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5.2.1 Antidepressants

Although further and better research is clearly needed in this area, it is safe to say, from the best available studies to date, that at least half of people who try to stop, or reduce, their antidepressants will experience withdrawal effects, while about half of those people describe the effects as ‘severe’, and the duration varies enormously.1

5.2.1.1 Withdrawal reactions

Table 1: Withdrawal effects of antidepressants

Flu-like symptoms
Nausea
Dizziness
‘Brain zaps’
Emotional blunting
Sexual dysfunction
Sweating
Vivid dreams

Muscle stiffness
Hallucinations
Imbalance
Agitation
Headaches
Insomnia
Anxiety
Irritability

Diarrhoea
Fatigue
Twitching
Heart palpitations
Sensory hypersensitivity
Confusion
Inability to cry

Shorter half-life antidepressants (such as venlafaxine, paroxetine, duloxetine and imipramine) are expelled from the body more rapidly (also see section 5.1). Antidepressants that are eliminated more slowly (e.g. fluoxetine) allow the body time to re-adapt to being without the drug and hence the withdrawal reactions are usually (but not always) less severe.

5.2.1.2 Incidence – How many people experience withdrawal reactions?

A recent systematic review of the literature on withdrawal from all types of antidepressants, but predominantly covering selective serotonin reuptake inhibitors (SSRIs), revealed 17 studies that contained data on withdrawal incidence – namely, on how many people taking antidepressants will experience withdrawal1.

Seventeen different studies were reviewed (these ranged from small, industry funded drug trials to large independent online surveys of people who take antidepressants). These produced incidence rates from five percent to 97%. Of these 17 studies, three were excluded on methodological grounds.* The remaining 14 studies were methodologically diverse (comprising six RCTs, five naturalistic studies and three surveys) and produced incidence rates ranging from 27% to 86%. When grouping the three types of study together, the weighted average for each group was:

  • The three surveys = 57.1% (1790/3137),
  • The five naturalistic studies – 52.5% (127/242)
    The six RCTs – 50.7% (341/673)

* Two excluded studies, which reported low incidence rates (12%), were simply ‘chart reviews’ of medical notes (Coupland et al., 1996; Himei & Okamura, 2006) which are notoriously weak owing to their reliance on practitioners being aware of, and recording, withdrawal reactions. A further excluded study, which reported very high incidence rates (97%), comprised 693 people who were all involved in a withdrawal programme using tapering strips (and were answering a question about their previous attempts to come off) (Groot & Van Os, 2018). This sample was unrepresentative because people who have not experienced withdrawal reactions are unlikely to enter a tapered withdrawal programme. (See 5.4.1 for information about tapering).

As getting similar findings from different methodologies is typically seen to strengthen confidence in an overall, combined estimate, the most recent evidence suggests that at least half of people suffer withdrawal reactions when trying to come off antidepressants (median 55%).

5.2.1.3 Treatment duration – does the length of time spent on an antidepressant affect withdrawal?

When comparing the studies, there was no obvious relationship between incidence of withdrawal reactions and duration of treatment, but, as noted above, the information on treatment duration was incomplete. There were some useful data, however, within some of the studies. Two studies found no significant difference in the treatment duration of those who did and did not experience withdrawal reactions,2,3 demonstrating that withdrawal reactions do not only occur in people who had been on the drugs for long periods of time. Both an international online survey4 and an even larger NZ survey5,6 found that those who had been on the drugs for more than three years were significantly more likely to report withdrawal effects, but these findings could partly be explained by a larger number of withdrawal attempts. Most participants in all four of these studies had been on antidepressants for months or years, so the studies were not able to assess whether there is a plateau, within the first few weeks of treatment, beyond which the probability of withdrawal reactions does not increase for most people.

5.2.1.4 Self-reported addiction

Another approach to the question of the incidence of withdrawal reactions is to ask how many people report becoming ‘addicted’ to or dependent on antidepressants. Traditional studies ignore this somewhat taboo topic. We do have important data, however, on how many recipients experience antidepressants as ‘addictive’.

Three studies have provided percentages, which range from 27% to 37%. Of 192 people taking antidepressants in the Netherlands, 30% described their drugs as addictive. The two large online surveys found that 27% of 1,5215 and 37% of 9434 also described their antidepressants as addictive. The weighted average of these three studies is 30.8%. While it is difficult to extrapolate these findings to the wider population of those taking antidepressants, it is nevertheless important to note in these studies that nearly a third of those taking antidepressants, when asked, report being addicted to the drugs, according to their definition of the term.

5.2.1.5 Severity of withdrawal based on surveys

Unfortunately, questions as to the severity of withdrawal have not been sufficiently addressed in randomised trials. Therefore, the preponderance of data we have on withdrawal severity is derived from direct-to-consumer surveys.1 As it is difficult to extrapolate from surveys to the general antidepressant population (e.g. people who experience withdrawal may be more likely to respond to surveys) population level estimates are hard to make. Nonetheless, the survey data are important as they indicate that for a proportion of those taking antidepressants withdrawal can be severe.

For example, in a recent New Zealand survey, 46% of the 750 who experienced withdrawal effects reported those effects to be ‘severe’ rather than ‘mild’ or ‘moderate’,5,6 which was very similar to the 43% finding in the international sample.4 Furthermore, a recent Dutch study found that of 671 people who had experienced some degree of withdrawal effects, 51% reported the most extreme of six levels of withdrawal. Additionally, a recent international survey of 605 people, all self-identifying on antidepressant withdrawal websites as experiencing withdrawal, asked participants to rate on a scale of 0–10 how severely withdrawal had impacted upon their life. The average rating was 8.4 with 41% indicating the highest level of severity on the scale.7

The percentages selecting the most extreme level of severity on offer in each of these four studies ranged from 41% to 51%, with a weighted average of 45.3%. So regardless of the scale used, nearly half of all people surveyed in these studies who experienced withdrawal effects ticked the most extreme level of severity on the scale they were presented with.

5.2.1.6 Difficulty, and duration, of withdrawal

In a recent UK survey, 245 responded to the question ‘How easy did you find it to come off your medication?’

  • 20% ticked ‘very easy’;
  • 51% ticked ‘fairly easy’; and
  • 29% ticked ‘not easy at all’.8

Of the 247 who responded to ‘How long did it take to come off your medication?’

  • the majority (68%) did so within three months;
  • but 21% took between three to six months;
  • 6% took between six and 12 months; and
  • 5% took more than a year.8

5.2.1.7 Duration of withdrawal reactions

A recent systematic review of antidepressant withdrawal identified 10 relevant studies that had gathered data on the duration of withdrawal reactions.1 While this review could not provide firm conclusions about the average duration of withdrawal reactions (because of the variety of methodologies and ways duration was reported), it did conclude that there is far more variability in duration than previously believed.E Nine of the 10 studies found that a significant number of people experience withdrawal reactions beyond a week, while seven of the 10 studies showed that it is not uncommon for people to experience withdrawal for several months.

This review’s findings were consistent with other reviews. For instance, a 2015 review of quantitative studies and case reports noted that in only four out of 18 case reports (22%) did withdrawal reactions spontaneously remit within two weeks, and in two cases withdrawal effects were ongoing a year after discontinuation. It concluded that withdrawal reactions ‘typically last a few weeks’ but noted that ‘many variations are possible, including…longer persistence of disturbances’.9 A more recent review, of research just on withdrawal from serotonin-norepinephrine reuptake inhibitors (SNRIs), concluded that ‘Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well’ and recommended that ‘Clinicians need to add SNRIs to the list of drugs potentially inducing withdrawal symptoms upon discontinuation’.9

Even longer durations have been reported by two real life samples of people experiencing difficulties with withdrawal. For instance, a recent international survey of people self-identifying as experiencing withdrawal found that when 605 people who had experienced withdrawal were asked ‘How long have you experienced withdrawal symptoms?’ 87% responded at least two months, 59% at least one year, and 16% more than three years.7 Additionally, a recent content analysis of a population likely to have experienced withdrawal difficulties assessed the content of 137 online posts about AD withdrawal in the real world. The mean duration of withdrawal reactions was 90.5 weeks for the 97 taking SSRIs and 50.8 weeks for the 40 taking SNRIs. Although neither of the above two study samples are representative of all those taking antidepressants, they nevertheless indicate that it is not as rare as sometimes thought for withdrawal reactions to last more than a year.1

5.2.1.8 Qualitative studies on antidepressant withdrawal

Qualitative studies are consistent with and serve to bring to life the findings of the recent review of quantitative research.1 Illustrative examples of personal testimony regarding the severity and duration of withdrawal effects follow:

“I am currently trying to wean myself off of Venlafaxine, which honestly is the most awful thing I have ever done. I have horrible dizzy spells and nausea whenever I lower my dose.

“It took me almost two years to get off Paroxetine and the side effects were horrendous. I even had to quit my job because I felt sick all the time. Even now that I am off of it, I still feel electric shocks in my brain.”10

“It took me two months of hell to come off the antidepressants. Was massively harder than I expected.

“I forgot to take my Citalopram for two days and woke up one morning with severe dizziness. It was so extreme that I fell over when I tried to get out of bed, and I threw up.”6

“The withdrawal effects if I forget to take my pill are severe shakes, suicidal thoughts, a feeling of too much caffeine in my brain, electric shocks, hallucinations, insane mood swings. … kinda stuck on them now coz I’m too scared to come off it.”11

“While there is no doubt I am better on this medication, the adverse effects have been devastating – when I have tried to withdraw – with ‘head zaps’, agitation, insomnia and mood changes. This means that I do not have the option of managing the depression any other way because I have a problem coming off this medication.

“The difficulty of getting off has been a tough road and taken me years of trying and is something that doctors could be more knowledgeable of and supportive with.”12

1. Davies, J. & Read, J. (2018). A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: Are guidelines evidence based? Addictive Behaviors. pii: S0306-4603(18)30834-7. doi: 10.1016/j.addbeh.2018.08.027. [Epub ahead of print]
2. Himei, A. & Okamura, T. (2006). Discontinuation syndrome associated with paroxetine in depressed patients: A retrospective analysis of factors involved in the occurrence of the syndrome. CNS Drugs 20, 665-672.
3. Yasui-Furukori, N., Hashimoto, K., Tsuchimine, S., Tomita, T., Sugawara, N., Ishioka, M. & Nakamura, K. (2016). Characteristics of escitalopram discontinuation syndrome: A preliminary study. Clinical Neuropharmacology, 39, 125–127.
4. Read, J. & Williams, J. (2018). Adverse effects of antidepressants reported by 1,431 people from 38 Countries: Emotional blunting, suicidality, and withdrawal effects. Current Drug Safety, 13. doi: 10.2174/15748863136661806050095.
5. Read, J., Cartwright, C. & Gibson, K. (2014). Adverse emotional and interpersonal effects reported by 1,829
New Zealanders while taking antidepressants. Psychiatry Research, 216, 67–73.
6. Read, J., Cartwright, C. & Gibson, K. (2018). How many of 1,829 antidepressant users report withdrawal symptoms or addiction? International Journal of Mental Health Nursing. doi.org/10.1111/inm.12488.
7. Davies, J. & Pauli, G. (2018). A survey of antidepressant withdrawal reactions and their management in primary care. Report from the All Party Parliamentary Group for Prescribed Drug Dependence (2018).
8. Read, J., Gee, A., Diggle, J. & Butler, H. (2018). Staying on and coming off: The experiences of 752 antidepressant users. Addictive Behaviors. doi.org/10.1016/j.addbeh.2018.08.021.
9. Fava, G., Gatti, A., Belaise, C., Guidi, J. & Offidani, E. (2015). Withdrawal symptoms after selective serotonin reuptake inhibitors discontinuation: A systematic review. Psychotherapy and Psychosomatics, 84, 72–81.
10. Pestello, F. & Davis-Berman, J. (2008). Taking anti-depressant medication: A qualitative examination of internet postings. Journal of Mental Health, 17, 349–360.
11. Gibson, K., Cartwright, C. & Read, J. (2016). ‘In my life antidepressants have been….’: A qualitative analysis of users’ diverse experiences of antidepressants. BMC Psychiatry, 16, 135.
12. Cartwright, C., Gibson, K., Read, J., Cowan, O. & Dehar, T. (2016). Long-term antidepressant use: Patient perspectives of benefits and adverse effects. Patient preference and adherence, 10, 1401–1407. doi:10.2147/PPA.S110632.

5.2.2 Benzodiazepines and Z-drugs

The incidence of withdrawal range in different studies from 20% to 100%. Rather than report all the studies that draw these estimates, it can safely be concluded that these drugs are highly addictive and that dependence and withdrawal reactions are common. For this reason, the British National Formulary (2012)1 recommends that uninterrupted usage, for both benzodiazepines and Z-drugs, does not exceed four weeks, because the drugs so quickly lead to tolerance and to physical and potentially psychological dependence. However, it is now clear that there are substantial numbers of people taking them for longer than two years (see 4.3.5).

Benzodiazepines are a drug-class that includes sedatives and anxiolytics:

  • Sedatives (otherwise known as hypnotics or sleeping pills), such as flurazepam, temazepam, nitrazepam and loprazolam, tend to be short acting.
  • Anxiolytics (also known as tranquillisers or anti-anxiety drugs), such as diazepam, alprazolam, chlordiazepoxide, oxazepam and lorazepam, are longer-acting.

‘Z-drugs’ are non-benzodiazepine sedatives/hypnotics. The Z-drugs available in the UK are zaleplon, zolpidem, and zopiclone.

Both benzodiazepines and Z-drugs boost the effect of a substance in the brain called Gabba Amino Butyric Acid (GABA), which is thought to have a calming effect. Because the Z-drugs are short-acting, it was hoped they may avoid or minimise dependence and withdrawal. However, there seems to be no robust evidence that they are significantly less addictive, or less often lead to withdrawal reactions, than short-acting benzodiazepines.

5.2.2.1 Withdrawal reactions

Someone who uses benzodiazepines for more than a few (two to four) weeks is likely to experience withdrawal reactions when they stop them. The reactions include anxiety, agitation, insomnia and muscle stiffness. Since benzodiazepines suppress nervous activity, stopping them increases the activity of the nervous system. Withdrawal can therefore induce unusual and usually unpleasant sensory experiences such as tingling and numbness, electric shock-like feelings and occasionally delusions and hallucinations.

Withdrawal reactions usually start between six and 48 hours of stopping, or after reducing the dose of a benzodiazepine, but can start later for longer-acting drugs, such as anxiolytics.

The most common withdrawal effects of these drugs include:

Table 2: Most common withdrawal effects of benzodiazepines and Z-drugs

Sweating
Nausea
Dizziness
Headaches

Insomnia
Anxiety
Irritability
Agitation

Muscle stiffness
Twitching
Heart palpitations
Sensory hypersensitivity

But many other reactions may be experienced, including:

Table 2.1: Other withdrawal effects of benzodiazepines and Z-drugs

Panic attacks
Weight loss
Depression
Agoraphobia
Restlessness
Abdominal cramps

Poor memory and concentration
Burning sensations in the skin
Flu-like symptoms
Blurred vision
Nightmares

Lethargy
Sore tongue and metallic taste
Tinnitus (ringing in the ears)
Tinging in the hands and feet
Hallucinations and delusions

Sudden cessation of benzodiazepines and Z-drugs increases the probability of these withdrawal reactions and may also cause grand mal seizures, hallucinations, and suicidality.1-7

5.2.2.2 Severity of withdrawal

The severity of these reactions increases with:

  • longer usage
  • higher dosage
  • the use of multiple benzodiazepines
  • oral rather than injected use
  • shorter half-life benzodiazepines (such as lorazepam or temazepam) because these are expelled from the body more rapidly. Drugs that are eliminated more slowly allow the body time to re-adapt to being without the drug and hence the withdrawal reactions are usually (but not always) less severe
  • an abrupt cessation, and so it is recommended that benzodiazepines are withdrawn slowly.

5.2.2.3 Incidence – How many people experience withdrawal reactions?

Although initially marketed as a non-addictive alternative to barbiturates, benzodiazepines have long been recognised as highly addictive. Estimates of how many people experience withdrawal effects are determined by how long they have been on the drugs, how quickly they withdrew from them, and the definition or measure used to assess the withdrawal effects. Approximately 40% of people will become addicted within six weeks of taking them.8 Some research finds that everyone who has been on benzodiazepines for at least six months and then tries to stop the drugs quickly will experience some withdrawal reactions, and for 40% the reactions will be moderate or severe.3

5.2.2.4 Duration

Estimates of how long withdrawal reactions last vary greatly, and are largely determined by duration of treatment, dosage and drug type. Almost all people stopping or reducing benzodiazepines will experience an ‘acute’ phase of withdrawal, which typically lasts for two weeks to two months. A minority will experience protracted (or ‘post-acute’) withdrawal phases, for a year or more,9,1,10,11 with anecdotal reports of five to 10 years.

1. British National Formulary (2012). BNF 63. London: Pharmaceutical Press.
2. Dodds, T. (2017). Prescribed benzodiazepines and suicide risk: A review of the literature. Primary Care Companion for CNS Disorders 19. doi:10.4088/PCC.16r02037.
3. Hood, S., Norman, A., Hince, D., Melichar, J. & Hulse, G. (2014). Benzodiazepine dependence and its treatment with low dose flumazenil. British Journal of Clinical Pharmacology 77, 285–94.
4. Lader, M. (2012). Benzodiazepine harm: How can it be reduced? British Journal of Clinical Psychopharmacology, 77, 295–301.
5. Mind (2018). Sleeping pills and minor tranquillisers. https://www.mind.org.uk/information-support/drugs-and-treatments/sleeping-pills-and-minor-tranquillisers/withdrawal-effects-of-benzodiazepines/#.W0SbC4cVCpo. (Accessed July 2018.)
6. Moncrieff, J. (2009). A straight talking introduction to psychiatric drugs. Ross: PCCS Books.
7. Petursson, H. (1994). The benzodiazepine withdrawal syndrome. Addiction 89, 1455–9.
8. Royal College of Psychiatry (2018). Benzodiazepines. https://www.rcpsych.ac.uk/healthadvice/treatmentsandwellbeing/benzodiazepines.aspx. (Accessed July 2018.)
9. Authier, N., Balayssac, D., Sautereau, M., Zangarelli, A., Courty, P., Somogyi, A. … & Eschalier, A. (2009). Benzodiazepine dependence: Focus on withdrawal syndrome. Annales Pharmaceutiques Francaises, 67, 408–13.
10. Murphy, S. & Tyrer, P. (1991). A double-blind comparison of the effects of gradual withdrawal of lorazepam, diazepam and bromazepam in benzodiazepine dependence. British Journal of Psychiatry, 158, 511–6.
11. Soyka, M. (2017). Treatment of benzodiazepine dependence. New England Journal of Medicine, 376, 1147–1157.

5.2.3 Antipsychotics

The most recent survey found that of 105 people who tried to come off antipsychotics, 65 (62%) experienced unwanted withdrawal effects ‘across the full-range of physical, emotional, cognitive, and functional domains’1

Drugs that were developed in the 1950s to treat people diagnosed with schizophrenia were initially described as ‘major tranquillisers’, acknowledging their powerful sedating effects. They have since become known as ‘antipsychotics’ or ‘neuroleptics’. They are now often used on other groups besides those diagnosed with schizophrenia, including prisoners; children with learning and other difficulties, and people in care homes for the elderly. The first antipsychotics included chlorpromazine, haloperidol, pimozide and trifluoperazine. These ‘first generation’ antipsychotics had a disturbing adverse effects’ profile (including tardive dyskinesia – a usually irreversible movement disorder). A second generation of antipsychotics, sometimes referred to as ‘atypical’ were developed, in the 1990s.2 These include: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone.

We were introduced to the concept of withdrawal effects after stopping antipsychotics in section 4.4.5, in relation to understanding efficacy studies. As is the case for other central nervous system drugs, such as benzodiazepines and alcohol, the brain can develop a tolerance to antipsychotics.3 Antipsychotics, however, are clearly not addictive, if one’s definition of addiction involves a craving for the drugs. In fact, because of the unpleasant adverse effects many people try hard to stop taking antipsychotics soon after commencing them,4,5 or have to be forced to take them against their will via the Mental Health Act, often with involuntary, long-acting injections.6 About half of people prescribed antipsychotics for ‘schizophrenia’ are ‘noncompliant’.5 In one large sample, 74% tried at least once to discontinue the antipsychotics within 18 months of starting treatment.7

The adverse effects that lead to people trying to come off these drugs include8-11:

Table 3: The adverse effects that lead to people trying to come off these drugs

Sedation
Dizziness
Sexual dysfunction

Cardiovascular effects (arrhythmia & sudden cardiac death)
Akathisia (extreme restlessness)
Metabolic effects (obesity, glucose intolerance, high cholesterol and diabetes)

In an international survey of 832 people taking antipsychotics, twice as many (395) cited ‘unpleasant side effects’ than ‘felt better and didn’t need it’ (195) as their main reason for wanting to stop their antipsychotics.12

Despite not being addictive in the strict sense of that word, there are two types of withdrawal syndrome that can make it very difficult to reduce, or come off, these drugs. The first type has much in common with the withdrawal effects of the other central nervous system drugs discussed in this guidance, such as benzodiazepines. The second type is somewhat more specific to psychosis and/or antipsychotics.

5.2.3.1 Classic withdrawal reactions

A recent review3 found that antipsychotics share a range of ‘classic symptoms of withdrawal’ with all central nervous system drugs. These reactions, which usually emerge within four days of stopping, include:

Table 4: Classic withdrawal reactions associated with antipsychotic drugs

Nausea
Tremor
Anxiety
Agitation
Headache

Irritability
Aggression
Depression
Sleep disturbances
Decreased concentration

The reviewers suggest that these reactions usually last ‘up to six weeks’ and ‘may last more than six weeks and become a post-withdrawal disorder’ but the review provides no data to support these suggestions.

There are, in fact, relatively few studies of the frequency or duration of classic withdrawal reactions following discontinuation of antipsychotics. The largest direct-to-user, international survey, of 832 people prescribed/taking antipsychotic medication, found that 65% reported withdrawal effects when trying to stop or reduce, and that half of those people (51%) described those withdrawal effects as ‘severe’.12 Reported withdrawal was strongly correlated with duration of treatment (p < .001).

5.2.3.2 Antipsychotic induced psychosis and tardive dyskinesia

As described in section 4.4.3, antipsychotics blockade, to a varying degree, the dopamine system and other neurotransmitter systems (along with many other effects on the brain and body).13 This led to the notion that ‘schizophrenia’ is ‘caused’ by an overactive dopamine system, a hypothesis that was never proved and that is now largely abandoned. The brain tries to compensate for the blockade.

As early as 1974 Dr Solomon Snyder, Professor of Psychiatry and Pharmacology at John Hopkins University warned that:

Something within the neurons recognises this sudden absence of neurotransmitter molecules at their appropriate receptor site and one way or another transmits a message back to the dopamine neurons saying something like the following: ‘We don’t have enough dopamine. Please send us some more!’ Whereupon the dopamine neuron in question proceeds to fire at a more rapid rate.14

It has since been established that the brain’s attempted compensation also includes an increase in the number, and sensitivity, of dopamine receptor cells,3 a process that is not unique to antipsychotics. When an antipsychotic, and the dopamine blockade, are removed, or reduced, the brain is effectively overwhelmed with dopamine, partly because of the abnormal drug-induced sensitivity and number of dopamine receptor cells. This process is likely to apply to the other neurochemical systems that antipsychotics influence. These effects may result in a withdrawal psychosis, which is often mistaken for a return of the ‘schizophrenia’ that the drugs were intended to treat. This in turn often leads to a reinstatement of the drugs that have, paradoxically, caused the neurotransmitter abnormalities.15,2,14

The first cases of dopamine ‘Supersensitivity Psychosis’ [SP] were reported 40 years ago.16 A 2006 reviewer of the available evidence concluded:

There is evidence to suggest that the process of discontinuation of some antipsychotic drugs may precipitate the new onset or relapse of psychotic symptoms. Whereas psychotic deterioration following withdrawal of antipsychotic drugs has traditionally been taken as evidence of the chronicity of the underlying condition, this evidence suggests that some recurrent episodes of psychosis may be iatrogenic [caused by medical treatment]. Clinicians may therefore want to re-evaluate the benefits of long-term treatment in some patients.15 [Definition added]

There have been two recent, comprehensive reviews of the research literature on what now tends to be called ‘antipsychotic-induced Dopamine Supersensitivity Psychosis’ or ‘Supersensitivity Psychosis’ [SP] for short.3,17 One of the reviewers has designed criteria for two SP-based withdrawal syndromes, differentiated primarily by duration.

5.2.3.3 Rebound psychosis

One set of criteria for ‘Rebound Psychosis’, or ‘Withdrawal Psychosis’, are new psychosis reactions occurring, or old psychotic reactions recurring at above pre-treatment levels, after antipsychotic discontinuation, reduction, switching or in between dose intervals, usually (but not always) after about three months continuous exposure to the drug (the time necessary for increased dopamine receptor density to occur), and causing distress or impairment in functioning.3 These reactions usually appear within roughly four days of stopping oral antipsychotics but can take several weeks to emerge after cessation of long-acting injections. Rebound psychosis seems to be rather rare and the evidence most clearly supports it in relation to withdrawal from clozapine. British psychiatrist Joanna Moncrieff prefers the term ‘Rapid Onset Psychosis’ because it is neutral about the underlying mechanisms that, she suggests, are unclear.15

5.2.3.4 Persistant Postwithdrawal Supersensitivity Psychosis (PPSP)

Some researchers think that if Rebound Psychosis lasts longer than six weeks it should be reclassified as ‘Persistent Postwithdrawal Supersensitivity Psychosis’,3 but this area is hard to research and there are a range of opinions on the topic. If PPSP does exist it is one of two long-lasting Postwithdrawal Disorders caused by antipsychotics. The other is the movement disorder Tardive Dyskinesia that is discussed later.

5.2.3.5 How many people experience Rebound Psychosis and PPSP and for how long?

Few studies have addressed the incidence or duration of withdrawal induced psychosis. The 2006 review mentioned earlier had reported mostly only case studies, including nine people with no previous history of psychosis, whose new psychosis (typically hallucinations or delusions) usually responded to reintroduction of the antipsychotic.15 It was possible, however, to estimate that 20–25% of people withdrawing from a specific antipsychotic, clozapine, experienced Supersensitivity Psychosis (SP) or, as the reviewer prefers to call it ‘Rapid Onset Psychosis’.

An early study estimated that between 22% and 43% of 224 outpatients diagnosed with schizophrenia had SP. Two recent studies of atypical antipsychotics have reported SP incidence rates of 65%18 and 72%.19 All three studies, however, included cases that occurred due to tolerance (see section 5.1) while the person was still taking the antipsychotics. In the latter study, 42% of the cases were identified as ‘Rebound Psychosis’, which means that overall 30% of the sample, not all of whom had tried to stop their antipsychotics, had experienced withdrawal-induced psychosis. Another study found SP in 26% of people while changing from one antipsychotic to another.20 This is, however, a very difficult issue to research because of the fluctuating nature of the underlying psychosis.

In a recent international survey of people taking antipsychotics, ‘new or increased psychosis’ was the second most frequently reported ‘other side effect’ (after ‘akathisia/restlessness’). Thirteen reported new reactions and six reported the exacerbation of previous reactions. It was not known, however, how many of the instances of new or exacerbated psychosis reactions followed withdrawal.12

There is some evidence that antipsychotics with shorter half-lives (e.g. clozapine, metroclopromide, sulpiride and amisulpiride) are more likely to provoke SP.15,3

5.2.3.6 Tardive Dyskinesia

Tardive Dyskinesia (TD), also mentioned briefly in section 4.4.7, is a disabling, often irreversible, antipsychotic-induced neurological disorder involving uncontrollable movements of the face, tongue, arms and legs. It is also associated with cognitive impairment.21 It is likely, but not proven, to be the result of the over activity of the dopamine system caused by changes such as increased receptor numbers and sensitivity caused by antipsychotics. Some researchers consider TD to be either a component or predictor of SP.3,18,19 The average prevalence of TD in people taking antipsychotics is about 30%,22,23,2 rising to 57% after 15 years of treatment with first generation antipsychotics.22 The prevalence was thought to be lower for second generation, ‘atypical’, antipsychotics, but the difference has found to be slight or non-existent,22,2 or the consequence of second generation antipsychotics being prescribed at lower dosages. It is listed here as a withdrawal effect because the reactions of TD are often masked by the withdrawal of antipsychotics. When the drugs are stopped, it is thought that dopamine activity increases due to the increased sensitivity of the dopamine system produced by long-term antipsychotic treatment. Increased dopamine activity can produce abnormal movements. Thus, the overt physical reactions (but not necessarily the cognitive reactions) of TD are often either seen for the first time, or are exacerbated, after discontinuation, reduction or switching of antipsychotics.22,2 People over 50 are three to five times more likely than younger people to develop TD.22

5.2.3.7 Withdrawing slowly, with support

A recent study exploring the personal accounts of individuals discontinuing antipsychotic drugs identified that ‘weaving a safety net to safeguard well-being’ was a pivotal process in drug reduction. This involved taking precautionary steps prior to reducing drugs taken to establish interpersonal alliances with family, friends, support groups and mental health professionals that can be activated should problems arise.23

In another study, 55% of 105 people who attempted discontinuation of APs described successfully stopping all APs for varying lengths of time, half reported no current use, and half described having some form of professional, family, friend, and/or service user or peer support for their attempt. Having support was associated with less relapse.1 Furthermore, withdrawing gradually across more than one month was positively associated with successful withdrawal.24 There will, of course, be large variability in how long people need to take to withdraw.

1. Larsen-Barr, M., Seymour, F., Read, J. & Gibson, K. (2018a). Attempting to discontinue antipsychotic medication: Withdrawal methods, relapse and success. Psychiatry Research, 270, 365–374
2. Hutton, P., Weinamann, S., Bola, J. & Read, J. (2013). Antipsychotic drugs. In J. Read & J. Dillon (eds.). Models of madness: Psychological, social and biological approaches to psychosis (2nd edition). London: Routledge, pp.105–24.
3. Chouinard, G., Samaha, A., Chouinard, V., Peretti, C., Kanahara, N., Takase, M. & Iyo, M. (2017). Antipsychotic-induced dopamine supersensitivity psychosis: Pharmacology, Criteria, and therapy. Psychotherapy and Psychosomatics, 86, 189–219.
4. Cooper, D., Moisan, J., Gaudet, M., Abdous, B. & Gregoire, J. (2005). Ambulatory use of Olanzapine and Risperidone:
A population-based study on persistence and the use of concomitant therapy in the treatment of schizophrenia. The Canadian Journal of Psychiatry, 50, 901–908.
5. Perkins, D. (2002). Predictors of noncompliance in patients with schizophrenia. Journal of Clinical Psychiatry, 63, 1121–1128.
6. West, J., Marcus, S., Wilk, J., Countis, L., Regier, D. & Olfson, M. (2008). Use of depot antipsychotic medications for medication nonadherence in schizophrenia. Schizophrenia Bulletin, 34, 995–1001.
7. Lieberman, J., Stroup, T., McEvoy, J., Swartz, M., Rosenheck, R., Perkins, D. … & Severe, J. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine, 353, 1209–1223.
8. Ho, B., Andreasen, N., Ziebell, S., Pierson, R. & Magnotta, V. (2011). Long-term antipsychotic treatment and brain volumes. Archives of General Psychiatry, 68, 128–137.
9. Longden, E. & Read, J. (2016). Assessing and reporting the adverse effects of antipsychotic medication: A systematic review of clinical studies, and prospective, retrospective, and cross-sectional research. Clinical Neuropharmacology, 39, 29–39.
10. Weinmann, S., Read, J. & Aderhold, V. (2009). The influence of antipsychotics on mortality in schizophrenia: A systematic review. Schizophrenia Research, 113, 1–11.
11. Weinmann, S. & Aderhold, V. (2010). Antipsychotic medication, mortality and neurodegeneration. Psychosis, 2, 50–69.
12. Read, J. & Williams, J. (2019). Positive and negative effects of antipsychotic medication: An international online survey of 832 recipients. Current Drug Safety, 14. doi: 10.2174/157488631 4666190301152734.
13. Moncrieff, J. (2009). A straight talking introduction to psychiatric drugs. Ross: PCCS Books.
14. Snyder, S. (1974). Madness and the Brain. New York: McGraw-Hill.
15. Moncrieff, J. (2006). Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse. Acta Psychiatrica Scandinavica, 114, 3–13.
16. Chouinard, G., Jones, B. D. & Annable, L. (1978). Neuroleptic-induced supersensitivity psychosis. The American journal of psychiatry.
17. Yin, J., Barr, A., Ramos-Miguel, A. & Procyshyn, R. (2017). Antipsychotic induced dopamine supersensitivity psychosis: A comprehensive review. Current Neuropharmacology, 15, 174–183.
18. Kimura, H., Kanahara, N., Komatsu, N., Ishige, M., Muneoka, K., Yoshimura, M. … & Hashimoto (2014). A prospective comparative study of risperidone long-acting injectable treatment-resistant schizophrenia with dopamine supersensitivity psychosis. Schizophrenia Research, 155, 52–58.
19. Suzuki, T., Kanahara, N., Yamanaka, H., Takase, M., Kimura, H., Watanabe, H. & Iyo, M. (2015). Dopamine supersensitivity psychosis as a pivotal factor in treatment-resistant schizophrenia. Psychiatry Research, 227, 278–282.
20. Takase, M., Kanahara, N., Oda, Y., Kimura, H., Watanabe, H., & Iyo, M. (2015). Dopamine supersensitivity psychosis and dopamine partial agonist: A retrospective survey of failure of switching to aripiprazole in schizophrenia. Journal of Psychopharmacology, 29(4), 383–389.
21. Waddington, J., Youssef, H. & Kinsella, A. (1990). Cognitive dysfunction in schizophrenia followed up over 5 years, and its longitudinal relationship to the emergence of tardive dyskinesia. Psychological Medicine, 20, 835–842.
22. D’Abreu, A., Akbar, U. & Friedman, J. (2018). Tardive dyskinesia: Epidemiology. Journal of Neurological Science, 389, 17–20.
23. Le Geyt, G., Awenat, Y., Tai, S. & Haddock, G. (2017). Personal accounts for discontinuing neuroleptic medication for psychosis. Qualitative Health Research, 27(4), 559–572. https://doi.org/10.1177/1049732316634047.
24. 24. Larsen-Barr, M., Seymour, F., Read, J. & Gibson, K. (2018b). Attempting to stop antipsychotic medication: Success, supports and efforts to cope. Social Psychiatry and Psychiatric Epidemiology, 53, 745–56.

5.2.4 Lithium and other ‘mood stabilisers’

The relatively small amount of research conducted suggests that reducing, or withdrawing from, Lithium does not seem to cause the physical reactions caused by coming off other psychiatric drugs. Several studies, however, show that stopping Lithium can cause a relapse of mania, and that the probability of having such a relapse when withdrawing after long-term use is higher than before Lithium was started.1–4

Lithium is a toxic alkali metal, similar to sodium and potassium. It is prescribed primarily for people who experience relatively extreme emotional highs and lows, who often receive the diagnostic label ‘Manic Depression’ or, more recently, ‘Bipolar Disorder’. The dose considered to be therapeutic is so close to the dose that causes a hazardous toxic state (which can be fatal if the Lithium is not stopped immediately) that levels of lithium in the blood have to be carefully monitored.2

The mental health charity Mind advises that:

There do not appear to be physical withdrawal symptoms with lithium. However, if you come off lithium too quickly you are very likely to have a rebound manic or psychotic episode and become quite ill, so you need to be cautious, reduce gradually – over at least one month, and much longer if you have been taking it for years. If relapse occurs, it happens in the first few months after withdrawal and then tails off.5
(Mind, 2018).

Some studies have reported increased suicidality following withdrawal from Lithium, especially if abrupt.6,7

Other drugs, sometimes described as ‘mood stabilisers’, include the three anticonvulsants carbamazepine (Tegretol), lamotrigine (Lamictal) and valproate (Depakote, Epilim). Little research has been conducted into the withdrawal reactions for people taking these drugs who do not have seizure disorders. A case series of six people coming off lamotrigine found distressing psychiatric reactions, especially anxiety and irritability.8 A study of 90 people who withdrew from carbamazepine found that 26 (29%) reported withdrawal reactions within four days of withdrawal. Reactions, which alleviated within one week, included insomnia, dysphoria, hallucination, hand fremitus (vibratory sensation), and headaches.9

For the withdrawal effects of asenapine (Sycrest), an antipsychotic which is sometimes used as a mood stabiliser, see the section on antipsychotics.

1. Balon, R., Yeragani, V., Pohl, R. & Gerson, S. (1988). Lithium discontinuation: Withdrawal or relapse? Comprehensive Psychiatry, 29, 330–334.
2. Moncrieff, J. (2009). The myth of the chemical cure: A critique of psychiatric drug treatment. New York: Palgrave Macmillan.
3. Post, R. (2007). Kindling and sensitization as models for affective episode recurrence, cyclicity, and tolerance phenomena. Neuroscience & Biobehavioral Reviews, 31, 858–873.
4. Suppes, T., Bladessarini, R., Faedda, G. & Tohen, M. (1991). Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Archives of General Psychiatry, 48, 1082–1088.
5. Mind (2018). Lithium and other Mood Stabilisers. https://www. mind.org.uk/information-support/drugs-and-treatments/lithium-and-other-mood-stabilisers/coming-off-mood-stabilisers/#.W0R0UYcVCpo. (Accessed July 2018.)
6. Baldessarini, R., Tondo, L. & Hennen, J. (1999). Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. Journal of Clinical Psychiatry, 60 (Supplement 2), 77–84.
7. Tondo, L., Baldessarini, R. J., Hennen, J., Floris, G., Silvetti, F. & Tohen, M. (1998). Lithium treatment and risk of suicidal behavior in bipolar disorder patients. The Journal of Clinical Psychiatry, 59(8), 405–414.
8. Frey, L., Strom, L., Shrestha, A. & Spitz, M. (2009). End-of-dose emergent psychopathology in ambulatory patients with epilepsy on stable-dose lamotrigine monotherapy: A case series of six patients. Epilepsy & Behavior, 15, 521–523.
9. Chen, M., Zhang, W., Guo, Z., Zhang, W., Chai, Y. & Li, Y. (2014). Withdrawal reaction of carbamazepine after neurovascular decompression for trigeminal neuralgia: A preliminary study. Journal of Neurological Science, 338, 43–45.

5.2.5 Stimulants prescribed for ADHD

The effects of withdrawing from stimulant drugs like cocaine and amphetamines that are taken for recreational purposes are well-documented. Even after taking stimulants for a day or two, people taking them typically experience a period characterised by reduced energy, depression, irritability, hunger and excessive sleeping, which can last for a couple of days. When someone has taken stimulants continuously for a long period, they may initially have insomnia, and feel anxious, sad and agitated, and they can experience chills and intense cravings for the drug.

After this, the person withdrawing will likely begin feeling both mental and physical exhaustion, start to sleep excessively, although they may still experience periods of insomnia, and become more depressed. They may continue to feel anxious and irritable and stop feeling pleasure, they may become less sensitive to stimuli such as touch and sound, be socially withdrawn and have vivid dreams.

The depression can be intense, and it may be accompanied by suicidal thoughts. The symptoms can persist for between a few days and several weeks or even months.1

Withdrawal from prescribed stimulants is less commonly described. Studies that have explored the consequences of withdrawal have focused only on whether or not it is associated with a relapse of the symptoms of ADHD, without considering the possible physiological and psychological effects of the withdrawal itself.2,3 However, it has long been recognised that use of prescribed stimulants by people with ADHD is associated with the phenomenon known as ‘rebound’.

This occurs when the effects of a dose of a stimulant wear off, usually towards the evening, and consists of a worsening of the symptoms of ADHD beyond their original level before treatment was started. Children, in which ‘rebound’ has mainly been noted, become highly excitable and distractible. Since low- dose stimulants reduce activity and increase focused attention, these rebound effects are a predictable response to the wearing off of the direct effects of the drug.

Rebound is also characterised by the onset of some new symptoms including tearfulness, irritability and emotional lability, which are not usually part of ADHD.4–6 These rebound effects suggest that stimulants restrict or dampen emotional responses at the doses used in clinical practice. It has also been shown to manifest in the worsening of driving performance in adults who had taken a dose of a stimulant several hours earlier compared to those who took a placebo.7

The existence of rebound suggests the presence of the drug has modified the brain in some way, which in itself consists of a form of withdrawal syndrome. The rebound phenomenon also illustrates how quickly the body adapts to the presence of a drug and how rapidly withdrawal symptoms can occur after the effects of a drug have worn off.

A few case reports document a withdrawal syndrome following the complete discontinuation of prescribed stimulants in children which, as in adults, includes depression and malaise. New episodes of migraine and psychosis have also been reported.8-10 However, there is no research that could confirm how common or severe this withdrawal syndrome is, and how long it might last when it occurs.

As with research on the long-term effects of other psychiatric drugs, the probable existence of a withdrawal syndrome following discontinuation of stimulant treatment is likely to confound attempts to assess relapse or recurrence of ADHD symptoms after medication is stopped.

1. Center for Substance Abuse Treatment (1999). Chapter 5: Medical aspects of stimulant use disorders. In Treatment for stimulant use disorders. Rockville, MD: Substance Abuse and Mental Health Services Administration. Available at: https://www.ncbi.nlm.nih. gov/books/NBK64323/. (Accessed 26 April 2019.)
2. Buitelaar, J., Asherson, P., Soutullo, C., Colla, M., Adams, D.H., Tanaka, Y. et al. (2015). Differences in maintenance of response upon discontinuation across medication treatments in attention-deficit/hyperactivity disorder. Eur Neuropsychopharmacol. 25(10), 1611–21.
3. Coghill, D.R., Banaschewski, T., Lecendreux, M., Johnson, M., Zuddas, A., Anderson, C.S. et al. (2014). Maintenance of efficacy of lisdexamfetamine dimesylate in children and adolescents with attention-deficit/hyperactivity disorder: Randomized-withdrawal study design. Journal of the American Academy of Child and Adolescent Psychiatry, 53(6), 647–57 e1.
4. Carlson, G.A. & Kelly, K.L. (2003). Stimulant rebound: How common is it and what does it mean? Journal of Child and Adolescent Psychopharmacology, 13(2), 137–42.
5. Sarampote, C.S., Efron, L.A., Robb, A.S., Pearl, P.L. & Stein, M.A. (2002). Can stimulant rebound mimic pediatric bipolar disorder? Journal of Child and Adolescent Psychopharmacology, 12(1), 63–7.
6. Lopez, F.A., Childress, A., Adeyi, B., Dirks, B., Babcock, T., Scheckner, B. et al. (2017). ADHD symptom rebound and emotional lability with lisdexamfetamine dimesylate in children aged 6 to 12 years. Journal of Attention Disorders, 21(1), 52–61.
7. Cox, D.J., Moore, M., Burket, R., Merkel, R.L., Mikami, A.Y. & Kovatchev, B. (2008). Rebound effects with long-acting amphetamine or methylphenidate stimulant medication preparations among adolescent male drivers with attention-deficit/hyperactivity disorder. Journal of Child and Adolescent Psychopharmacology, 18(1), 1–10.
8. Krakowski, A. & Ickowicz, A. (2018). Stimulant withdrawal in a child with autism spectrum disorder and ADHD: A case report. Journal of the Canadian Academy of Child & Adolescent Psychiatry, 27(2), 148–51.
9. Brown, R.T., Borden, K.A., Spunt, A.L. & Medenis, R. (1985). Depression following pemoline withdrawal in a hyperactive child. Clinical Pediatrics, Philadelphia, 23(3), 174.
10. Rosenfeld, A.A. (1978). Depression and psychotic regression following prolonged mehtylphenidate use and withdrawal: Case report. American Journal of Psychiatry, 136, 226–7.

5.2.6 Polypharmacy

Polypharmacy, the prescribing of more than one drug at the same time, has increasingly become the norm in psychiatry.1 By the 1990s 80% of people receiving psychiatric intervention were on more than one drug.2 A particularly common combination is antidepressants and benzodiazepines.3 A 2009 study found that up to one third of psychiatric outpatients were on three or more psychiatric drugs.4

Despite its commonality, little research has explored the role that this multiple prescribing has on the frequency, severity or duration of withdrawal effects, or has studied how polypharmacy affects the process of coming off the various combinations of drugs.

In the large New Zealand online survey5 people who were taking, or had taken, more than one antidepressant reported a higher incidence of withdrawal effects (68.3%) than those who had taken just one antidepressant (e.g. Fluoxetine – 35.5%), with the exception of Paroxetine (75.9%) and Venlafaxine (70.4%).

In the large international online survey6 55.4% of those who had taken only antidepressants reported withdrawal effects, compared to 65.9% of those who had taken both antidepressants and antipsychotics. The figures for reported addiction were 36.8% and 47.7% respectively.

1. Preskorn, S. & Flockhart, D. (2006). Guide to psychiatric drug interactions. Primary psychiatry, 13, 35–64.
2. Rittmannsberger, H. (2002). The use of drug monotherapy in psychiatric inpatient treatment. Progress in Neuro-Psychopharmacology & Biological Psychiatry 26, 547–551.
3. Read, J., Gee, A., Diggle, J., Butler, H. (2017). The interpersonal adverse effects reported by 1,008 users of antidepressants; and the incremental impact of polypharmacy. Psychiatry Research, 256, 423-427.
4. Mojtabai, R. & Olfson, M. (2010). National trends in psychotropic medication polypharmacy in office-based psychiatry. Archives Of General Psychiatry, 67, 26–36.
5. Read, J., Cartwright, C. & Gibson, K. (2018). ‘How many of 1829 antidepressant users report withdrawal effects or addiction?’, International Journal of Mental Health Nursing, 27(6), pp.1805–1815.
6. Read, J. & Williams, J. (2018). Adverse effects of antidepressants reported by a large international cohort: Emotional blunting, suicidality, and withdrawal effects. Current Drug Safety, 13(3), 176–86.

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