Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly

Govoni, Stefano; Racchi, Marco; Masoero, Elisabetta; Zamboni, Michele; Ferini‐Strambi, Luigi

doi:10.1038/sj.mp.4000801

Cited by 30 publications

(19 citation statements)

References 58 publications

(66 reference statements)

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“…Thus, results from experiment 1 showed that FLX administration exacerbates Parkinsonian-like motor dysfunctions induced by a low dose of TBZ in rats. These results are consistent with studies showing potentiation of haloperidol-induced motor impairments (eg, catalepsy and bradykinesia) by FLX in rodents (Tatara et al, 2012), and with numerous clinical reports linking motor side effects and worsening Parkinsonism with FLX treatment of depression (Leo, 1996;Gerber and Lynd, 1998;Govoni et al, 2001;Madhusoodanan et al, 2010).…”

Section: Discussionsupporting

confidence: 87%

“…Yet, controlled clinical trials, metaanalyses, and systematic review collectively suggest that SSRIs are no more effective than placebo in treating depression in the context of PD (Skapinakis et al, 2010;Aarsland et al, 2009). Furthermore, SSRI administration has been associated with a number of motor side effects, and may be implicated in increased motor disability in PD patients (Leo, 1996;Richard et al, 1997;Govoni et al, 2001;Veazey et al, 2005;Aarsland et al, 2009). There are presently more than 100 published reports of 'extrapyramidal' symptoms (eg dystonia, akathisia, dyskinesia, and Parkinsonism, including tremor) associated with SSRI treatment; fluoxetine (Prozac; ( ± )-N-methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine hydrochloride; FLX) has been implicated in the majority of these reports (Madhusoodanan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…FLX primarily functions as an inhibitor of the serotonin (5-HT) transporter, preventing uptake of 5-HT and ultimately resulting in increased activation of a variety of 5-HT receptors, including the 5-HT 1A , 5-HT 2A , and 5-HT 2C receptors found throughout the striatum (Nutt et al, 1999;Alex and Pehek, 2007;More et al, 2014). Interactions between 5-HT and DA neurotransmission are strongly implicated in the generation of motor dysfunctions associated with FLX treatment (Morelli et al, 2011), as DA release and metabolite production are inhibited by increased synaptic levels of 5-HT (Govoni et al, 2001;Morelli et al, 2011). Activation of 5-HT 2C receptors has been linked to decreased DA synthesis, neural activity, and release in the nigrostriatal and mesolimbic DA pathways (Alex and Pehek, 2007;More et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism

Podurgiel

Milligan

Yohn

et al. 2015

Neuropsychopharmacol

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The cardinal motor symptoms of Parkinson's disease (PD) include resting tremor, akinesia, bradykinesia, and rigidity, and these motor abnormalities can be modeled in rodents by administration of the VMAT-2 (type-2 vesicular monoamine transporter) inhibitor tetrabenazine (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7, 11b hexahydrobenzo[a]quinolizin-2-one; TBZ). Depression is also commonly associated with PD, and clinical data indicate that selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine ((±)-N-methyl-γ-[4-(trifluoromethyl)phenoxy]benzenepropanamine hydrochloride; FLX) are frequently used to treat depression in PD patients. The aim of the present study was to characterize the effect of FLX on the motor dysfunctions induced by a low dose of TBZ (0.75 mg/kg), and investigate the neural mechanisms involved. This low dose of TBZ was selected based on studies with rat models of depressive symptoms. In rats, coadministration of FLX (2.5, 5.0, and 10.0 mg/kg) increased TBZ-induced oral tremor (tremulous jaw movements), and decreased locomotor activity compared with administration of TBZ alone. Coadministration of the serotonin 5-HT2A/2C antagonist mianserin (2.5 and 5.0 mg/kg) attenuated the increase in oral tremor induced by coadministration of TBZ (0.75 mg/kg) with FLX (5.0 mg/kg). Consistent with these behavioral data, coadministration of TBZ and FLX decreased DA tissue levels in the rat ventrolateral neostriatum compared with TBZ alone, and coadministration of mianserin with TBZ and FLX attenuated this effect, increasing DA tissue levels compared with the TBZ/FLX condition. These data suggest that SSRI administration in PD patients may result in worsening of motor symptoms, at least in part, by exacerbating existing DA depletions through 5-HT2A/2C-mediated modulation of DA neurotransmission.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fluoxetine Administration Exacerbates Oral Tremor and Striatal Dopamine Depletion in a Rodent Pharmacological Model of Parkinsonism

Podurgiel

Milligan

Yohn

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

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“…All these studies were negative, probably not surprisingly given the lack of theoretical basis for such combination in EPS. Moreover, the SSRIs are reported to even cause EPS in patients with major depressive disorder ( Govoni et al, 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia

Terevnikov¹,

Joffe²,

Stenberg³

2015

IJNPPY

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Background:Despite adequate treatment with antipsychotics, a substantial number of patients with schizophrenia demonstrate only suboptimal clinical outcome. To overcome this challenge, various psychopharmacological combination strategies have been used, including antidepressants added to antipsychotics.Methods:To analyze the efficacy of add-on antidepressants for the treatment of negative, positive, cognitive, depressive, and antipsychotic-induced extrapyramidal symptoms in schizophrenia, published randomized controlled trials assessing the efficacy of adjunctive antidepressants in schizophrenia were reviewed using the following parameters: baseline clinical characteristics and number of patients, their on-going antipsychotic treatment, dosage of the add-on antidepressants, duration of the trial, efficacy measures, and outcomes.Results:There were 36 randomized controlled trials reported in 41 journal publications (n=1582). The antidepressants used were the selective serotonin reuptake inhibitors, duloxetine, imipramine, mianserin, mirtazapine, nefazodone, reboxetin, trazodone, and bupropion. Mirtazapine and mianserin showed somewhat consistent efficacy for negative symptoms and both seemed to enhance neurocognition. Trazodone and nefazodone appeared to improve the antipsychotics-induced extrapyramidal symptoms. Imipramine and duloxetine tended to improve depressive symptoms. No clear evidence supporting selective serotonin reuptake inhibitors’ efficacy on any clinical domain of schizophrenia was found. Add-on antidepressants did not worsen psychosis.Conclusions:Despite a substantial number of randomized controlled trials, the overall efficacy of add-on antidepressants in schizophrenia remains uncertain mainly due to methodological issues. Some differences in efficacy on several schizophrenia domains seem, however, to exist and to vary by the antidepressant subgroups—plausibly due to differences in the mechanisms of action. Antidepressants may not worsen the course of psychosis. Better designed, larger, and longer randomized controlled trials are needed.

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“…These cases have not escaped the awareness of clinician authors, and as such, several reviews have been published over time. [4][5][6][7][8][9][10][11][12][13][14] Typically, EPRs are related to antipsychotic treatment and are believed to be related to postsynaptic dopamine-2 (D2) receptor antagonism in the nigrostriatum. As a result, patients who are treated with an antipsychotic are routinely monitored for the development of one, or more, EPR.…”

Section: Introductionmentioning

confidence: 99%