Effects of gradual discontinuation of selective serotonin reuptake inhibitors in panic disorder with agoraphobia

In the third patient in Fava et al. 2007, all treatment approaches failed, and PAWS persisted beyond the 12 months of study follow-up.

“In the third patient, all treatment approaches failed, and PAWS persisted beyond the 12 months of study follow-up.”

Two included studies indicate that long-term paroxetine use may carry an increased risk of PAWS.

“Two of the included studies indicate that in particular long-term paroxetine use may carry an increased risk of PAWS (Belaise et al., 2012; Fava et al., 2007)”

Fava et al. 2007 reported three patients with PAWS in whom symptoms lasted for at least 3 months before psychopharmacological interventions led to symptom relief in two of them.

“One small prospective cohort study (Fava et al., 2007) reported on three patients with PAWS, in whom symptoms lasted for at least 3 months before psychopharmacological interventions led to symptom relief in two of them.”

New withdrawal symptoms are usually the same and common to all psychotropic medications during withdrawal, but also specific and unique for a drug class.

“New symptoms are usually the same, common to all psychotropic medications during withdrawal [12, 15, 23] (e.g., nausea, headaches, sleep disturbances) [10], but also specific and unique for a drug class (e.g., specific serotonin-related symptoms: flu-like symptoms, diarrhea, confusion) [10].”

In Fava et al. 2007, 3 out of 20 participants (15%) developed PAWS after slow drug tapering.

“In this small prospective cohort study (Fava et al., 2007), it was found that 3 out of 20 participants (15%), all of whom had been prescribed the antidepressant paroxetine long-term, developed PAWS after slow drug tapering.”

One included study was a prospective cohort study but included only 20 patients with panic disorder and agoraphobia treated in a single outpatient clinic in Italy.

“One study was a prospective cohort study (Fava et al., 2007), but it included only 20 patients with panic disorder and agoraphobia treated in a single outpatient clinic in Italy.”

Fava et al. 2007 described a severe pattern of alternating symptoms, including worsened mood, fatigue, emotional instability, sleep disturbances, irritability, and hyperactivity in all three patients with PAWS.

“The prospective cohort study by Fava et al. (2007) described a severe pattern of alternating symptoms, including worsened mood, fatigue, emotional instability, sleep disturbances, irritability, and hyperactivity in all three patients with PAWS.”

The Fava et al. 2007 sample was drawn from a single outpatient clinic in Italy and all participants were diagnosed with panic disorder and agoraphobia, which restricts the representativeness of the prevalence estimate.

“The study sample of n = 20 was drawn from a single outpatient clinic in Italy and the participants were all diagnosed with a panic disorder and agoraphobia, which further restricts the representativeness of this prevalence estimate.”

Fava et al. 2007 described three patients in whom low-dose clonazepam and/or reinstitution of the original antidepressant medication helped to ameliorate the withdrawal symptoms in two of three patients.

“Fava et al. (2007) described three patients in whom low-dose clonazepam and/or reinstitution of the original antidepressant medication helped to ameliorate the withdrawal symptoms in two of three patients.”

The syndromes in Fava et al. 2007 met the DSM-IV criteria for cyclothymic disorder except for the required duration criterion.

“The syndromes met the DSM-IV criteria for cyclothymic disorder except for the required duration criterion.”

All three participants who developed PAWS in Fava et al. 2007 had been prescribed paroxetine long-term.

“In this small prospective cohort study (Fava et al., 2007), it was found that 3 out of 20 participants (15%), all of whom had been prescribed the antidepressant paroxetine long-term, developed PAWS after slow drug tapering.”

Based on the scientific literature, specifically the findings of Fava et al. (2007) and Lewis et al. (2021), persistent antidepressant withdrawal symptoms do certainly exist.

“Based on the scientific literature, specifically emphasizing the findings of a small but rigorous cohort study (Fava et al., 2007) and the results of a large RCT (Lewis et al., 2021), we can merely conclude that persistent antidepressant withdrawal symptoms do certainly exist.”

Elimination rates of benzodiazepines predict the time of onset of new withdrawal symptoms.

“Elimination rates of benzodiazepines also predict the time of onset [15] of new withdrawal symptoms”

The scientific literature on protracted antidepressant withdrawal consists mainly of a few qualitative studies and case reports, with one small cohort study of three PWS cases.

“The scientific literature’s foundation of case reports documenting withdrawal syndrome thus far contains only a few studies qualitatively describing protracted withdrawal,19,20,35,36 and one small cohort study including three cases of PWS.37”

New withdrawal symptoms are common to all CNS drugs, including opioids, barbiturates, alcohol, antidepressants, antipsychotics, and benzodiazepines.

“They are common to all CNS drugs, including opioids, barbiturates, alcohol, antidepressants, antipsychotics, and benzodiazepines [5,10,11] .”

Other new withdrawal symptoms more specific to a certain class of CNS drugs include lacrimation, rhinorrhea, and sneezing for opiates, paroxysmal sweats for alcohol, and increased appetite for nicotine.

“Other new withdrawal symptoms that may be more specific to a certain class of CNS drugs include lacrimation, rhinorrhea, and sneezing for opiates, paroxysmal sweats for alcohol, and increased appetite for nicotine [10,23,24] .”

The appearance or onset of withdrawal symptoms depends on the duration of action; short-acting drugs have an early peak of onset.

“The appearance or onset of withdrawal symptoms depends on the duration of action; for example, short-acting drugs have an early peak of onset [10] .”

High potency and short and intermediate half-life compounds tend to carry greater risks for withdrawal symptoms, in addition to drug dependence.

“High potency and short and intermediate half-life compounds tend to carry greater risks for withdrawal symptoms, in addition to drug dependence [6,9,10] .”

Major complications of withdrawal may occur, such as seizures, suicide and psychoses, and in cases of barbiturate or alcohol abuse, even death.

“However, major complications of withdrawal may occur, such as seizures, suicide and psychoses [10] , and, in cases of barbiturate or alcohol abuse, even death [25] .”

Rebound with short-acting drugs may be best illustrated by withdrawal from cocaine and heroin, which both have a rapid onset and brief duration of action.

“Rebound with short-acting drugs may be best illustrated by withdrawal from cocaine and heroin, which both have a rapid onset and brief duration of action [10,23] .”

Persistent postwithdrawal disorders have been described with different classes of CNS drugs (e.g. protracted insomnia for alcohol and benzodiazepine withdrawal and major depression/dysphoria for cocaine and amphetamine withdrawal), and even more so with specific drugs (e.g. quetiapine and paroxetine) within a drug class.

“Persistent postwithdrawal disorders have been described with different classes of CNS drugs (e.g.protracted insomnia for alcohol and benzodiazepine withdrawal [10,36] and major depression/dysphoria for cocaine and amphetamine withdrawal [10,23] ), and even more so with specific drugs (e.g.quetiapine and paroxetine) within a drug class [6,15,16,33] .”