dimension to the pharmacotherapy of depression. Their lack of sedative and anticholinergic effects together with relative safety in overdose, has led some authors to suggest that the older tricyclic antidepressants (TCAs) should not now be considered a first-line treatment (Montgomery, 1988). However, since a report by Teicher et a! (1990) of suicidal preoccupation associated with fluoxetine treatment, there has been both intense media interest and animated correspondence in clinical and scientific journals (O'Donnell, 1991). The view that an SSRI like fluoxetine could exacerbate suicidal thinking and behaviour is at variance with current biochemical formulations of affective disorder, which suggest that suicidal patients are particularly likely to have evidence of decreased brain 5-HT function (see Golden et a!, 1991). In addition, studies in animals, and some in humans, indicate that decreased brain 5-HT function may be associated with impulsive and aggressive behaviour (Katz, 1980; van Praag, 1991), and that drugs which .nhance this function may inhibit various aggressive ‘¿ts (Lindgren & Kantak, 1987; Cowen, 1990). Several reviews have concluded that the balance evidence is not in favour of an association between @Iuoxetine and the emergence of suicidal ideation @Baldwin et a!, l991a; Mann & Kapur, 1991; Consumers' Association, 1992), but disquiet remains among clinicians. One recent correspondent to the American Journal of Psychiatry caustically remarked: “¿When one of my patients killed himself years ago the lawyers blamed not imipramine but me. I regret that fluoxetine was not available then―(Balon, 1991). Clinical studies Anecdotal accounts Teicher et a! (1990) described six cases of intense suicidal preoccupation two to seven weeks after the 735
start of fluoxetine therapy. Their cases were complex diagnostic problems: in association with major depressive disorder, cases 4 and 5 had concomitant diagnoses of borderline personality disorder, case 6 had a diagnosis of multiple personality disorder, case 3 had associated bulimia, paranoia, agoraphobia, and dissociation, while case 2 had a 21-year history of dysthymia. Only case 1 had a relatively uncomplicated diagnosis of major depression with melancholia. All except case 2 had previous suicidal ideation or gestures, and all had experienced previous multiple treatment regimes. Three patients were started on fluoxetine two weeks after ceasing to take monoamine oxidase inhibitors (MAOIs), and four appeared to develop suicidal ideation in association with akathisia; all could have been considered non-responders to fluoxetine. These complicating factors have made it difficult to interpret a specific relationship between fluoxetine and the emergence of suicidal ideation in Teicher's cases (Berkley, 1990; Tollefson, 1990; Mann & Kapur, 1991). Nevertheless, further case reports have followed. Masand eta! (1991) reported two depressed patients, in one of whom the suicidal ideation occurred ten days after a gradual increase in the dose of fluoxetine from 20 mg to 60 mg, associated with akathisia. In the second case, suicidal ideation occurred on 20 mg. In both, the onset of suicidal ideation occurred within one week and ceased within ten days of stopping treatment. Dasgupta (1990) reported a patient with depressive symptoms and persistent pelvic pain (thought to be partially psychogenic in origin) who developed intense suicidal ideation and attempted suicide by carbon monoxide poisoning, four weeks after starting 20 mg of fluoxetine daily. Creaney et al (1991) reported a further case of suicidal ideation and behaviour associated with fluoxetine that may have been linked to the development of a dissociative state. The most convincing anecdotal evidence linking fluoxetine and suicidal behaviour is provided by the three depressed cases reported by Rothschild & Locke (1991); all three developed severe akathisia and attempted suicide while taking fluoxetine alone in daily doses of 40mg (1 case) or 60mg (2 cases). The Thie
One
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CEQ9-SBZ-TP7A
736
POWER & COWEN
attempts occurred within a week of an increase in the dose in each case. When the patients were rechallenged with fluoxetine, the akathisia and suicidal ideation returned, but in two cases, this remitted when the akathisia was treated with propranolol; in the third, the suicidal ideation and akathisia disap peared within 72 hours of discontinuing fluoxetine.
Wirshing et a! (1992) reported five further patients who developed akathisia and suicidal ideation during
criticised becauseof thelow incidence of suicidal gestures in the placebo-treated group (Oswald, 1991), and for lack of sensitivity in measuring suicidal ideation using item 3 of the Hamilton Rating Scale for Depression (Healy & Creaney, 1991). Two other meta-analyses have been reported from these laboratories. One (Beasleyeta!, 1992)concerned suicidal
ideation
in patients
receiving
fluoxetine
Fava & Rosenbaum (1991) surveyed 27 practising
(20—60mgdaily) (n = 266) or placebo (n = 89) in con trolled studiesof obsessive-compulsivedisorder. Judged by ratings on item 3 of the Hamilton scale, pre-existing suicidal ideation worsened significantly more in patients receiving placebo(14.8%)thanin those receiving fluoxetine (4.6%),and theincidence of emergent suicidal ideation did not differ significantly between the groups. Interestingly, however, the three patients whose emergent suicidal ideation was noted clinically as an adverse event during the double-blind
psychiatrists
with
trials were all taking fluoxetine (60mg daily). A third
antidepressants during 1989, and found that the percentages of patients who became suicidal only after treatment with antidepressants was initiated were: 3.5°lo for those taking fluoxetine alone; 6.5% for those treated with fluoxetine in combination with TCAs; and 1.3% for those treated with TCAs alone or in combination with lithium. The difference in incidence of suicidal ideation was not significant between those treated with fluoxetine alone and those receiving the other antidepressants, but a statistically significant difference was found between new-onset
analysis examined the incidence of aggressivebehaviour in patients receiving fluoxetine in a range of doses (5-80mg daily) for a variety of indications, including depression, obesity, and alcoholism (Heiligenstein
fluoxetine treatment: in three, their symptoms were associated with an increase in dose from 20mg to
40mg daily, and in two cases, treatment benzodiazepines relieved symptoms.
with
Retrospective survey
suicidality
who had treated
1017 patients
in the group taking the combination
of
tncycics and fluoxetine, compared with the group receiving tricyclics alone or in combination with lithium. However, Brewerton (1991) reanalysed the data from this study. He regrouped the patients into those receiving fluoxetine (with or without TCAs) and those receiving other antidepressant treatments, fmding a significantly higher frequency of new-onset suicidality in the fluoxetine (2.77%) versus the non fluoxetine group (0.75%).
Controlled clinical trials Workers at Lilly Research Laboratories carried out a meta-analysis on pooled data from 17 double-blind trials in depressed patients (Beasley eta!, 1991). They found that the emergence of substantial suicidal ideation was 1.2% for fluoxetine (n = 1765), 2.6% for placebo (n = 569), and 3.6% for TCAs (n = 735);
the incidence with fluoxetine was significantly less than with either placebo or TCAs. There was no significant difference between the three groups in worsening of pre-existing suicidal ideation or in the number of suicidal acts. The meta-analysis has been
et a!, unpublished). In some studies, fluoxetine had been compared with placebo, and in others with TCAS.
Overall, patients receiving fluoxetine (n = 2615) were significantly less likely to experience an adverse event suggestive of aggression than those receiving placebo (n=1377)(0.l5%v.0.65°lo). Two othercontrolled studies indepressed patients haveexaminedtheeffect of fluoxetine on suicidal ideation. Muijeneta!(1988)foundthatsuicidal feelings were reduced more in patients receiving fluoxetine than in those having mianserin or placebo. Sacchetti eta!(1991) foundthatclomipramine and fluoxetine (both drugswithsignificant 5-HTreuptake blocking actions) were superior to desipramine and nortriptyline in the treatment of depressed patients with a history of suicide attempts. Studies with other SSRIshavealsosuggested thatthesedrugsmay be more effective than standardantidepressants in decreasing suicidal ideation indepressed patients, but the data are not consistent (Mann & Kapur, 1991). Conclusions from clinical trials Neither the controlled trials with fluoxetine nor the combinedmeta-analysis ofBeasley eta!(1991) offer support for the hypothesis that fluoxetine predisposes to the emergence or worsening of suicidal ideation or behaviour in depressed patients. It is possible, how ever, that even large controlled investigations may fail to detect rare but clinically important adverse events. In addition, the conditions that obtain during con trolled trials often differ from those of routine clinical
FLUOXETINE AND SUICIDAL BEHAVIOUR practice. For example, various groups of depressed patients, including those at high risk of self-harm, those who have not responded to other antidepressant drugs, and those with additional psychiatric diagnoses make up a substantial proportion of psychiatric practice but may well be excluded from trials of anti depressant drugs. Furthermore, while in clinical trials the use of concomitant psychotropic medication is strictly controlled, in routine clinical practice patients with complex psychiatric problems often receive more than one class of psychotropic agent, increasing the risk of adverse events through drug interaction. Taken together, the anecdotal accounts reviewed above provide some evidence that rare adverse reactions involving suicidal ideation and behaviour may occur during fluoxetine treatment. The most consistent factor implicated in these adverse reactions has been the development of akathisia with agitation, restlessness, and dysphoria. While akathisia is most commonly caused by neuroleptics, different classes of antidepressant drugs (including SSRIs) have occasionally been implicated in this syndrome (Zubenko eta!, 1987; Lipinski eta!, 1989; Baldwin et a!, l99lb). Importantly, akathisia is known to be associated with a state of severe subjective distress, which some patients find intolerable. There are, for example, reports of serious suicidal and aggressive behaviour in the setting of neuroleptic induced akathisia (van Putten, 1975; Shear et a!, 1983; Drake & Ehrlich, 1985; Sachdev & Loneragan, 1991). Depressed patients who experience increasing agitation and dysphoria may understandably attribute
this to worsening of their illness rather than to a side effect of medication; despair may result.
increasing
hopelessness
and
737
the knowledge that 5-HT pathways express multiple 5-HT receptor subtypes, which respond differentially to the repeated administration of antidepressant drugs
(Cowen, 1991).The function of some of these receptor subtypes in the human brain can be assessed by neuro endocrine challenge tests; these reveal that repeated administration of SSRIs produces a sustained increase in neurotransmission at post-synaptic 5-HTIA recep tors which is similar to but somewhat greater than the effect of TCAs (Fig. 1) (Charney eta!, 1984; Cowen, 1988; Price et a!, 1989). In contrast, fluoxetine but not TCAs increases the cortisol response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP) (Meltzer, 1990), which is, in part, a measure of neurotransmission at post-synaptic 5-HT2 receptors (Lee et a!, 1991). The lack of effect of TCAs on 5-HTP-induced cortisol release is probably attributable to their ability to competitively block and downregulate post synaptic 5-HT2 receptors (Peroutka & Snyder, 1980; Goodwin et a!, 1984): this action presumably out weighs any increase in 5-HT neurotransmission that might be achieved by their moderate inhibition of presynaptic 5-HT uptake. In contrast, SSRIs lack 5-HT2 receptor antagonist properties, and although some animal studies suggest that post-synaptic 5-HT2 receptor down-regulation occurs during repeated SSRI treatment (see Johnson, 1991), the net effect of SSRI administration in humans may well be to increase 5-HT2 neurotransmission.
The 5-HT-mediated behavioural syndrome In animals, large increases in brain 5-HT function produced by a non-selective MAO! and a 5-HT
A number of the adverse reactions to fluoxetine in the published reports noted above have occurred after a comparatively brief period of withdrawal from MAOIs, and some authors have proposed that previous MAOI treatment may predispose patients to the development of agitation when fluoxetine is introduced (Berkley, 1990; Brewerton, 1991). It has been pointed out that combination of SSRIs with MAOIs has been reported to produce a 5-HT toxicity syndrome, which includes features such as agitation and restlessness (Feighner et a!, 1990; Sternbach,
C U a) 0 C
a) a)
a) U C
1991). Below, we briefly review the effect of SSRIs on brain 5-HT function and attempt to relate this to the pharmacology of the 5-HT syndrome and akathisia.
SSRIs,5-HT toxicity and akathisia Effects of SSRIs on brain 5-HT function Descriptions of the effects of psychotropic drugs on brain 5-HT function have now to be reconciled with
0
5-HT uptake blockade
Fig. 1 The mean @10 increase in prolactin response to L-tryptophan (a 5-HTIA receptor-mediated response) produced by repeated administration of mianserin (MIAN), desipramine (DM1), ami triptyline (AM!) and fluvoxamine (FLUVOX) in depressed patients. The increase in prolactin response correlates with ability of the antidepressant to inhibit the uptake of 5-HT.
POWER & COWEN
738
precursor or a MAO! and a SSRI causea 5-HT behavioural syndrome consisting of hyperactivity, stereotyped movements, and increased core tempera ture (Grahame-Smith, 1971; Marley & Wozniak, 1984). An analogous syndrome with myoclonus, agitation, affective change and confusion is believed to underlie the toxic reactions that have been reported with MAOIs and fluoxetine in humans (Feighner eta!,1990). 5-HT toxicity hasalsobeen reported following combinations of fluoxetine and the 5-HT precursor L-tryptophan, where agitation, restlessness, and aggression have been described (Steiner & Fontaine, 1986). Lithium facilitates brain 5-HT neurotransmission (Cowen et a!, 1991), and while lithium and SSRIs can often be combined to good therapeutic effect, there are occasional reports of 5-HT neurotoxicity developing withthis drugcombi nation (Committee on Safety of Medicines, 1989). Studies in rats suggest that the 5-HT behavioural syndrome is produced predominantly by activation of post-synaptic 5-HT1Areceptors, but that certain aspects of the syndrome are facilitated by simul taneous stimulation of 5-HT2 receptors (Glennon eta!, 1991). The facility with which SSRIs produce a
5-HT toxicity syndrome in combination with MAOIs and other 5-HT-enhancing drugs could therefore reflect two factors: (a) particularly potent 5-HT uptake blockade, and (b)an ability to increase both 5-HT1A and 5-HT2 neurotransmission (see above). Interestingly, it seems that hyperthermia, which is one of the most serious complications of the 5-HT toxicity syndrome, is likely to be mediated by 5-HT2 receptor stimulation (Gudelsky eta!,1986). In rats, the beta-adrenoceptor antagonist pro panolol abolishes the 5-HT behavioural syndrome through blockade of post-synaptic 5-HT1Areceptors, for which it has a high affinity (Hoyer, 1988).Interest ingly, propanolol abolishes 5-HT-mediated behaviour, whether this is induced by selective 5-HT1Areceptor agonists or agonists with combined actions on 5-HT1A and 5-HT2 receptors (Goodwin & Green, 1985). Propanolol has also been reported to be of benefit in the management of the 5-HT toxicity syndrome in humans, but this has not been studied
receive a significant 5-HT innervation from the raphe nuclei (Parent eta!, 1981). The interaction between ascending 5-HT pathways and dopamine systems is complex and not fully understood. However, there is evidence that certain 5-HT neurons are inhibitory to dopamine cell firing (see Baldessarim eta!, 1992); therefore, increases in brain 5-HT function, produced
for example by an SSRI, would be expected to decrease dopamine neurotransmission in mesocortical regions. This could predispose to the development of akathisia (Lipinski et a!, 1989). The 5-HT2 receptor antagonist ritanserin increases dopaminergic cell firing in the ventral tegmental area (Ugedo et a!, 1989), suggesting that the inhibitory effects of 5-HT in this brain region may be mediated by 5-HT2 receptors. From this, it might be expected that SSRIs would be associated with a higher frequency of akathisia than TCAs, because SSRI treatment is more likely to activate 5-HT2 receptors (see above). Whether this is in fact the case, though, is not clear from the current literature (Lipinski eta!, 1989; Baldwin eta!, 1991b), and this is therefore an area where further clinical studies are needed. In addition, studies in rodents do not reveal consistent
effects of fluoxetine on dopamine
metabolism (Baldessarmni et a!, 1992). It would, however, be of interest to study the effects of SSRI treatment on extrapyramidal function anddopamine neurotransmission indepressed patients. Propanolol isrecognised tobeauseful treatment in neuroleptic-induced akathisia, although its mechanism ofaction hasbeendebated (Adler eta!, 1986; Sachdev & Loneragan,1991). We proposethatfluoxetine induced akathisia may represent a form of 5-HT toxicity, and that the efficacy of propanolol in this setting, asinthe5-HT behavioural syndrome, isdue toblockade of5-HTreceptors. Whether5-HTreceptor blockade canexplain theeffect ofpropanololin neuro leptic-induced akathisia remains to be explored. Safetyof fluoxetine inrelation to other antidepressant drugs Noradrenalin
uptake inhibitors
It is important to note that antidepressant drugs other than fluoxetine have been linked to the development or worsening of suicidal ideation and behaviour. For Akathisia and brain 5-HT function example, a one-year prospective placebo-controlled Neuroleptic-induced akathisia is believed to result study of the selective noradrenalin uptake inhibitor fromblockade ofpost-synaptic dopaminereceptorsmaprotiline found an increase in the number of suicide in mesocortical brain regions because in rats, lesion attempts in patients treated with maprotiline compared of the dopamine pathways innervating this area with those receiving placebo (Rouillon et a!, 1989). There are also anecdotal accounts of the emergence causes a hyperactivity syndrome (see Marsden & of suicidal ideation in depressed patients receiving Jenner, 1980). The cells of origin of the mesocortical dopamine system lie in the ventral tegmental area and a variety of other antidepressant drugs, including the systematically
(Sternbach,
1991).
739
FLUOXETINE AND SUICIDAL BEHAVIOUR noradrenalin uptake inhibitors desipramine and nortriptyline (Damluji & Ferguson, 1988). These
or to other intercurrent factors unrelated to drug
reactions
patients taking fluoxetine may experience rare adverse reactions that can be associated with the development of suicidal thinking and behaviour. In the case of fluoxetine, the evidence suggests that these reactions are most commonly associated with the development of akathisia, which may represent a form of 5-HT toxicity. The following guidelines, drawn from the current literature, are aimed at miimising this risk. Apart from specific dosage recommendations, much of the following advice would be applicable to the use of SSRIs in general. (a) The dose of fluoxetine in depression should not exceed 20mg daily initially: it may be increased at intervals of six to eight weeks, but in general there is little evidence for an increasing level of antidepressant efficacy above this dose, although individual patients may respond to higher doses. Except in unusual
are sometimes
associated
with insomnia,
agitation, and dysphoria; whether this represents an akathisia-like reaction is unclear. Fluoxetine and other SSRIs Direct comparisons of the adverse effects of the various SSRIs are problematic because of differences
in patient exposure, dosing regime, and methods of data collection. In general, the clinical trials suggest that fluoxetine may have a more ‘¿activating' profile than some other SSRIs, with a correspondingly greater tendency to cause nervousness and anxiety (Cooper, 1988; Doogan & Caillard, 1988; Burton, 1991; Dunbar eta!, 1991). However, these data must be received with caution: firstly, there are no studies that directly compare the profile of adverse events
of different SSRIs, and secondly, a summary from the Committee on Safety of Medicines (1992) indicated a similar frequency of reports of restlessness, insomnia, and anxiety for fluvoxamine and fluoxetine. Interestingly, both these drugs have been associated with extrapyramidal disorders, including Parkinsonism and akathisia (Baldwin et a!, 1991b; Committee on Safety of Medicines, 1992). Dose is important in evaluating the profile of adverse effects of fluoxetine, in comparison with other SSRIs and TCAS. While many earlier studies of depressed patients used rapidly escalating dosing regimes of up to 80 mg daily over two weeks, it is now recognised that 20mg daily of fluoxetine is usually sufficient, if enough time is allowed for a therapeutic response to become apparent (Altamura et a!, 1988; Dornseif eta!, 1989;Schweizer eta!, 1990).The active metabolite of fluoxetine, norfluoxetine, has a long half-life (7—15 days) (Bergstrom eta!, 1988), so that steady-state plasma levels will not be reached for five weeks or more after an increase in dosage. A 20 mg daily dose of fluoxetine is significantly less likely than higher doses to be associated
with
insomnia and anxiety (Cooper, 1988). Most of the severe adverse reactions described above occurred in patients receiving in excess of 20 mg fluoxetine daily, often shortly after an increase. Some depressed
patients will in fact respond to doses of fluoxetine as low as 5 mg daily (Altamura et a!, 1988). Clinical use of fluoxetine Used appropriately,
fluoxetine is safe and effective.
All depressed patients require close monitoring early in treatment, and the emergence or worsening of suicidal thinking during this period can frequently be attributed to the natural history of the disorder
treatment.
situations
However, as with other antidepressants,
(Stoll et a!, 1991), the dose in depressed
patients should not exceed 60mg daily. Whether this dosing regime will apply to other indications such as obsessive—compulsivedisorder is uncertain. In the treatment of bulimia nervosa, for example, 60 mg daily is recommended (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992). (b)Increasing restlessnessand agitation, particularly following the introduction of fluoxetine or an increase in dose, may represent the development of akathisia, although in some patients subjective symptoms such as fear and irritability may dominate
theclinical picture. Akathisia shouldbemanagedby cessation of treatment, or,ifclosemonitoring is possible,
by continuation
of fluoxetine
with the
addition of propanolol or short-term benzodiazepine treatment. It may be helpful to offer advice at the beginning of treatment about the possibility of this rare reaction, so that patients will seek help quickly if the relevant symptoms occur and not regard them as evidence of a worsening of their depression. (c) Previous MAO! treatment may sensitise patients to the development of 5-HT toxicity, with agitation and restlessness when starting fluoxetine; 5-HT toxicity may also present with changes in mental state, such as mixed affective symptoms
and confusion.
The minimum MAO! wash-out period recommended before beginning fluoxetine is presently two weeks, but in some patients persisting MAO! inhibition may be pharmacologically demonstrable for at least four weeks after cessation of treatment (Insel eta!, 1982). Accordingly, we suggest that after a two-week wash out from MAOIs (and probably for four weeks after this), fluoxetine treatment should begin with a dose of 20mg every other day. A liquid formulation of fluoxetine, allowing for lower daily doses, should be
740
POWER & COWEN
available in the UK shortly. Because of the prolonged activity of norfluoxetine (see above), it has been recommended
that at least five weeks should elapse
BURTON,S. W. (1991) A review of fluvoxamine and its uses in depression. International Clinical Psychopharmacology, 6 (suppl. 3), 1—21.
CHARNEY, D. S., HENINGER, 0. R. & STERNBERG, D. E. (1984)
following discontinuation of fluoxetine before MAO! Serotonin function and the mechanism of action of antidepressant treatment is started. treatment: effects of amitriptyline and desipramine. Archives of Genera!Psychiatry, 41, 359—365. (d) Other drugs, such as lithium, that may 0. (1991) Fluoxetine and preoccupation with suicide potentiate the effects of fluoxetine on brain 5-HT CHOUINARD, (letter). American Journal of Psychiatry, 148, 1258-1259. function should be used with caution. In addition, COMMITTEEON SATE1Y OF MEDICINES(1989) Fluvoxamine and concomitant prescription of neuroleptics may poten fluoxetine —¿ interaction with monoamine oxidase inhibitors, lithium and tryptophan. Current Problems (May). tiate the ability of fluoxetine to cause extrapyramidal disorders such as akathisia (Chouinard, 1991; Com fluvoxamine (Faverin). Current Problems (June). mittee on Safety of Medicines, 1992). CONSUMERS' AssOCIATIoN (1992) Fluoxetine, suicide and aggression. (e) Patients who have not responded to previous Drug and TherapeuticsBulletin, 30, 5-6. trials ofantidepressant treatment should bemonitored CoOPER, 0. L. (1988) The safety of fluoxetine - an update. British —¿
carefully
when fluoxetine
is introduced.
Although
increasing anxiety and insomnia early in treatment is a recognised side-effect of fluoxetine and other SSRIs, tolerance to these effects usually occurs and depressed patients with prominent symptoms of anxiety who are able to persist with treatment often do well. !n such patients, consideration can be given to starting fluoxetine at a dose of 20 mg every other day. Depressed patients with a history of panic attacks may be particularly sensitive to the stimulant effects of fluoxetine, as they are to other antidepressant
drugs.
(1992)
Safety
of
fluoxetine
(Prozac):
comparison
with
Journal of Psychiatry, 153 (suppl. 3), 77—86.
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A. C. Power, MSc,MRCPsych, Senior Registrar, WarnefordHospital, Oxford; *P. J. Cowen, MD,FRCPsych, MRC Clinical Scientist and Honorary Consultant Psychiatrist, Littlemore Hospital, Oxford 0X4 4XN 5Correspondence
Fluoxetine and suicidal behaviour. Some clinical and theoretical aspects of a controversy. A C Power and P J Cowen BJP 1992, 161:735-741. Access the most recent version at DOI: 10.1192/bjp.161.6.735
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British Journal of Psychiatry (1992), 161, 735—741
Fluoxetine and Suicidal Behaviour Some Clinical and Theoretical
Aspects of a Controversy
A. C. POWER and P. J. COWEN
“¿In the practical decisions of life it will scarcely ever be possible to go through all the arguments in favour of or against one possible decision, and one will therefore always have to act on insufficient evidence― Werner Heisenberg (1962).
The development of selective serotonin (5-hydroxy tryptamine, 5-HT) reuptake inhibitors (SSRIs) has added a new dimension to the pharmacotherapy of depression. Their lack of sedative and anticholinergic effects together with relative safety in overdose, has led some authors to suggest that the older tricyclic antidepressants (TCAs) should not now be considered a first-line treatment (Montgomery, 1988). However, since a report by Teicher et a! (1990) of suicidal preoccupation associated with fluoxetine treatment, there has been both intense media interest and animated correspondence in clinical and scientific journals (O'Donnell, 1991). The view that an SSRI like fluoxetine could exacerbate suicidal thinking and behaviour is at variance with current biochemical formulations of affective disorder, which suggest that suicidal patients are particularly likely to have evidence of decreased brain 5-HT function (see Golden et a!, 1991). In addition, studies in animals, and some in humans, indicate that decreased brain 5-HT function may be associated with impulsive and aggressive behaviour (Katz, 1980; van Praag, 1991), and that drugs which .nhance this function may inhibit various aggressive ‘¿ts (Lindgren & Kantak, 1987; Cowen, 1990). Several reviews have concluded that the balance evidence is not in favour of an association between @Iuoxetine and the emergence of suicidal ideation @Baldwin et a!, l991a; Mann & Kapur, 1991; Consumers' Association, 1992), but disquiet remains among clinicians. One recent correspondent to the American Journal of Psychiatry caustically remarked: “¿When one of my patients killed himself years ago the lawyers blamed not imipramine but me. I regret that fluoxetine was not available then―(Balon, 1991). Clinical studies Anecdotal accounts Teicher et a! (1990) described six cases of intense suicidal preoccupation two to seven weeks after the 735
start of fluoxetine therapy. Their cases were complex diagnostic problems: in association with major depressive disorder, cases 4 and 5 had concomitant diagnoses of borderline personality disorder, case 6 had a diagnosis of multiple personality disorder, case 3 had associated bulimia, paranoia, agoraphobia, and dissociation, while case 2 had a 21-year history of dysthymia. Only case 1 had a relatively uncomplicated diagnosis of major depression with melancholia. All except case 2 had previous suicidal ideation or gestures, and all had experienced previous multiple treatment regimes. Three patients were started on fluoxetine two weeks after ceasing to take monoamine oxidase inhibitors (MAOIs), and four appeared to develop suicidal ideation in association with akathisia; all could have been considered non-responders to fluoxetine. These complicating factors have made it difficult to interpret a specific relationship between fluoxetine and the emergence of suicidal ideation in Teicher's cases (Berkley, 1990; Tollefson, 1990; Mann & Kapur, 1991). Nevertheless, further case reports have followed. Masand eta! (1991) reported two depressed patients, in one of whom the suicidal ideation occurred ten days after a gradual increase in the dose of fluoxetine from 20 mg to 60 mg, associated with akathisia. In the second case, suicidal ideation occurred on 20 mg. In both, the onset of suicidal ideation occurred within one week and ceased within ten days of stopping treatment. Dasgupta (1990) reported a patient with depressive symptoms and persistent pelvic pain (thought to be partially psychogenic in origin) who developed intense suicidal ideation and attempted suicide by carbon monoxide poisoning, four weeks after starting 20 mg of fluoxetine daily. Creaney et al (1991) reported a further case of suicidal ideation and behaviour associated with fluoxetine that may have been linked to the development of a dissociative state. The most convincing anecdotal evidence linking fluoxetine and suicidal behaviour is provided by the three depressed cases reported by Rothschild & Locke (1991); all three developed severe akathisia and attempted suicide while taking fluoxetine alone in daily doses of 40mg (1 case) or 60mg (2 cases). The Thie
One
I@ I@ I@ II@IUIII@ III01111 IIIII@ IIIIIll
CEQ9-SBZ-TP7A
736
POWER & COWEN
attempts occurred within a week of an increase in the dose in each case. When the patients were rechallenged with fluoxetine, the akathisia and suicidal ideation returned, but in two cases, this remitted when the akathisia was treated with propranolol; in the third, the suicidal ideation and akathisia disap peared within 72 hours of discontinuing fluoxetine.
Wirshing et a! (1992) reported five further patients who developed akathisia and suicidal ideation during
criticised becauseof thelow incidence of suicidal gestures in the placebo-treated group (Oswald, 1991), and for lack of sensitivity in measuring suicidal ideation using item 3 of the Hamilton Rating Scale for Depression (Healy & Creaney, 1991). Two other meta-analyses have been reported from these laboratories. One (Beasleyeta!, 1992)concerned suicidal
ideation
in patients
receiving
fluoxetine
Fava & Rosenbaum (1991) surveyed 27 practising
(20—60mgdaily) (n = 266) or placebo (n = 89) in con trolled studiesof obsessive-compulsivedisorder. Judged by ratings on item 3 of the Hamilton scale, pre-existing suicidal ideation worsened significantly more in patients receiving placebo(14.8%)thanin those receiving fluoxetine (4.6%),and theincidence of emergent suicidal ideation did not differ significantly between the groups. Interestingly, however, the three patients whose emergent suicidal ideation was noted clinically as an adverse event during the double-blind
psychiatrists
with
trials were all taking fluoxetine (60mg daily). A third
antidepressants during 1989, and found that the percentages of patients who became suicidal only after treatment with antidepressants was initiated were: 3.5°lo for those taking fluoxetine alone; 6.5% for those treated with fluoxetine in combination with TCAs; and 1.3% for those treated with TCAs alone or in combination with lithium. The difference in incidence of suicidal ideation was not significant between those treated with fluoxetine alone and those receiving the other antidepressants, but a statistically significant difference was found between new-onset
analysis examined the incidence of aggressivebehaviour in patients receiving fluoxetine in a range of doses (5-80mg daily) for a variety of indications, including depression, obesity, and alcoholism (Heiligenstein
fluoxetine treatment: in three, their symptoms were associated with an increase in dose from 20mg to
40mg daily, and in two cases, treatment benzodiazepines relieved symptoms.
with
Retrospective survey
suicidality
who had treated
1017 patients
in the group taking the combination
of
tncycics and fluoxetine, compared with the group receiving tricyclics alone or in combination with lithium. However, Brewerton (1991) reanalysed the data from this study. He regrouped the patients into those receiving fluoxetine (with or without TCAs) and those receiving other antidepressant treatments, fmding a significantly higher frequency of new-onset suicidality in the fluoxetine (2.77%) versus the non fluoxetine group (0.75%).
Controlled clinical trials Workers at Lilly Research Laboratories carried out a meta-analysis on pooled data from 17 double-blind trials in depressed patients (Beasley eta!, 1991). They found that the emergence of substantial suicidal ideation was 1.2% for fluoxetine (n = 1765), 2.6% for placebo (n = 569), and 3.6% for TCAs (n = 735);
the incidence with fluoxetine was significantly less than with either placebo or TCAs. There was no significant difference between the three groups in worsening of pre-existing suicidal ideation or in the number of suicidal acts. The meta-analysis has been
et a!, unpublished). In some studies, fluoxetine had been compared with placebo, and in others with TCAS.
Overall, patients receiving fluoxetine (n = 2615) were significantly less likely to experience an adverse event suggestive of aggression than those receiving placebo (n=1377)(0.l5%v.0.65°lo). Two othercontrolled studies indepressed patients haveexaminedtheeffect of fluoxetine on suicidal ideation. Muijeneta!(1988)foundthatsuicidal feelings were reduced more in patients receiving fluoxetine than in those having mianserin or placebo. Sacchetti eta!(1991) foundthatclomipramine and fluoxetine (both drugswithsignificant 5-HTreuptake blocking actions) were superior to desipramine and nortriptyline in the treatment of depressed patients with a history of suicide attempts. Studies with other SSRIshavealsosuggested thatthesedrugsmay be more effective than standardantidepressants in decreasing suicidal ideation indepressed patients, but the data are not consistent (Mann & Kapur, 1991). Conclusions from clinical trials Neither the controlled trials with fluoxetine nor the combinedmeta-analysis ofBeasley eta!(1991) offer support for the hypothesis that fluoxetine predisposes to the emergence or worsening of suicidal ideation or behaviour in depressed patients. It is possible, how ever, that even large controlled investigations may fail to detect rare but clinically important adverse events. In addition, the conditions that obtain during con trolled trials often differ from those of routine clinical
FLUOXETINE AND SUICIDAL BEHAVIOUR practice. For example, various groups of depressed patients, including those at high risk of self-harm, those who have not responded to other antidepressant drugs, and those with additional psychiatric diagnoses make up a substantial proportion of psychiatric practice but may well be excluded from trials of anti depressant drugs. Furthermore, while in clinical trials the use of concomitant psychotropic medication is strictly controlled, in routine clinical practice patients with complex psychiatric problems often receive more than one class of psychotropic agent, increasing the risk of adverse events through drug interaction. Taken together, the anecdotal accounts reviewed above provide some evidence that rare adverse reactions involving suicidal ideation and behaviour may occur during fluoxetine treatment. The most consistent factor implicated in these adverse reactions has been the development of akathisia with agitation, restlessness, and dysphoria. While akathisia is most commonly caused by neuroleptics, different classes of antidepressant drugs (including SSRIs) have occasionally been implicated in this syndrome (Zubenko eta!, 1987; Lipinski eta!, 1989; Baldwin et a!, l99lb). Importantly, akathisia is known to be associated with a state of severe subjective distress, which some patients find intolerable. There are, for example, reports of serious suicidal and aggressive behaviour in the setting of neuroleptic induced akathisia (van Putten, 1975; Shear et a!, 1983; Drake & Ehrlich, 1985; Sachdev & Loneragan, 1991). Depressed patients who experience increasing agitation and dysphoria may understandably attribute
this to worsening of their illness rather than to a side effect of medication; despair may result.
increasing
hopelessness
and
737
the knowledge that 5-HT pathways express multiple 5-HT receptor subtypes, which respond differentially to the repeated administration of antidepressant drugs
(Cowen, 1991).The function of some of these receptor subtypes in the human brain can be assessed by neuro endocrine challenge tests; these reveal that repeated administration of SSRIs produces a sustained increase in neurotransmission at post-synaptic 5-HTIA recep tors which is similar to but somewhat greater than the effect of TCAs (Fig. 1) (Charney eta!, 1984; Cowen, 1988; Price et a!, 1989). In contrast, fluoxetine but not TCAs increases the cortisol response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP) (Meltzer, 1990), which is, in part, a measure of neurotransmission at post-synaptic 5-HT2 receptors (Lee et a!, 1991). The lack of effect of TCAs on 5-HTP-induced cortisol release is probably attributable to their ability to competitively block and downregulate post synaptic 5-HT2 receptors (Peroutka & Snyder, 1980; Goodwin et a!, 1984): this action presumably out weighs any increase in 5-HT neurotransmission that might be achieved by their moderate inhibition of presynaptic 5-HT uptake. In contrast, SSRIs lack 5-HT2 receptor antagonist properties, and although some animal studies suggest that post-synaptic 5-HT2 receptor down-regulation occurs during repeated SSRI treatment (see Johnson, 1991), the net effect of SSRI administration in humans may well be to increase 5-HT2 neurotransmission.
The 5-HT-mediated behavioural syndrome In animals, large increases in brain 5-HT function produced by a non-selective MAO! and a 5-HT
A number of the adverse reactions to fluoxetine in the published reports noted above have occurred after a comparatively brief period of withdrawal from MAOIs, and some authors have proposed that previous MAOI treatment may predispose patients to the development of agitation when fluoxetine is introduced (Berkley, 1990; Brewerton, 1991). It has been pointed out that combination of SSRIs with MAOIs has been reported to produce a 5-HT toxicity syndrome, which includes features such as agitation and restlessness (Feighner et a!, 1990; Sternbach,
C U a) 0 C
a) a)
a) U C
1991). Below, we briefly review the effect of SSRIs on brain 5-HT function and attempt to relate this to the pharmacology of the 5-HT syndrome and akathisia.
SSRIs,5-HT toxicity and akathisia Effects of SSRIs on brain 5-HT function Descriptions of the effects of psychotropic drugs on brain 5-HT function have now to be reconciled with
0
5-HT uptake blockade
Fig. 1 The mean @10 increase in prolactin response to L-tryptophan (a 5-HTIA receptor-mediated response) produced by repeated administration of mianserin (MIAN), desipramine (DM1), ami triptyline (AM!) and fluvoxamine (FLUVOX) in depressed patients. The increase in prolactin response correlates with ability of the antidepressant to inhibit the uptake of 5-HT.
POWER & COWEN
738
precursor or a MAO! and a SSRI causea 5-HT behavioural syndrome consisting of hyperactivity, stereotyped movements, and increased core tempera ture (Grahame-Smith, 1971; Marley & Wozniak, 1984). An analogous syndrome with myoclonus, agitation, affective change and confusion is believed to underlie the toxic reactions that have been reported with MAOIs and fluoxetine in humans (Feighner eta!,1990). 5-HT toxicity hasalsobeen reported following combinations of fluoxetine and the 5-HT precursor L-tryptophan, where agitation, restlessness, and aggression have been described (Steiner & Fontaine, 1986). Lithium facilitates brain 5-HT neurotransmission (Cowen et a!, 1991), and while lithium and SSRIs can often be combined to good therapeutic effect, there are occasional reports of 5-HT neurotoxicity developing withthis drugcombi nation (Committee on Safety of Medicines, 1989). Studies in rats suggest that the 5-HT behavioural syndrome is produced predominantly by activation of post-synaptic 5-HT1Areceptors, but that certain aspects of the syndrome are facilitated by simul taneous stimulation of 5-HT2 receptors (Glennon eta!, 1991). The facility with which SSRIs produce a
5-HT toxicity syndrome in combination with MAOIs and other 5-HT-enhancing drugs could therefore reflect two factors: (a) particularly potent 5-HT uptake blockade, and (b)an ability to increase both 5-HT1A and 5-HT2 neurotransmission (see above). Interestingly, it seems that hyperthermia, which is one of the most serious complications of the 5-HT toxicity syndrome, is likely to be mediated by 5-HT2 receptor stimulation (Gudelsky eta!,1986). In rats, the beta-adrenoceptor antagonist pro panolol abolishes the 5-HT behavioural syndrome through blockade of post-synaptic 5-HT1Areceptors, for which it has a high affinity (Hoyer, 1988).Interest ingly, propanolol abolishes 5-HT-mediated behaviour, whether this is induced by selective 5-HT1Areceptor agonists or agonists with combined actions on 5-HT1A and 5-HT2 receptors (Goodwin & Green, 1985). Propanolol has also been reported to be of benefit in the management of the 5-HT toxicity syndrome in humans, but this has not been studied
receive a significant 5-HT innervation from the raphe nuclei (Parent eta!, 1981). The interaction between ascending 5-HT pathways and dopamine systems is complex and not fully understood. However, there is evidence that certain 5-HT neurons are inhibitory to dopamine cell firing (see Baldessarim eta!, 1992); therefore, increases in brain 5-HT function, produced
for example by an SSRI, would be expected to decrease dopamine neurotransmission in mesocortical regions. This could predispose to the development of akathisia (Lipinski et a!, 1989). The 5-HT2 receptor antagonist ritanserin increases dopaminergic cell firing in the ventral tegmental area (Ugedo et a!, 1989), suggesting that the inhibitory effects of 5-HT in this brain region may be mediated by 5-HT2 receptors. From this, it might be expected that SSRIs would be associated with a higher frequency of akathisia than TCAs, because SSRI treatment is more likely to activate 5-HT2 receptors (see above). Whether this is in fact the case, though, is not clear from the current literature (Lipinski eta!, 1989; Baldwin eta!, 1991b), and this is therefore an area where further clinical studies are needed. In addition, studies in rodents do not reveal consistent
effects of fluoxetine on dopamine
metabolism (Baldessarmni et a!, 1992). It would, however, be of interest to study the effects of SSRI treatment on extrapyramidal function anddopamine neurotransmission indepressed patients. Propanolol isrecognised tobeauseful treatment in neuroleptic-induced akathisia, although its mechanism ofaction hasbeendebated (Adler eta!, 1986; Sachdev & Loneragan,1991). We proposethatfluoxetine induced akathisia may represent a form of 5-HT toxicity, and that the efficacy of propanolol in this setting, asinthe5-HT behavioural syndrome, isdue toblockade of5-HTreceptors. Whether5-HTreceptor blockade canexplain theeffect ofpropanololin neuro leptic-induced akathisia remains to be explored. Safetyof fluoxetine inrelation to other antidepressant drugs Noradrenalin
uptake inhibitors
It is important to note that antidepressant drugs other than fluoxetine have been linked to the development or worsening of suicidal ideation and behaviour. For Akathisia and brain 5-HT function example, a one-year prospective placebo-controlled Neuroleptic-induced akathisia is believed to result study of the selective noradrenalin uptake inhibitor fromblockade ofpost-synaptic dopaminereceptorsmaprotiline found an increase in the number of suicide in mesocortical brain regions because in rats, lesion attempts in patients treated with maprotiline compared of the dopamine pathways innervating this area with those receiving placebo (Rouillon et a!, 1989). There are also anecdotal accounts of the emergence causes a hyperactivity syndrome (see Marsden & of suicidal ideation in depressed patients receiving Jenner, 1980). The cells of origin of the mesocortical dopamine system lie in the ventral tegmental area and a variety of other antidepressant drugs, including the systematically
(Sternbach,
1991).
739
FLUOXETINE AND SUICIDAL BEHAVIOUR noradrenalin uptake inhibitors desipramine and nortriptyline (Damluji & Ferguson, 1988). These
or to other intercurrent factors unrelated to drug
reactions
patients taking fluoxetine may experience rare adverse reactions that can be associated with the development of suicidal thinking and behaviour. In the case of fluoxetine, the evidence suggests that these reactions are most commonly associated with the development of akathisia, which may represent a form of 5-HT toxicity. The following guidelines, drawn from the current literature, are aimed at miimising this risk. Apart from specific dosage recommendations, much of the following advice would be applicable to the use of SSRIs in general. (a) The dose of fluoxetine in depression should not exceed 20mg daily initially: it may be increased at intervals of six to eight weeks, but in general there is little evidence for an increasing level of antidepressant efficacy above this dose, although individual patients may respond to higher doses. Except in unusual
are sometimes
associated
with insomnia,
agitation, and dysphoria; whether this represents an akathisia-like reaction is unclear. Fluoxetine and other SSRIs Direct comparisons of the adverse effects of the various SSRIs are problematic because of differences
in patient exposure, dosing regime, and methods of data collection. In general, the clinical trials suggest that fluoxetine may have a more ‘¿activating' profile than some other SSRIs, with a correspondingly greater tendency to cause nervousness and anxiety (Cooper, 1988; Doogan & Caillard, 1988; Burton, 1991; Dunbar eta!, 1991). However, these data must be received with caution: firstly, there are no studies that directly compare the profile of adverse events
of different SSRIs, and secondly, a summary from the Committee on Safety of Medicines (1992) indicated a similar frequency of reports of restlessness, insomnia, and anxiety for fluvoxamine and fluoxetine. Interestingly, both these drugs have been associated with extrapyramidal disorders, including Parkinsonism and akathisia (Baldwin et a!, 1991b; Committee on Safety of Medicines, 1992). Dose is important in evaluating the profile of adverse effects of fluoxetine, in comparison with other SSRIs and TCAS. While many earlier studies of depressed patients used rapidly escalating dosing regimes of up to 80 mg daily over two weeks, it is now recognised that 20mg daily of fluoxetine is usually sufficient, if enough time is allowed for a therapeutic response to become apparent (Altamura et a!, 1988; Dornseif eta!, 1989;Schweizer eta!, 1990).The active metabolite of fluoxetine, norfluoxetine, has a long half-life (7—15 days) (Bergstrom eta!, 1988), so that steady-state plasma levels will not be reached for five weeks or more after an increase in dosage. A 20 mg daily dose of fluoxetine is significantly less likely than higher doses to be associated
with
insomnia and anxiety (Cooper, 1988). Most of the severe adverse reactions described above occurred in patients receiving in excess of 20 mg fluoxetine daily, often shortly after an increase. Some depressed
patients will in fact respond to doses of fluoxetine as low as 5 mg daily (Altamura et a!, 1988). Clinical use of fluoxetine Used appropriately,
fluoxetine is safe and effective.
All depressed patients require close monitoring early in treatment, and the emergence or worsening of suicidal thinking during this period can frequently be attributed to the natural history of the disorder
treatment.
situations
However, as with other antidepressants,
(Stoll et a!, 1991), the dose in depressed
patients should not exceed 60mg daily. Whether this dosing regime will apply to other indications such as obsessive—compulsivedisorder is uncertain. In the treatment of bulimia nervosa, for example, 60 mg daily is recommended (Fluoxetine Bulimia Nervosa Collaborative Study Group, 1992). (b)Increasing restlessnessand agitation, particularly following the introduction of fluoxetine or an increase in dose, may represent the development of akathisia, although in some patients subjective symptoms such as fear and irritability may dominate
theclinical picture. Akathisia shouldbemanagedby cessation of treatment, or,ifclosemonitoring is possible,
by continuation
of fluoxetine
with the
addition of propanolol or short-term benzodiazepine treatment. It may be helpful to offer advice at the beginning of treatment about the possibility of this rare reaction, so that patients will seek help quickly if the relevant symptoms occur and not regard them as evidence of a worsening of their depression. (c) Previous MAO! treatment may sensitise patients to the development of 5-HT toxicity, with agitation and restlessness when starting fluoxetine; 5-HT toxicity may also present with changes in mental state, such as mixed affective symptoms
and confusion.
The minimum MAO! wash-out period recommended before beginning fluoxetine is presently two weeks, but in some patients persisting MAO! inhibition may be pharmacologically demonstrable for at least four weeks after cessation of treatment (Insel eta!, 1982). Accordingly, we suggest that after a two-week wash out from MAOIs (and probably for four weeks after this), fluoxetine treatment should begin with a dose of 20mg every other day. A liquid formulation of fluoxetine, allowing for lower daily doses, should be
740
POWER & COWEN
available in the UK shortly. Because of the prolonged activity of norfluoxetine (see above), it has been recommended
that at least five weeks should elapse
BURTON,S. W. (1991) A review of fluvoxamine and its uses in depression. International Clinical Psychopharmacology, 6 (suppl. 3), 1—21.
CHARNEY, D. S., HENINGER, 0. R. & STERNBERG, D. E. (1984)
following discontinuation of fluoxetine before MAO! Serotonin function and the mechanism of action of antidepressant treatment is started. treatment: effects of amitriptyline and desipramine. Archives of Genera!Psychiatry, 41, 359—365. (d) Other drugs, such as lithium, that may 0. (1991) Fluoxetine and preoccupation with suicide potentiate the effects of fluoxetine on brain 5-HT CHOUINARD, (letter). American Journal of Psychiatry, 148, 1258-1259. function should be used with caution. In addition, COMMITTEEON SATE1Y OF MEDICINES(1989) Fluvoxamine and concomitant prescription of neuroleptics may poten fluoxetine —¿ interaction with monoamine oxidase inhibitors, lithium and tryptophan. Current Problems (May). tiate the ability of fluoxetine to cause extrapyramidal disorders such as akathisia (Chouinard, 1991; Com fluvoxamine (Faverin). Current Problems (June). mittee on Safety of Medicines, 1992). CONSUMERS' AssOCIATIoN (1992) Fluoxetine, suicide and aggression. (e) Patients who have not responded to previous Drug and TherapeuticsBulletin, 30, 5-6. trials ofantidepressant treatment should bemonitored CoOPER, 0. L. (1988) The safety of fluoxetine - an update. British —¿
carefully
when fluoxetine
is introduced.
Although
increasing anxiety and insomnia early in treatment is a recognised side-effect of fluoxetine and other SSRIs, tolerance to these effects usually occurs and depressed patients with prominent symptoms of anxiety who are able to persist with treatment often do well. !n such patients, consideration can be given to starting fluoxetine at a dose of 20 mg every other day. Depressed patients with a history of panic attacks may be particularly sensitive to the stimulant effects of fluoxetine, as they are to other antidepressant
drugs.
(1992)
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of
fluoxetine
(Prozac):
comparison
with
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A. C. Power, MSc,MRCPsych, Senior Registrar, WarnefordHospital, Oxford; *P. J. Cowen, MD,FRCPsych, MRC Clinical Scientist and Honorary Consultant Psychiatrist, Littlemore Hospital, Oxford 0X4 4XN 5Correspondence
Fluoxetine and suicidal behaviour. Some clinical and theoretical aspects of a controversy. A C Power and P J Cowen BJP 1992, 161:735-741. Access the most recent version at DOI: 10.1192/bjp.161.6.735
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