Fluoxetine as monotherapy in psychotic depression:
Report of 4 cases

JORGE MARIO TAMAYO, M.D.
(Department of Psychiatry - Universidad de Antioquia - Medellín, Colombia)

Summary
Key Words
Introduction
Cases
Discussion
References

Summary

Four (4) inpatients with a diagnosis of psychotic depression (major depressive disorder with psychotic features) according to DSM - IV criteria, were treated with fluoxetine as monotherapy. A rapid and satisfactory response with resolution of the acute episode was observed in three cases with maintenance of the same results after one month post-hospitalization; the other one required a greater dose and time of administration and likewise with complete resolution of the episode.

These findings are hopeful because of fewer side effects with fluoxetine monotherapy compared to the traditional combination of tricyclic antidepressants and neuroleptics. However controlled studies are required in order to conclude if fluoxetine as monotherapy is so effective as the tricyclic antidepressants / neuroleptics combination.

Key Words

Fluoxetine, psychotic depression, serotonin-dopamine interaction

Introduction

Psychotic (delusional) depression is a severe form of affective disorder characterized by delusions and/or hallucinations accompanying an episode of major depressive disorder. The delusions can be classified as congruent or incongruent with mood. The hallucinations can be auditory, visual or somatic, but with a presentation limited to the period in which the patient exhibits a full affective disorder (Goodwin, F.K. & Jamison, K.J., 1990; Kendler, K.S., 1991; Schatzberg, A.F & Rotschild, A.J., 1992a).

Patients with delusional depression constitute 20% - 30% of those with diagnosis of major depression hospitalized in the USA and 5% of the admissions through accident and emergency departments, with hospitalization rates that are twice those of patients with non delusional depression. Delusional depression constitutes 10% to 25% of patients with major depressive disorder (Spiker, D.G., 1985). Suicidal risk and suicidal ideation do differ meaningfully between delusional and non-delusional depression in several studies (Wolfersdorf, M .,1987; Black, D.W. et al., 1988; Isometsa, E.T. et al., 1994), but the ECA study (Epidemiological Catchment Area) found more suicidal attempts and greater morbidity in the patients with psychotic depression after one year (Johnson, J. et al., 1991).

As a rule, patients with psychotic depression follow the standard chronic disease path and present a higher number of readmissions during the first year of post - hospitalization for psychiatric or medical causes (22.8% vs. 14.7% of the non psychotics, p <0.05) (Robinson, D.G. & Spiker, D.G., 1985; Johnson, J. et al., 1991).

ECT (electroconvulsive therapy) has been proposed by several authors as the most appropriate first line treatment in patients with psychotic depression. The response rates are close to 80%; however, other authors recommend it only when there is no response to the antidepressant - antipsychotic combination or to Amoxapine (Glassman, A. et al., 1975; Charney D.S. & Nelson, J.C., 1981). Fluoxetine has been reported once combination with Perphenazine for the treatment of psychotic depression, according to MEDLINE. This combination was found to have a response rate similar to conventional treatments, with side effects similar to the ones reported with Amoxapine: dry mouth (40%), blurred vision (40%), tremor or rigidity (40%) and orthostatic hypotension or dizziness (27%) (Rothschild, A.J. et al., 1993). This study contrasts with an isolated report of a patient with psychotic depression who had delusions of guilt and persecution after two attempts of fluoxetine administration (20 to 40 mg / day) (Narayan, M. et al., 1995). Paroxetine has also been evaluated in combination with neuroleptics (Zotepine or Haloperidol) with a good response without side effects (Wolfersdorf, M. et al., 1995).

There is unanimous support for the finding that psychotic depression does not respond to placebo when compared with non delusional depression: 0 vs. 30% (p <0.02) (Spiker, D.G., 1985) and 0 vs. 13.3% (Glassman, A.H. & Roose, S.P., 1981).

In terms of maintenance therapy , different studies state that the best way to avoid relapses with pharmacological therapy with antidepressants or with antidepressants plus antipsychotics combination. However, Lykouras, L. et al. (1988) question monotherapy with antidepressants in the prevention of relapses in a prospective study with 6 years follow-up .

Several studies have been carried out to evaluate the effect of other antidepressants as monotherapy in acute psychotic depression but with poor results: Phenelzine (Janicak et al., 1988), Desipramine (Nelson, J. & Bowers, M., 1978 ), and Lithium (Coryell, W. & Tsuang, M.T., 1985; Aronson, T.A. et al., 1988). The only study that showed good results with an antidepressant as monotherapy was accomplished with Tranylcypromine in 4 patients with psychotic depression (Lieb, J. & Collins, L ., 1978). There are no studies with fluoxetine as monotherapy in psychotic depression reported in the scientific literature.

Patients with psychotic depression often have high rates of non supression of cortisol in the Dexamethasone supression test (DST) according to various studies (Arana, G.W. et al., 1983; Schatzberg, A.F. et al., 1983). This has led to speculation that the delusions are possibly due to effects of hypercortisolism. Hypercortisolism in the dopaminergic systems leads to an increase in the levels of cerebral dopamine in mice and an increase of homovallinic acid (HVA) in the CSF of human beings (Aberg-Wistedt, A. & Bertilsson, L ., 1985; Agren, H. & Terenius, L., 1985). Patients with psychotic depression have high levels of 5-HIAA in CSF, in close correlation with the levels of HVA (p <0.001); the ratio of HVA / 5-HIAA is significantly high in CSF (p < 0.01) which suggests alterations in the dopaminergic and serotonergic function (Schatzberg, A.F. et al., 1983). Furthermore, it has been found an increase in the platelets reuptake of serotonin in the patients with such disorder. Good results in psychotic depression have been described with Amoxapine, an antidepressant with antagonistic properties at 5-HT2 receptors (Schatzberg, A.F. & Rotschild, A.J., 1992b).

Recent studies demonstrate that serotonin exhibits a regulatory dopaminergic action by inhibiting the release of dopamine through 5-HT2A somatodendritic receptors in the surface of dopaminergic neurons; thus 5-HT2A antagonists (Altanserin) and 5-HT1A agonists (which may exert subtle inhibitory effects on dopaminergic cell bodies in the substantia nigra by means of autoreceptors ; Kelland, M.D. et al., 1990) or injury to the serotonergic tracts (Dray, A. et al., 1978), produce a disinhibition of dopaminergic neurons in the middle brain with modest increases in the release (Ennis, C. et al.,1981) and possibly in the synthesis of dopamine (Spampinato, U. et al., 1985) in the nucleus accumbens and the prefrontal cortex (Waldmeier, P.C. & Delini-Stula, A.A., 1979; Nedergaard, S. et al., 1988; Kelland, M.D. et al., 1990; Leysen, J.E. et al., 1994). On the other hand, some of the effects of the serotonin in the dopaminergic system can be mediated in indirect form through the modulation of the GABA and the cholinergic system (Dewey, S.L. et al., 1993). Fluoxetine and its active metabolite, norfluoxetine, have a serotonergic profile inhibiting serotonin reuptake the synaptic cleft (Lucas, R.A., 1992). However, the effect of the fluoxetine on other monoaminergic systems is not clearly established. Fluoxetine has been associated with the development of bradykinesia and rigidity, akathisia, shuffling gait, cogwheeling, tremor and akathisia, possibly by the activation of 5-HT2a receptors in dopaminergic neurons (Bouchard, R.H. et al., 1989; Lipinski, J.F. Jr. et al., 1989; Arya, D.K., 1994; Coulter, D.M. & Pillans, P.I., 1995) in a proportion similar to 1 out of 1000 individuals that consume SSRIs (Choo, V ., 1993). Fluoxetine, by increasing the serotonergic activity in the projections toward the substantia nigra from the dorsal raphe nuclei, can inhibit the firing rate of dopaminergic neurons, in such a way that the dopamine blockers in combination with fluoxetine can lead to extrapyramidal effects in patients even when they haven’t experienced adverse effects when treated only with antipsychotics (Levinson, M.L. et al., 1991). In spite of such findings, fluoxetine has relatively few side effects, especially when compared with the tricyclic antidepressants (Cooper, G.L., 1988) or with Amoxapine (Anton, R.F. & Burch, E.A., 1990).

This report describes fluoxetine monotherapy in four patients with psychotic depression whose diagnosis accorded with DSM - IV criteria (APA, 1995). In 3 out of 4 cases there was a waiting period of 2 weeks to observe a satisfactory response before considering the possibility of adding antipsychotics, (which finally was not necessary).

Case 1

A 37 year old married housewife, with a 16-17 week pregnancy at hospitalisation. Her first episode of depression in 1992 was characterised by psychomotor retardation, loss of appetite, fatigue, insomnia, anxiety and constant references to death with fear of being murdered She was treated with Amitriptyline, 100 mg / day and Thioridazine, 30 mg / day.

She relapsed after two years. It was an episode of 4 months of social withdrawal, lack of self-care, psychomotor retardation and frequent weeping, that progressed to negativism, posturing and catalepsy. It was treated then with Amitriptyline, 200 mg / day and Thioproperazine, 40 mg / day (MAYEPTIL, a phenothiazine antipsychotic of the piperazine group).; during the recovery period she again expressed a fear of being murdered and had auditory hallucinations related to this fear. There was no evidence of previous personality disorder or depression before 1992. She denied consumption of psychoactive substances or alcohol. She had a family history of major depression in a maternal aunt.

Her most recent episode, in September 1995, was characterized by a cluster of symptoms over 1 month with anorexia, hypersomnia, psychomotor retardation, subjective sadness that progressed to mutism, and catatonia.

She was adminstered an antidepressant with a fair safety profile in the first trimester of the pregnancy, (as is the case of fluoxetine at a dose of 20 mg / day) classified in the category B by the FDA with no risks detected in humans (Pastuszak, A. et al., 1993; FDA, 1995). All the laboratory investigations excluded relevant general medical conditions.

From the fifth day of administration, the patient became responsive to the environment, expressed auditory hallucinations in the second and third person telling her: "We are going to kill your daughters, we are going to injure them", and leading to persecutory delusions expressed thus, "They are going to kill my family", " I know that they are going to injure them". She manifiested furthermore a feeling of sadness, lack of "energy", anhedonia and delusions of guilt for the death of her father and her brother four years before: "I was not praying enough". Fourteen days after the beginning of the medication, she presented partial recovery of the major depressive symptoms, without hallucinations, but with persistence of the delusion and the catalepsy. Twenty-two days afterwards, the delusional ideas, and the depressive disappeared.

The patient was evaluated 1 month after being discharged; she maintained the recovery obtained during the hospitalization and an adequate tolerance to the medication.

The evolution of this case motivated the evaluation of the fluoxetine in a further three patients with psychotic depression which are described below .

Case 2

A 42 year old married housewife. The first episode appeared when she was 20 years old, fulfilling criteria for the retrospective diagnosis of major depressive disorder according to DSM - IV. Since then, she had multiple hospitalisations for similar episodes (6 in total); the 3 last ones with psychotic features (hallucinations and delusions) that necessitated the addition of an antipsychotic (Amitriptyline and Thioproperazine). The patient took the medication irregularly due to undesirable side effects (tremor, rigidity, dry mouth and constipation). She had relatives with major depressive disorder. The last episode, in October 1995, initially consisted of psychomotor retardation, anorexia, anhedonia, subjective sadness and suicidal ideation. She began to show delusions of a persecutory type accompanied with congruent auditory hallucinations. On admission, she showed accompanying catatonic features. She was prescribed fluoxetine, 20 mg/day, and the first changes were observed after 7 days of administration with disappearance of the catatonic features. After 16 daysm, the major depressive symptoms and the auditory hallucinations had disappeared. The patient was discharged after 26 days with complete recovery of her current episode, with absence of major depressive, psychotic and catatonic symptoms. The laboratory investigations revealed a hypothyroidism with high TSH and reduced T3 and T4 ; these results were known 1 week after her discharge. The hypothyropidism was treated as an outpatient.

A month later, she was evaluated as an outpatient, and it was found that she was doing well and had adequate tolerance to the medication.

Case 3

A 27 year old medical specialist. Her first episode occurred at the age of 26; characterised by a subjective sadness, anhedonia, initial insomnia, frequent suicidal ideation without suicidal attempts, mutism and overvalued ideas of guilt and poverty: "I am a burden for my parents; they are going through a difficult time and I do not earn enough for my own expenses". Additionally, she has auditory hallucinations expressed as whispering voices without a clear content. At the time, she was treated with the combination of Amitriptyline and Thioproperazine, with initial adequate response, but with a variety of side effects (rigidity, tremor and difficulty in walking). This led the patient to discontinue the medication one month after discharge.

A year later there was a similar two week episode with isolation, psychomotor retardation and anhedonia, with abandonment of her work and family life. A few days prior to hospitalisation, auditory hallucinations had reappeared. The patient was treated with fluoxetine 20 mg / day, wi

th gradual recovery of the depressive symptoms and disappearance of the hallucinations after three weeks. The subsequent laboratory investigations were normal as was the EEG.

Case 4

A 48 year old housewife who had five previous admissions with episodes of major depressive disorder with psychotic features. Previous episodes were treated with the combination of Amitriptyline and Thioproperazine. The most recent episode began a month before her admission to hospital in October 1995. On admission she had psychomotor inhibition, stupor, anhedonia, anorexia, subjective loss of weight, ideas of guilt and auditory hallucinations: "I hear several voices that tell me: you are evil! Evil !"; "I am separated from God!". Treatment began with fluoxetine 20 mg / day, with partial improvement of the stupor, but with persistence of the depressive and psychotic symptoms until the end of the second week. For that reason, she was then given Thioproperazine, 20 mg /day in addition, followed by a gradual increase of the fluoxetine up to doses of 80 mg / day. At 6 weeks, the patient showed a gradual recovery of her depressive symptoms and the antipsychotics were tailed off.

Discussion

This is the first report in the literature on the effect of the fluoxetine as monotherapy for psychotic depression according DSM - IV criteria.

Therefore, the present report has obviously several limitations:

1) The small number of reported cases do not permit us to discard the possibility that the response of these patients to monotherapy corresponds to the 23% - 40% found by several authors with other antidepressants.

2) The patients were evaluated during hospitalisation and only two of them were seen a month after being released. Therefore, there is nothing to be said about the prophylactic effect of the fluoxetine as monotherapy in this type of patient.

3) All patients exhibited a remarkable psychomotor retaradation that went from depressive stupor to catatonia; and although this is an equally striking event, inasmuch as there are no reports on the use of the fluoxetine as monotherapy in major depressive disorder with catatonic features, it constitutes a variable that could affect whether findings in this report could be generalised.

In spite of these points fluoxetine as monotherapy, with variable doses, led to the disappearance of the depressive and psychotic symptoms in three out of four patients. The therapeutic effect began during the first 2 weeks in these three cases.

This suggests that the fluoxetine could be a promising alternative in the treatment of patients with psychotic depression. One benefit of monotherapy would be a smaller number of side effects, a greater tolerance on the part of patient to the treatment, a greater cost efficacy and a better tolerance of prophylaxis. The possible benefits of the hypothesis presented in this short essay can only be proved after a series of comparative studies of fluoxetine against the traditional therapeutic options for psychotic depression..

References