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This chapter reviews the scientific literature on adverse psychiatric effects associated with antidepressants, especially the SSRIs and newer antidepressants. Many of the adverse psychiatric reactions produced by the newer antidepressants can be viewed as occurring along a continuum of activation or stimulation, culminating in mania and psychosis. In addition, these drugs can produce a blunting or lobotomy-like deactivation in the form of an apathy syndrome, especially after longer periods of use. They can also cause an obsessive syndrome that can lead to violence or suicide. Few drugs are as medication spellbinding as the newer antidepressants. All antidepressants cause mania, and mania is an acknowledged adverse effect in the FDA-approved label of all antidepressants. As noted in chapter 6 - and now built into the FDA-approved labels for antidepressants - mania is the extreme expression of drug-induced overstimulation that includes insomnia, anxiety, agitation, irritability, hostility and aggression, emotional lability, akathisia, and hypomania and mania. It can lead to crashing into depression and suicidality.
At one end of the continuum, the individual becomes mildly irritable, a little emotionally labile, or slightly agitated. At the other end of the continuum, the individual becomes classically manic, at times perpetrating violence or crashing into depression and suicidality. On occasion an individual will traverse the whole continuum, starting with irritability or insomnia, for example, and ending up in a manic state. At other times the individual may experience only one of the drug-induced stimulant symptoms, such as agitation, akathisia, or hostility.
SSRI labels tend to be organized in ways calculated to avoid any implication that the medications can cause a pattern of overstimulation, but detailed analyses of the labels disclose that these drugs do in fact produce a continuum of stimulation (see Breggin, 2002a [210], for an analysis of the Luvox label; Breggin et al., 1994a [219], for an analysis of the Prozac label). Table 7.1 was compiled to illustrate the spectrum of SSRI-induced adverse drug reactions and illustrate the frequency of stimulant-like effects. All of the effects listed in the table can also occur with stimulants such as amphetamine and cocaine, and many are typical of these stimulants, including hypomania/mania, euphoria, insomnia, nervousness, anxiety, agitation, central nervous system stimulation, emotional lability, tremor, sweating, and palpitation. They also include paranoid reactions, psychosis, and hostility, all of which are also associated with stimulant drugs.
| Mental and Behavioral Adverse Drug Reactions in Adults | |
| Caused by Paroxetine | |
| Frequent* | Infrequent** |
| Mania/hypomania (2.2% of bipolar patients) | Paranoid reaction |
| Mania/hypomania (1% of depressed patients) | Psychosis |
| Insomnia (13%) | Hostility |
| Nervousness (5%) | Euphoria |
| Anxiety (5%) | Delirium |
| Agitation (1%) | Hallucinations |
| Drugged feeling (2%) | Abnormal thinking |
| Confusion (1%) | Depersonalization |
| Central nervous system stimulation | Neurosis |
| Emotional lability | Lack of emotion |
| Concentration impairment | Libido increased |
| Amnesia | |
| Depression | |
| Tremor (8%) | |
| Sweating (11%) | |
| Palpitation (3%) | |
* Frequent means at a rate of 1% or greater.
** Infrequent means at a rate between 1% and 0.1%. All adverse drug reactions (ADRs) with percentages (%) are for depressed patients in placebo-controlled clinical trials. ADRs without percentages are taken from the entire data pool of 7,678 patients administered Paxil, including 6,145 depressed patients.
Note: From the 2001 FDA-approved label for Paxil. Table compiled from the label by Peter R. Breggin.
Confirmation of the stimulant syndrome was provided in a previously undisclosed internal document from Eli Lilly and Company, the manufacturer of fluoxetine (Prozac) [403]. The document was obtained during discovery in product liability suits against the company and is now available on my Web site (http://www.breggin.com; Beasley, 1988 [114]; Fentress Trial Exhibit 70, 1993). Charles Beasley, of the company's Division of Clinical Neurosciences, evaluated what he called activation in patients taking fluoxetine or placebo in the controlled clinical trials used for FDA approval of Prozac for depression. Beasley defined activation as including any of the following: nervousness, anxiety, agitation, and insomnia. Beasley found that 38% of fluoxetine-treated patients developed activation, but only 19% of placebo patients developed these symptoms. The proportion of patients activated by fluoxetine would have been higher if other expressions of stimulation had been included such as akathisia, hyperactivity, euphoria, and mania. It would have been further increased if many of the patients had not been prescribed sedative tranquilizers to quiet their symptoms of stimulation (Breggin et al., 1994a [219]).
Reports authored by psychiatrist Richard Kapit (1986b [732], 1986c [733]), the FDA official in charge of evaluating adverse drug effects during the approval process of Prozac for depression, repeatedly warned that fluoxetine had a stimulant profile similar to amphetamines. He was concerned that stimulant effects such as insomnia, nervousness, anorexia, and weight loss would produce agitated depression and worsen the condition of some depressed patients (details about Kapit's reports are in chapter 14).
Clinically, agitated depression is an unstable condition that can lead to violence against self or others more frequently. A number of reports cited in the following sections will mention agitation in patients who behave abnormally as a result of antidepressant effects.
Koukopoulos and Koukopoulos (1999) [783] provided a remarkable discussion of varied manifestations of agitated depression and suggested that it should be viewed as a separate diagnostic entity called mixed depression. They warned about the risk of giving antidepressants to patients with agitated depressions:
"Today's extensive use of antidepressant drugs in the treatment of all forms of depression makes the question of the real nature of agitated depression a critical issue. Many of these patients are seen to have such adverse outcomes as increased agitation, intractable panic, heightened risk of suicide, manifestation of psychotic symptoms, and warsening of subsequent course of the illness." (p. 547, emphasis added)
In other words, antidepressants can worsen agitated depression.
Koukopoulos and Koukopoulos (1999) [783] proposed a definition of agitated depression as a major depressive episode with one of the following: motor agitation, psychic agitation or intense inner tension, and racing or crowded thoughts. This condition, which has also been referred to as black mania, "can worsen dramatically under the effect of antidepressants".
Unfortunately, Koukopoulos and Koukopoulos (1999) [783] do not grasp that antidepressants, regardless of the patient's condition, can by themselves cause an agitated depression, with all of the associated unfortunate outcomes. In chapter 6, we found this clinical reality embedded and expressed in the new class labels for antidepressants that describe the association between antidepressants and insomnia, agitation, anxiety, hostility, aggression, and mania as well as an overall worsening of the patient's condition. We will find illustrative cases in the review that follows.
In general, the pattern of adverse reactions is similar among all the SSRIs and some of the other new antidepressants that block the reuptake of serotonin, especially venlafaxine. As a result, the FDA has required class label warnings for them in regard to suicidality and to the array of stimulant adverse reactions, from agitation and hostility to mania.
A British study conducted on the basis of prescription-even monitoring (PEM) involved cohorts exceeding 10,000 patients for paroxetine, fluvoxamine, sertraline, and fluoxetine (Mackay et al., 1997 [861]). The study confirmed the general similarity of reported adverse events, with two possible exceptions: Fluvoxamine (Luvox) had an increased number of reported adverse events, and paroxetine (Paxil) had an increased number of reported withdrawal reactions.
A Norwegian study by Olav Spigset [1207] utilizing that country's Adverse Drug Reactions Monitor Center reviewed 1,202 reports describing 1,861 adverse reactions to SSRIs. Again, the pattern of reports for the individual SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) was very similar, with three exceptions. Fluvoxamine reports were comparatively elevated for gastrointestinal symptoms, fluoxetine reports were increased for dermatological symptoms, and sertraline reports were elevated for psychiatric symptoms. There was a broad range of antidepressant-induced psychiatric symptoms, with anxiety the most frequent, followed by confusion, hallucinations, sleep disturbances, hypomania/mania, depersonalization, amnesia, nightmares, aggression, insomnia, psychosis, concentration impairment, agitation, personality change, euphoria, and pathological inebriation. There were 13 reports of aggression, and they occurred more often in men.
SSRIs cause a wide range of neurological impairments. Spigset (1999) [1207] found the following neurological reports in order of frequency: parethesias, headache, dizziness, tremor, seizures, acute dystonia, dyskinesia, muscle cramps, muscle weakness, parkinsonism, muscle stiffness, akathisia, myoclonus, extrapyramidal reactions, increased muscle tone, and migraine. There have been reports of irreversible tardive dyskinesia caused by SSRIs (see subsequent section).
Chapter 6 described the FDA-mandated studies of suicidality in adults that found an increased rate of suicidality in young adults taking SSRIs in placebo-controlled clinical trials. The chapter also evaluated the May 2006 letter concerning Paxil sent by GlaxoSmithKline [524] to health care providers describing an increased suicidality risk for adults of all ages with major depressive disorder when taking Paxil. In addition, chapter 6 examined evidence from the FDA's analysis (Stone and Jones, 2006) [1218] that Paxil was the one antidepressant that by itself demonstrated a statistically significant increase in suicidality and that this increase occurred in all diagnostic categories and all age groups. The following section deals with additional cogent evidence for a causal connection between SSRI antidepressants and suicidality.
An unpublished document obtained during discovery in product liability suits against the drug company disclosed that Eli Lilly, the manufacturer of fluoxetine (Prozac) [403], had evaluated the comparative rates of suicide attempts on fluoxetine, amitriptyline, and placebo (the documents are available from http://www.breggin.com). The data were generated during controlled clinical trials conducted for the FDA approval process for Prozac for depression. On the basis of the company's data for controlled clinical trials, patients taking fluoxetine were 12 times more likely to attempt suicide than a similar group of patients taking older antidepressants or placebos (details in chapter 14). An evaluation by a consultant to the company, Avery Winokur, concluded that the increased rate might be due to fluoxetine-induced overstimulation of the depressed patients.
Aursnes et al. (2005) [73] discussed how the inclusion of unpublished data had been shedding new light on the risk of suicide associated with antidepressants prescribed to children in controlled clinical trials. They located unpublished data from controlled clinical trials not previously available for a total of 16 studies in which Paxil had been randomized against placebo. They found a statistically significant total of seven suicide attempts among 916 patients given Paxil and one among 550 patients receiving placebo. The data revealed that Paxil "is connected with an increased intensity of suicide attempts per year". Together with other published meta-analyses of antidepressant-induced suicidality, they found "a strong case for the conclusion, at least with a short time perspective, that adults have an increased risk of suicide attempts" on Paxil. Aursnes et al. concluded, "Our findings support the results of recent meta-analyses. Patients and doctors should be warned that the increased suicidal activities observed in children and adolescents taking certain antidepressant drugs may also be present in adults."
Fergusson et al. (2005) [429] searched the literature and found 702 randomized clinical trials (87,650 patients) comparing SSRIs with either placebo or an active non-SSRI control medication. They found a statistically significant, more than two-fold increased risk of suicide attempts in on SSRIs compared to placebo. The odds ratio of suicide attempts in SSRI-treated patients versus placebo patients was 2.28 (p = 0.02) and a 95% confidence interval (CI) of 1.14-4.55. They also found an increased suicide risk between SSRIs and other medications, excluding tricyclic antidepressants. There was no difference between the SSRIs and tricyclics in suicide risk. Overall, their results "documented an association between suicide attempts and the use of SSRIs".
Fergusson et al. (2005) [429] estimated the risk at 5.6 suicide attempts per 1,000 patient years. They observed, "Although small, the incremental risk remains a very important population health issue because of the widespread use of SSRIs." They also believed that suicide attempts were underreported. In addition, the trials averaged 10.8 weeks in duration, with only a fraction of patients (fewer than 7%) followed for more than 6 months. Because individual trials were relatively small, they decreased the likelihood of a particular risk being identified.
Healy (2003) [608] reviewed and reanalyzed data comparing the number of suicides and suicide attempts per patient in worldwide placebo-controlled clinical trials used for the FDA antidepressant approval process (Khan et al., 2001 [755]; Khan et al., 2000 [756]). The drugs included four SSRIs (sertraline, paroxetine, citalopram, and fluoxetine). As a percentage of patient numbers, there was a statistically significant difference between combined suicides and suicide attempts among all SSRIs patients (1.55%) and among all SSRI trial placebo patients (0.48%). There were also a significantly greater number of completed suicides on SSRIs in the combined suicide and suicide attempt group as well as in the paroxetine group individually, compared to placebo. One set of data showed a 3 times greater rate for suicide attempts on SSRIs compared to other antidepressants.
Donovan et al. (1999) [372] found a significantly increased rate of suicide among patients treated with SSRIs compared to those treated with tricyclic and other antidepressants. After correcting the data for the number of prescriptions for each drug, SSRIs were 3.5 times more likely to be associated with suicide. The authors concluded, "The overall occurrence of suicide by any method was lowest in patients prescribed TCAs [tricyclic antidepressants] and highest in those prescribed SSRIs. This difference s statistically significant (p < 0.01)". The study was conducted in three regions of England and Ireland and involved 222 suicides.
Donovan et al. (2000) [371] conducted a prospective study of 2,776 consecutive cases of deliberate self-harm among subjects age 17 and older who were seen at the accident and emergency department of Derbyshire Royal Infirmary as a consequence of any act of deliberate self-harm during a 2-year period (1995-1996). Acts of deliberate self-harm included overdoses, other forms of suicide attempts, and cutting oneself. Of the 2,776 cases, 307 had received an antidepressant 30 days or less prior to the incident of deliberate self-harm. With the rate of prescribing in Derbyshire taken into account, the relative incidence of deliberate self-harm was significantly higher (p < .001) in patients who were prescribed the SSRIs fluoxetine, paroxetine, and sertraline compared to patients who were prescribed the tricyclics amitriptyline, dothiepin, and imipramine. The relative incidence of deliberate self-harm per 10,000 prescriptions was broken down in a table, as follows: fluoxetine (19.8), sertraline (14.8), paroxetine (12.1), all SSRIs (16.6), imipramine (3.5), amitriptyline (3.0), and all tricyclics (5.6). Compared to amitryptyline, the relative risk for all SSRIs was considerably higher: fluoxetine (6.6), sertraline (4.9), paroxetine (4.0), and all SSRIs (5.5). Patients on Paxil were 4 times more likely to harm themselves than patients on the older non-SSRI antidepressants. Of interest in regard to causation, the risk for the tricyclic clomipramine was very high as well, with a relative incidence of 13.8 and a relative risk compared to amitryptyline of 4.6. Among the tricyclics, clomipramine has the strongest inhibitory effect on serotonin reuptake and great tendency toward overstimulation (see, e.g., Drug Facts and Comparisons, 2003 [379]). Jick et al. (1995) [691] conducted an epidemiological study of reports from general practices (primary care) in the United Kingdom involving 172,598 patients, including 143 who committed suicide, who had at least one prescription for 1 of 10 antidepressants. Rates of suicides were compared for patients on the various antidepressants. Patients taking fluoxetine were twice as likely to commit suicide compared to patients on other antidepressants. In comparison to three more sedating antidepressants-doxepin, imipramine, and amitryptyline-fluoxetine was 4 times more likely to be associated with suicide. The relative risk for patients taking Prozac compared to patients taking the non-SSRI antidepressant dothiepin was 3.8 (95% CI of 1.7-1.86).
Jick et al. (1995) [691] stretched beyond reason to take their position that Prozac might not be the cause of the suicides15. They found that "when the analysis was restricted to those without a history of having felt suicidal or who had taken only one antidepressant, the increased risk for those who took fluoxetine was reduced". Thus, the increased risk was reduced by these manipulations but not eliminated. Data in a table show that after taking into account a past history of suicidal behavior and/or antidepressant use, Prozac remained twice as likely to be associated with suicide as any other antidepressant. In fact, Prozac became the only antidepressant that was associated with increased risk of suicide.
Jick et al. (2004) [690] examined data on suicide attempts among 159,810 adults and children taking Prozac, Paxil, and the non-SSRI antidepressants amitriptyline or dothiepin. They found that the risk of suicide was increased during the first month of medication exposure, "especially during the first 1 to 9 days". Comparing the first 9 days to the first 90 days, there was a statistically significant increase in both suicide attempts and completed suicides. This is consistent with observations that I have made, as well as the recent FDA label changes, and is consistent with the drugs causing suicidality.
Juurlink et al. (2006) [715] reviewed more than 1,000 cases of suicide and found that during the first month of therapy, SSRI antidepressants were associated with a nearly fivefold higher risk than other antidepressants. The results were statistically significant (OR 4.8, 95% CI 1.2-12.2.) The authors concluded that "initiation of SSRI therapy is associated with an increased risk of suicide during the first month of therapy compared with other antidepressants".
Muijen et al. (1988) [957] conducted a 6-week double-blind study comparing fluoxetine, mianserin, and placebo with 26, 27, and 28 starters, respectively, and 14, 14, and 16 finishers, respectively. Two of the fluoxetine patients "took an overdose within two weeks of starting the study, and in both cases this was related to a deteriorating clinical state that necessitated hospitalization" (p. 386). None of the patients in the other drug group or the placebo group suffered from this decline and suicidality. Remarkably, the authors did not include these reactions among the adverse drug effects. At this point in time, few researchers were aware of the connection between SSRIs and suicidality.
Gorman et al. (1987) [549] conducted an open trial of fluoxetine involving 16 patients with panic disorder. They reported, "Two of the non-responders became depressed and had suicidal ideation while taking fluoxetine. Only one of the two had a history of depression" (p. 331). Still in the era before recognition of SSRI-induced suicidality, the authors did not comment on this finding.
Frankenfield et al. (1994) [487] conducted a retrospective case review of all deaths in Maryland where either fluoxetine or tricyclic antidepressants was forensically detected. The study covered a 3.5-year period of time. They found a statistically significant increase in violent suicides in association with fluoxetine (65% vs. 23%). Violence was defined to include "gunshot or shotgun wounds, suffocation, stabbing, strangulation, drowning, falls and jumping in front of a moving vehicle" (p. 109). The evaluations of the suicide attempts were blind to which medications were involved.
Bost and Kemp (1992) [161] reviewed a series of coroner's reports in Dallas, Texas, involving 15 suicides associated with fluoxetine treatment. The study covered a 9-month period. While they appreciated that their data were impressionistic, they warned that the proportion of patients taking fluoxetine and committing suicide was high enough to be of concern to health care providers.
On November 13, 2006, NIMH [974] announced a new NIMH initiative aimed at studying the connection between SSRIs and suicidality and in the process made clear that consensus exists within the psychiatric establishment that SSRI antidepressants cause suicidality. NIMH director Thomas Insel, M.D., was quoted: "These new multi-year projects will clarify the connection between SSRI use and suicidality" and "they will help determine why and how SSRIs may trigger suicidal thinking and behavior in some people but not others, and may lead to new tools that will help us screen for those who are most vulnerable".
There are many case reports in the scientific literature documenting the capacity of SSRIs to cause mania in adults, often in association with irritability and aggression. Some cases display overstimulation that falls short of mania.
Medwar et al. (2002) [913] reviewed e-mails sent to the British TV show Panorama and described cases of suicidality and withdrawal reactions associated with SSRIs. Medwar et al. (2003-2004) [912] continued their observations, comparing patient and physician reports, and discussed the public health implications of using these kinds of sources. The researchers were impressed with the great numbers of responses that were received in response to the TV show, and they advocated making greater use of these kinds of public responses as signals of adverse drug reactions. In reality, for many years Web sites throughout the world have been describing adverse psychiatric reactions to SSRI antidepressants, including mania, violence, and suicide, while the pharmaceutical industry and organized medicine ignored these "signals" that the drugs were causing disastrous reactions. As another, similar use of public data, Talking Back to Prozac (Breggin et al., 1994a [219]) listed dozens of newspaper reports describing violence and suicide in association with taking Prozac; but the FDA, psychiatry and the drug industry dismissed these data.
Healy et al. (2006) [610] described nine cases in England, Scotland, Australia, and the United States as illustrations of antidepressant-induced violence. Two paroxetine, three sertraline, and one fluoxetine case resulted in homicide. One paroxetine case resulted in assault, one venlafaxine case resulted in attempted murder, and one fluoxetine case resulted in assault and robbery. Some were associated with maniclike symptoms. They also evaluated clinical trial data (see subsequent discussion).
Okada and Okajima (2001) [1005] described three cases of aggressive and violent behavior induced by fluvoxamine. On 150 mg/day, a 32-year-old woman became both irritable and aggressive, and she expressed impulsive violence during arguments with her family. She improved after her fluvoxamine was reduced (but not stopped). A 29-year-old woman on 150 mg of fluvoxamine daily became nervous and irritable and then impulsively violent and was admitted to a psychiatric hospital. She improved with discontinuation of the drug and further treatment with other medications. A 28-year-old woman receiving 150 mg of fluvoxamine daily exhibited signs of irritability and aggressive behavior and expressed violence toward her mother. She improved when the fluvoxamine was stopped and other medications instituted. They warned about the existence of impulsive and aggressive behavior induced by fluvoxamine.
Severe stimulation reactions were reported in four of six fluoxetine-treated patients with posttraumatic stress disorder, requiring three of them to withdraw from the study: "Two experienced agitation and worsening of hyperarousal symptoms; one patient's panic symptoms markedly worsened. A fourth patient also suffered severe agitation and greater anxiety" (Marshall et al., 1995, p. 1238 [881]).
Mania and hostility frequently go together, and mania is one cause of Prozac-induced violence. Crashing after mania can cause depression and suicide as well. There are many other reports of varying degrees of psychosis caused by Prozac (Chouinard et al., 1986 [279]; Lebegue, 1987 [818]; Settle et al., 1984 [1158]; Turner et al., 1985 [1271]). LaPorta et al. (1987) [813] described two cases and Mendhekar et al. (2003) [923] described one case of mania caused by Zoloft.
Ramasubbu (2001) [1069] described five cases of hypomanic reactions on SSRI antidepressants, including paroxetine (two) and citalopram (three). A man who had a prior history of depression associated with "one minor stroke and one transient ischemic attack" was put on citalopram and became "increasingly verbally abusive, aggressive and excitable in social situations". He also admitted to becoming "more angry and irritable in social situations for trivial reasons". But he also justified his angry outbursts on the basis of other people's behavior. (A typical medication spellbinding effect.) Reducing the dose from 40 to 20 mg/day "resolved is verbal aggression". Ramasubbu (2004) [1070] also described two cases of dose-dependent mania in response to sertraline in patients with no bipolar history.
Mundo et al. (1993) [961] gave a general description of their experience with patients who developed mania while taking clomipramine, fluoxetine, or fluvoxamine in their obsessive compulsive disorder (OCD) clinic. According to the authors, "when these patients were treated with proserotonergic antiobsessional drugs, they experienced reduced impulse control, dysphoria, and increased aggressiveness and reckless acts, symptoms similar to those found in mania".
During the seventh week of citalopram, a patient developed "a manic episode with insomnia, euphoria, psychomotor agitation, logorrhea, flight of ideas, disinhibition, injudicious spending, and delusional ideas of megalomania and persecution developed" (Bryois et al., 1994 [234]). Bobo and Grammer (2003) [152] described a florid mania caused by escitalopram. Christensen (1995) [287] reported on the case of a 32-year-old man who developed his first manic episode while taking paroxetine. He became psychotic and "threatened his parents with physical harm" (p. 1400). Vesely et al. (1997) [1296] presented six cases of SSRI mania, one on paroxetine and five on citalopram. Other reports cite fluvoxamine as a causative agent (e.g., Burrai et al., 1991 [242]; Dorevitch et al., 1993 [373]; Okada et al., 2001 [1005]).
Dorevitch et al. (1993) [373] described three cases of fluvoxamine-induced mania. Each case was recognized quickly, and the drug was reduced in dose or stopped so that potentially disastrous outcomes were avoided. Had the patients been more secretive or the monitoring less effective, the results could have been more drastic in outcome. In the first case, the patient developed a psychotic manic state with auditory hallucinations. In the second case, the patient became euphoric; displayed increased energy and inappropriate behavior, with sexual advances toward other patients; was irritable; and had fears that people were out to kill him. In the third case, the patient developed multiple signs of mania, from excessive sexual activities to excessive talking and argumentativeness. Manic patients who are argumentative can sometimes become very aggressive when thwarted.
In another case report, a woman taking fluvoxamine became suicidal and had to be hospitalized (Bastani et al., 1996 [107]). In the hospital, the fluvoxamine dose was increased from 50 mg/day to 150 mg/day, whereupon her condition worsened and she began to experience auditory hallucinations. The fluvoxamine was discontinued, and she recovered within 24 hours, confirming that the medication had caused the depression and psychosis.
This chapter has already mentioned cases in which SSRI-induced akathisia played a role in the worsening of the patient's condition and suicidality. Akathisia is a painful inner agitation that manifests as the inability to sit still or stop moving. The hyperactivity may manifest itself subtly as a feeling of jitteriness or grossly as frantic pacing or repeatedly sitting up and down.
Akathisia was first described in association with neuroleptic drugs. The inner agitation associated with akathisia can become extremely uncomfortable, causing the individual to feel tortured from within (see vivid descriptions in Van Putten, 1974 [1282], 1975a&b [1283] & [1284]; Breggin, 1997a [198]), leading to extreme irritability and suicide or violence.
In the neuroleptic literature, Crowner et al. (1990) [323] drew a direct connection between akathisia and violence. They filmed activities on a psychiatric unit 3 days a week, from 8:00 A.M. to noon, for 2 years. They screened the films for incidents of violence "resulting in injury or with the potential to do so". They only rated segments where the participants, and at least two nonparticipating bystanders, were visible for at least 2 min of the 5-min rating period. Their findings are remarkable: "The assailants were akathisic before about half of all the assaults, as were the victims." Only 4 out of 24 nonparticipants displayed akathisia. This confirms an observation I have made over the years: that most violence on psychiatric wards stems from the treatments, including drug toxicity and (unstudied in this project) provocation by staff.
Although akathisia by definition usually involves a hyperactive movement component, clinical experience indicates that it may be accompanied with a feeling of jitteriness without actual physical movement; that is, the same jittery, agitated subjective experience, accompanied by irritability, violence, or suicidal feelings, can occur without the specific component of feeling driven to move about. Indeed, on earlier occasions, the individual may have experienced the associated compulsion toward hyperactivity. Healy (1994) [606] made similar observations.
Adler and Angrist (1995) [19] described a case of a depressed patient who developed akathisia with pacing and rocking foot to foot. The symptoms appeared 7 days after starting Paxil and 4 days after the dose was increased to 20 mg/day. The patient reported difficulty standing still and was so distressed that he considered signing out of the hospital because of worsening depression. Rather than reducing the medication, he was treated with the addition of propranolol and lorazepam to subdue the akathisia. This unfortunate practice bombards the nervous system and continues exposure to an agent that is causing neurological dysfunction.
Bonnet-Brilhault et al. (1998) [155] also presented a case of paroxetine-induced akathisia. They terminated the treatment with a complete resolution of the problem. They observed that in most cases the first and best option is to discontinue the offending agent. LaPorta (1993) [812] treated two cases of sertraline-induced akathisia that cleared up after terminating the medication. Olivera (1996) [1007] described a case of paroxetine-induced akathisia that was mistaken for an exacerbation of the patient's so-called panic anxiety: The dose was doubled, and the condition worsened. The akathisia resolved when paroxetine was replaced by clomipramine.
Baldassano et al. (1996) [89] described a depressed 18-year-old student who was started on paroxetine 20 mg/day and clonazepam 0.5 mg at night who developed worsening insomnia, a need to move about, restlessness, physical tiredness, and anxiety. The akathisia resolved on propranolol. The authors reviewed their charts and found 3 cases of akathisia among 67 patients (4%) treated with paroxetine. They concluded,
"The gravest consequence of akathisia is its reported association with suicide. The patient population receiving antidepressants for affective illness are [sic] at high risk for suicide, and the additive effect of untreated akathisia could be tragic."
Lipinski et al. (1989) [846] reported on five cases of akathisia caused by fluoxetine. They also reviewed the literature and found rates of 9.7% to 25% for fluoxetine-induced akathisia. They concluded, "In summary, fluoxetine, and perhaps other antidepressant drugs as well, may produce the side effect of akathisia fairly frequently" (p. 342). The Public Citizen's Health Research Group (1990) [1059] estimated a rate of 15% to 25%. While studies of SSRI-induced akathisia vary greatly in the frequency with which this disorder is observed, they confirm that it is common.
Lane (1998) [809] observed, "SSRI-induced akathisia may represent a form of serotonergic overstimulation or serotonin toxicity" (p. 203). He also cited research linking the phenomenon to the impact of SSRIs on the dopaminergic system. He warned, "The emergence of symptoms of akathisia could be mistaken for a worsening of depression, especially the conversion of a non-agitated depression to an agitated form" (p. 206). This error in judgment could lead to the prescription of increased doses of the offending medication, resulting in a severely worsened condition. Lane cited studies indicating that "fluoxetine is not an appropriate choice of antidepressant for depressed patients with agitation and restlessness" (p. 206) because it can lead to increased rates of agitation, anxiety, and manic reactions. He noted that patients may feel "death is a welcome result" when suffering from unbearable Prozac-induced akathisia.
Rothschild and Locke (1991) [1111] reported on three cases of fluoxetine induced suicidality associated with akathisia. Each case of suicidality developed on fluoxetine (challenge) and then resolved when the drug was stopped (dechallenge). The suicidality then returned when the drug was started a second time (rechallenge) and stopped again when the drug was stopped (a second dechallenge). During rechallenge, each of the patients developed akathisia and reported that this feeling had caused them to become suicidal each time.
Wirshing et al. (1992) [1348] reported on five cases of a fluoxetine-induced syndrome consisting of akathisia and suicidality. In all five cases, the akathisia and the suicidality remitted when the drug was stopped or reduced in dosage. In one case, a rechallenge with an increased dose of fluoxetine again produced the syndrome. They concluded, "Our cases appear to confirm that certain subjects experience akathisia while taking fluoxetine and that this effect is dose-related in the individual patient. ... Furthermore, like the akathisia in the neuroleptic-treated schizophrenic population, `fluoxetine akathisia' can apparently be associated with suicidal ideation, sometimes of a ruminative intensity" (p. 581).
Masand et al. (1991) [883] reported on two cases of suicidality in association with fluoxetine. One of the patients suffered from akathisia. In both cases, the suicidal feelings subsided shortly after stopping the medication. Neither patient had prior suicidal ideation. Both developed violent fantasies (hanging and jumping out a window).
Hamilton and Opler (1992) [593] wrote about the clinical qualities and potential biological mechanisms of antidepressant-induced akathisia. They described a depressed woman who developed "panic-like symptoms, anxiety, and palpitations" 10 days after starting fluoxetine 20 mg/day. The dose was reduced to 5 mg, with resolution of those symptoms; but within 3 more weeks, she complained of symptoms she had never before experienced, "feeling restless and out of control. ... I feel like I need to hold onto my chair or else I'll jump out of the window". Although she said she felt good, "she was afraid that she would kill herself because of these restless and out-of-control feelings". While she had experienced mild to moderate suicidal feelings in the past, without any intent or attempts, she now felt suicidal in a more "frightening manner". Her fluoxine was stopped, and within several days, the restlessness and suicidal fellings stopped.
Hamilton and Opler (1992) [593] suggested that akathisia results from the influence of the serotonergic system on the dopaminergic system, with inhibition of the nigrostriatal dopamine tract, impacting on the extrapyramidal system. They identified the disorder as "Extrapyramidal-Induced Dysphoric Reaction, one extreme manifestation of which is the emergence of suicidal ideation".
Leo (1996) [832] discussed the possible biological mechanisms underlying akathisia in some detail and concluded that "SSRI-induced EPS [extrapyramidal symptoms] are probably related to agonism of serotonergic input to dopaminergic pathways within the [central nervous system]".
In various case reports in this chapter, we will find that akathisia can found in combination with SSRI-induced mania and aggression.
A number of clinical reports have described a syndrome of obsessive SSRI-induced suicidality and aggression that seems particular to these drugs, starting with Teicher et al. (1990) [1243]. These cases bear some similarity to akathisia-driven suicidality, but compulsion toward self-harm is not accompanied by the specific symptoms of akathisia. They summarized, "Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment" (p. 207). Additional cases and potential mechanisms of action were analyzed by Teicher et al. (1993) [1244].
Dasgupta (1990) [330] described a similar case of "intense suicidal preocupation" (p. 1570) after 4 weeks of fluoxetine treatment in a woman who had not been previously suicidal. She, too, rapidly recovered on stopping the fluoxetine. Hoover (1990) [630] described another similar case in which the patient developed intense, violent suicidality on the two occasions that he was exposed to fluoxetine.
Creaney et al. (1991) [318] described two patients who became suicidal on SSRIs. One patient developed dysphoria and manic symptoms on fluoxetine and then developed a similar syndrome, this time with suicidal feelings, on fluvoxamine. Another patient became intensely and violently suicidal 16 days after starting fluoxetine.
Gualtieri (1991) [573] described the "case of a mentally handicapped gentleman whose rates of self-injurious behavior doubled on fluoxetine, and then fell to baseline after the drug was withdrawn" (p. 393). Gualtieri pointed out that fluoxetine can cause apathy and indifference in some patients and, conversely, mania in others.
Goder et al. (2000) [532] reported that a 32-year-old man with OCD with preexisting obsessive, aggressive impulses developed "nausea, a strong sense of guilt, aggression, fear of losing control and increasing restlessness" after his first dose of 10 mg of paroxetine. He also had severe restlessness. He was prescribed neuroleptics and continued on paroxetine for 4 days, after which he had to be transferred to a closed ward because of his fear that he would give way to impulses to kill other people. On the following day, he attempted to kill himself by jumping off a wall and was severely injured. The paroxetine was terminated, he was treated with neuroleptics, and he recovered.
The clinical phenomenon of SSRI apathy and indifference has become of increasing interest in the literature. The mixture of apathy and disinhibited aggressiveness reported by Healy (2006) [610] and other researchers is found in a portion of patients who act uncharacteristically suicidal or violent as a result of taking SSRIs (Breggin, in press). In my clinical experience, feelings of apathy and loss of interest are among the main reasons patients seek help in trying to withdraw from SSRIs. Unfortunately, by the time the spellbinding apathy syndrome is recognized, the individual has often been taking the drugs for years and thus has considerable difficulty withdrawing from them.
Hoehn-Saric et al. (1990) [623], who were among the first to report it, described "apathy and indifference in patients on fluvoxamine and fluoxetine" as well as loss of initiative and disinhibition with and without hypomania in five patients. Levine et al. (1987) [836] reported that 7% of 59 nondepressed obese patients became depressed following a rapid increase in fluoxetine to a dose of 80 mg/day, but they did not identify apathy as an aspect of this drug-induced depression.
Apathy was reported as an "infrequent" adverse reaction during the testing of Prozac for depression (Physicians' Desk Reference, 2000 [1036]). However, it has become sufficiently common to be described in The American Psychiatric Publishing Textbook of Clinical Psychiatry (Marangell et al., 2003 [870]; see also Marangell et al., 1999 [871]):
"Apathy syndromes: We and others have noted an apathy syndrome in some patients after months or years of successful treatment with SSRIs. Patients often confuse this syndrome with a recurrence of depression, but the two conditions are quite distinct. The syndrome is characterized by a loss of motivation, increased passivity, and often feelings of lethargy and `flatness'. ... Mistakenly interpreting the apathy and lethargy for a relapse of depression, and hence increasing the dose of medication, will worsen the symptoms."
Note that the apathy syndrome is so spellbinding that patients "often confuse this syndrome with a recurrence of depression". As the textbook indicates, doctors can make the same mistake of failing to identify the drug as causal.
In my clinical experience, apathy or indifference is one of the main reasons patients want to stop taking SSRI antidepressants. Over months and years, they became increasingly unable to respond to loved ones and to the world around them, losing interest in favorite subjects and activities and existing in an emotionally dulled state. Usually, they have felt a return of their normal interest in life after stopping the medications. The lobotomy-like effect usually renders people passive, rather than aggressive, but it may be mixed with irritability and anger that more often occur during the start of treatment, dose changes, or withdrawal.
Barnhart et al. (2004) [103] reviewed the literature on apathy syndrome and found 12 relevant case reports and one open-label treatment trial. They pointed out the difficulty in distinguishing apathy from clinical depression but noted that patients can often tell the difference. In my experience, patients suffering from SSRI-induced apathy experience an indifference or lack of interest, even when their own rational assessment tells them that they do not feel sad or depressed, when in fact they would like to feel more involved in life. Whereas depressed patients typically lapse into feeling helpless and withdrawn, these individuals want to become more interested in their loved ones, friends, work, or hobbies but find themselves unaccountably stifled in their capacity to do so. They otten feel frustrated rather than depressed. Or if spellbound, they may actually claim to feel "fine," even while they display indifference to their surroundings.
Furthermore, as Barnhart et al. (2004) [103] pointed out, "cerebral blood flow changes, evidenced by single proton emission computed tomography, as well as the pattern demonstrated in neuropsychological testing, support the hypothesis that the effect in question is a reversible front lobe syndrome rather than a residual component of mental illness". The evidence in this regard is very preliminary but, in my opinion, probably will be confirmed.
In their review of 12 reported cases, Barnhart et al. (2004) [103] found three cases associated with fluvoxamine, seven with fluoxetine, and two with paroxetine. The apathy states improved or resolved with dose reduction or discontinuation. The authors believed that the syndrome frequently goes undetected "despite its significant clinical impact". Opbroek et al. (2002) reported that 80% of patients with SSRI-induced sexual dysfunction reported suffering from "treatment-emergent emotional blunting". This is consistent with my clinical observations that so-called sexual dysfunction in patients receiving antidepressants often involves a more generalized loss of interest in both sex and loved ones.
The syndrome has been described in children (see subsequent sections).
On the basis of the literature and my clinical experience, the syndrome of SSRI-induced obsessive suicidality and violence includes many, and sometimes all, of the following:
Concerning the extremely violent and/or bizarre quality of patients overcome with this syndrome, Grounds et al. (1995) [571] made interesting observations based on several of their own cases:
"striking feature of this syndrome is that most of the patients do not want to die - they just want to kill or harm themselves. None of our patients have actually suicided. ... The sufferers do not usually become preoccupied with taking overdoses, just with violent self injury. Quotes which illustrate this include: `I didn't want to die, I just felt like tearing my flesh to pieces. I suddenly found myself purposely driving dangerously - such as driving through a red light and driving on the wrong side of the road. I got frightened but I had to do it. I got my 'cane cutters' knife in my right hand and wanted to cut my left hand off at the wrist.' "
They also pointed out that the syndrome "tends to occur soon after commencement of treatment, or a dose increase. Cessation of fluoxetine results in abatement of the problem, and it usually recurs on rechallenge".
In my clinical experience, the sudden compulsion to harm oneself or others can occur after the first one or two doses of the antidepressant or within a day or two of a dose change, especially an increase. It can also occur shortly after the addition of another stimulating drug to the treatment regimen.
The clinical syndrome of mania is commonly associated with increased irritability, aggressiveness, physical violence, and a variety of antisocial and criminal behaviors (American Psychiatric Association [APA], 2000, pp. 357-362 [44]). Many studies of antidepressant-induced mania involve aggression.
Healy et al. (2006b) [610] evaluated data produced by GlaxoSmithKline (2006b) [524] in response to a recent review by British regulators. They also examined the company's data on controlled clinical trials for children. The authors summarized,
"In these trials, hostile events are found to excess in both adults and children on paroxetine compared with placebo, and are found across indications, and both on therapy and during withdrawal. The rates were highest in children with obsessive compulsive disorder (OCD), where the odds ratio of a hostile event was 17 times greater (95% confidence interval [CI], 2.22-130.0)."
Healy et al. (2006) [610] posited a variety of possible mechanisms for SSRI-induced violence, including akathisia, emotional blunting (a lobotomy-like apathy syndrome), and manic or psychotic reactions.
Healy (2000) [607] conducted a randomized double-blind crossover study comparing the effects of sertraline to a non-SSRI antidepressant (reboxetine) in a group of healthy volunteers. Many of the 20 individuals developed adverse mental and neurological effects while taking the sertraline, and two became severely disturbed. Case A, a 30-year-old woman, became withdrawn and ruminated over impulsive, disinhibited actions. She was also tearful and did not feel like herself. In addition, her diary recorded impulsiveness, irritability, oversensitivity, and marked suspicion. She became obsessed with killing herself and almost threw herself beneath a car or train. Case B, an otherwise peaceful 28-year-old woman, experienced severe road rage and actually grabbed a teenage boy and threatened to knock him down. On the SSRI, she felt aggressive and fearless. While emotionally disturbed and out of control (disinhibited), the two individuals nonetheless felt and appeared emotionally blunted.
The FDA conducted an epidemiological study comparing fluoxetine to a more sedating antidepressant, trazodone, in regard to spontaneous reports concerning hostility and intentional injury (Food and Drug Administration [FDA], 1991 [460]; available from http://www.breggin.com). When the FDA factored in the greater number of prescriptions for fluoxetine, it still had a higher frequency of reports for aggressive and violent behavior than trazodone. Furthermore, the reports began to accumulate before the controversy surrounding fluoxetine and violence had become public.
Fisher et al. (1993) [447] conducted a phone survey of pharmacy patients taking various antidepressants and compared fluoxetine to trazodone. They concluded that fluoxetine caused "a higher incidence of psychologic/psychiatric adverse clinical events, including delusions and hallucinations, aggression, and suicidal ideation" (p. 235, emphasis added). In a follow up study, Fisher et al. (1995) [449] found that many of the same side effects reported in regard to Prozac were also reported for Zoloft. Both drugs had equal numbers of reports for suicidality. Their research confirmed the hazards of SSRIs as a single class of drug with similar adverse effects.
The following studies make clear that the newer antidepressants very commonly cause mania. Too many prescribing health care providers seem oblivious to this risk or explain it away as an "unmasking" of an underlying mania, a rationalization that has no scientific justification.
The initial euphoria associated with mild cases of drug-induced mania often offer relief and hope, however unrealistic, to the patients who experience it. If the euphoria does not progress to full-blown mania, it is likely to wear off, and then apathy becomes more dominant over time. This often leads patients to ask for one antidepressant after another in the hope of recapturing that brief "high".
Some of the most tragic medical-legal cases I have evaluated began with the patient in effect telling the doctor shortly after starting the medication, "I've never felt better in my life". Too often this signals the start of a drug-induced manic reaction, technically called a substance-induced mood disorder with manic features.
As documented in the FDA-approved labels for SSRIs, clinical studies conducted for the FDA approval process have shown increased rates of mania, but usually the rates are much less than those found in scientific reports based on prescribing practices and conditions in comunity settings. For example, in the relatively short 4- to 6-week trials used for the approval of Prozac for depression, slightly more than 1% of patients developed hypomania and mania (see, e.g., the 1990 label for Prozac for depression). An unpublished FDA report obtained through the Freedom of Information Act indicated that fluoxetine caused mania at a 3 times greater rate than tricyclic antidepressants given in the same studies (Kapit, 1986c [733]). Furthermore, in 23 of the 33 cases, fluoxetine caused mania in patients with no past history of mania. In no cases did the older antidepressants cause mania in patients with no prior history. This data contradicts the commonly held clinical notion that SSRI-induced mania is limited to patients with an underlying bipolar disorder.
Martin et al. (2004) [882] used an administrative national data base of more than 7 million privately insured individuals, aged 5-29 years, to find new diagnoses of bipolar illness made in association with antidepressant treatment. They found a statistically significant correlation between exposure to all categories of antidepressants and the subsequent diagnosis of bipolar disorder. During a median follow-up of 41 weeks, manic conversion occurred in 5.4% of patients. The highest risk was in 10- to 14-year-olds. This latter finding highlights the risk of treating children with antidepressants and helps to explain the escalating rate of bipolar disorder diagnoses in children. In my clinical experience, nearly all maniclike episodes in children, especially preadolescents, occur in reaction to prescribed medications, usually antidepressants and sometimes stimulants.
Preda et al. (2001) [1053] carried out a retrospective study of 533 psychiatric hospital admissions over a 14-month period and found that 43 (8.1%) could be attributed to antidepressant-induced mania and/or psychosis. The SSRIs (70%) were the predominant offenders, but Effexor, Serzone, Wellbutrin, and the other antidepressants were also represented. Twelve of the cases were new-onset mania or psychosis, again contradicting the mistaken notion that antidepressants only unmask preexisting mania. The three illustrative cases were severe, including two with marked suicidal potential. A 52-year-old married woman with a past history of bipolar disorder developed "command auditory hallucinations with suicidal content" (p. 31) while taking desipramine and fluvoxamine as well as risperidone, zolpidem, and oxazepam. A 42-year-old woman with a 1-year history of depression "began to experience derogatory and then command auditory hallucinations to kill herself" (p. 31) while on fluoxetine as well as lithium and thioridazine. Finally, a 49-year-old woman taking venlafaxine for "low mood and anxiety" (p. 31) developed symptoms of paranoia, feelings of doom, and a delusion that television messages were being directed at her. All three patients improved rapidly with treatment that included termination of the antidepressants.
Morishita and Arita (2003) [948] carried out a retrospective review of 79 patients treated for depression with paroxetine and found that 7 (8.6%) developed hypomania or mania. Three of the seven patients were suffering from unipolar depression.
Howland (1996) [634] found 11 cases of SSRI-induced mania among approximately 184 (6%) patients treated at a university clinic and hospital with a variety of SSRIs, including fluoxetine, paroxetine, and sertraline. The episodes were "generally quite severe" (p. 426). Eight of the 11 patients became psychotic, and 4 were so agitated that they had to be put in seclusion, even though they were probably receiving additional medication to control their iatrogenic mania.
Ebert et al. (1997) [391] attempted to develop a rate estimate for severe mental aberrations caused by fluvoxamine. They carried out a prospective study of 200 inpatients over a total of 8,200 treatment days with the SSRI. Fourteen patients (17%) developed hypomania according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; APA, 1994 [43]) criteria. Three patients (1.5%) developed insomnia, agitation, confusion, and incoherent thoughts. These patients became potentially violent and suicidal. One, a 35-year-old man, developed agitation and restless legs that progressed to insomnia, confusion, paranoid ideas, and hallucinations. He recovered after fluvoxamine was stopped. Another patient, a 38-year-old man, developed psychomotor agitation with insomnia that progressed to aggressiveness, incoherent thoughts, confusion, auditory hallucinations, and paranoid ideas. He also recovered when fluvoxamine was stopped. A third patient, another 35-year-old man, developed insomnia and then became agitated with restless legs and severely depressed with suicidal ideas. He was also incoherent and confused with paranoid ideas. He, too, recovered within a few days after stopping the medication. On the basis of the clinical descriptions, all three patients may have suffered from akathisia.
Ebert et al. (1997) [391] summarized the syndrome of SSRI-induced manialike symptoms as consisting of insomnia, confusion, incoherent thoughts, agitation, hallucinations, and paranoid ideas. They observed that it was especially frequent in combination with other drugs. They considered it rare, but their data indicate that it was common. Adding up the 14 hypomanic patients and the 3 psychotic and aggressive patients, there were at least 17 severe psychiatric adverse reactions among 200 patients, for a rate of 8.5%16.
Troisi et al. (1995) [1266] used 20 mg/day of fluoxetine to treat 19 inpatients with mental retardation and epilepsy and a current or recent history of aggressive behavior. All of them were taking other medications as well. Using a standardized rating scale for assessing behavior before, during, and after treatment with fluoxetine, they found an increase in aggressive behavior in nine patients while taking the medication. Unexpecteddly, the behavior decreased to below pretreatment levels after withdrawal of the fluoxetine. The authors concluded that fluoxetine can worsen aggression in patients with mental retardation and impulsive aggressive behavior.
Peyre et al. (1992) [1032] reviewed the histories of 189 patients treated with fluvoxamine and found a rate of 2.5% for manic switches, that is, the development of mania during treatment for major depression.
Henry and Demotes-Mainard (2003) [615] reviewed the literature covering all categories of antidepressants in regard to conversion of depression to mania in unipolar as well as bipolar patients and during antidepressant withdrawal. They found that with tricyclic antidepressants, switches occured shortly after the start of antidepressant treatment, with a mean of 5.8 weeks and a range from 3 to 10 weeks; with SSRIs, switches occurred later (mean of 12 weeks), and even later with second-generation antidepressants when given with mood stabilizers. They confirmed that patients with a personal or family history of manic episodes are more prone to switch from depression to mania when taking antidepressants (see the following section).
Levy et al. (1998) [837] carried out a blind retrospective chart assessment of 167 patients with anxiety disorders, rather than depressive disorders, to see if antidepressants were related to emergence of hypomania or mania in these patients. They reported, "Five patients (2.99%) were identified as having an episode of antidepressant-associated mania within 3 months of initiation of treatment."
Henry and Demotes-Mainard (2003) [615] cited Koukopoulos and Koukopoulos (1999) [783] concerning the dangerousness of driving an ordinary depression into a more serious agitated depression. They discussed the role of agitation in depression in causing aggression and suicidality. Many cases of violence and suicide occur when an otherwise apathetic depression is converted into an agitated depression by antidepressants.
Although the labels for all antidepressants mention the risk of inducing mania, none of them mention the high frequency of this adverse drug reaction, and none describe its potentially devastating impact on the victim's life.
There are many studies of patients diagnosed with bipolar disorder converting from depression to mania when being treated with antidepressants. The rates are astonishingly high, contradicting the common practice of giving antidepressants to patients who have had previous hypomanic or manic episodes.
Henry et al. (2001) [616] followed 44 patients meeting DSM-IV [43] criteria for bipolar disorder. They found that switches from hypomania to mania occurred in 24% of patients treated with SSRIs. Most (16%) had frank manic episodes. Goldberg and Truman (2003) [537] reviewed the literature and found that about 20% to 40% of bipolar patients were converted into manic states by antidepressants of all classes. They concluded, "About one quarter to one-third of bipolar patients may be inherently susceptible to antidepressant induced manias."
Bipolar patients with so-called breakthrough major depressive episodes, despite adequate treatment, were placed in a randomized double blind 10-week study and treated with bupropion, sertraline, or venlafaxine augmentation (Post et al., 2001 [1048]). Switches to hypomania or mania occurred in 14% of the patients. Those who responded positively to the treatment were continued for 1 year in a blinded maintenance trial, and 33% switched into hypomania or mania. In a second phase of their antidepressant augmentation studies, 18.2% switched into hypomania or mania during the acute phase of treatment and 35.6% during the continuation phase (Post et al., 2003 [1049]).
Ghaemi et al. (2002) [513], who reviewed 85 charts of outpatients with affective disorder seen in a clinic, concluded that 37% had an undiagnosed bipolar disorder and that 23% of them had developed "a new or worsening rapid-cycling course attributable to antidepressant use". They concluded, "Antidepressants seem to be associated with a worsened course of bipolar illness." Ghaemi et al. (2003) [514] reviewed the literature and looked further into the issue of manic conversion. They drew the following conclusions:
(i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15-20% of bipolar depressed patients). (emphasis added)
Unfortunately, health care providers tell many of their patients, whether diagnosed with unipolar or bipolar depression, that they must take antidepressants for the remainder of their lives. Recognition that this promotes future manic reactions and even rapid cycling episodes should greatly reduce or stop this practice.
Stroll et al. (1994) [1221], from Harvard's McLean Hospital, compared the blinded charts of 49 consecutive inpatient admissions with antidepressant-induced mania with 49 matched cases of spontaneous mania over a 1-year period, from March 1, 1990, to February 28, 1991. The patients had been exposed to tricyclics (n = 19), fluoxetine (n = 13), monoamine oxidase inhibitors (n = 8), bupropion (n = 6), and mixed antidepressants (n = 3). (lt is striking that these doctors were already aware of the risk of Prozac-induced mania approximately 2 years after the January 1988 introduction of Prozac into the market. Meanwhile, too many health care providers remain in denial about this significant risk.)
The patients with antidepressant-associated manic states required monitoring and restrictions for shorOter periods of time and had "significantly less severe levels of delusions, hallucinations, psychomotor agitation, and bizarre behavior" than patients with spontaneous mania. Stroll et al. (1994) [1221] concluded, "Antidepressant-associated mania appears to be a milder and more time-limited syndrome than spontaneous mania and may represent a distinct clinical entity."
This study confirmed my own observations from dozens of cases, many seen for medical-legal evaluations, that patients with antidepressant-induced mania recover quickly when the offending agent is removed (Breggin, in press). The study also confirmed that antidepressant-induced mania is not merely an unmasking of a preexisting manic tendency; its clinical course is actually different.
Stroll et al. (1994) [1221] also observed that "MAOIs and bupropion may be associated with milder manic states than either tricyclic drugs or fluoxetine. ... Clinical lore suggests that fluoxetine produces a more severe and prolonged manic state than other antidepressants, mainly because of its long duration of action." This underscores a risk seldom considered within psychiatry: that longer-acting medications, including extended-release delivery systems, cause a more severe risk of lengthy adverse reactions.
In a variety of forensic activities, including criminal and civil cases, the courts sometimes rely on authoritative or standard texts to demonstrate that the opinions rendered are supported by a significant portion of the medical or scientific community.
The DSM-IV (1994) [43] and the fourth edition text revision (DSM-IV-TR; APA, 2000 [44]) are written by committees made up of professionals considered experts by many of their colleagues in their respective fields. The conclusions therefore provide a professional consensus or body of conventional wisdom in psychiatry that can at times be useful in clinical practice and in forensics. Many aspects of the DSM-IV [43] are controversial. However, when such an essentially conservative consensus document provides evidence for SSRI-induced adverse reactions related to mania, suicide, and violence, it should alert clinicians to the existence of these clinical phenomena and can provide an avenue for communicating in the courtroom concerning these risks.
The DSM-IV [43] was published in 1994, several years after the advent of SSRI antidepressants, and makes clear that all antidepressants can cause mania. The first SSRI, fluoxetine, was approved by the FDA in December 1987 and was in widespread use when the following observations about antidepressants were published in the manual.
The DSM-IV [43] makes multiple references to the fact that antidepressants can cause mania or manidike behavior. It states, for example, "Symptoms like those seen in a Manic Episode may be due to the direct effects of antidepressant medication" (p. 329). Similarly, it observes, "Symptoms like those seen in a Manic Episode may also be precipitated by antidepressant treatment such as medication" (p. 331). References to antidepressant-induced mania and mood disorder can also be found elsewhere in the manual as well (e.g., pp. 332 [note at bottom of table], 334, 336, 337, 351, 371, and 372). The DSM-IV-TR [44] contains the same statements. It emphasizes that a diagnosis of mania or bipolar disorder should not be made when the symptoms hypomania or mania first appear while taking a medication that can cause them and "usually disapear when the individual is no longer exposed to the substance". Of great clinical importance, it adds, "but resolution of symptoms can take weeks or months and may require treatment" (p. 191).
The association between mania and antisocial behavior, including violence, is underscored in the DSM-IV [43]. Aggression is specifically mentioned as a feature of manic behavior. It is noted that "antisocial behaviors may accompany the Manic Episode," "ethical concerns may disregarded even by those who are typically very conscientious," "the person may become hostile and physically threatening to others" and "physically assaultive," and "the mood may shift rapidly to anger or depression" (p. 330). The very next page in the DSM-IV [43] repeats the reminder that "symptoms like those seen in a Manic Episode may also be precipitated by antidepressant treatment such as medication" (p. 331).
Mania is characterized by "increased involvement in goal-directed activities" (DSM-IV, p. 328 [43]). Therefore the individual does not lack the capacity to plan and carry out inappropriate or destructive actions or to attempt to cover them up once they have been enacted. To the contrary, individuals undergoing mania often feel driven to carry out elaborate plans, however bizarre, violent, or doomed they may be.
According to the DSM-IV [43], an "elevated, euphoric or irritable mood" is sufficient to qualify for a diagnosis of substance-induced mood disorder with manic features (pp. 370,375; DSM-IV-TR [44], pp. 405-406). This descriptor for manic features is sufficiently broad to encompass some or all symptoms associated with stimulation and aggression. Therefore an SSRI-induced stimulant-like or aggressive reaction can often be diagnosed as a drug-induced mood disorder with manic features. When drug-induced mood swings occur from mania to depression, sometimes accompanied by switches from violence to suicidality, the diagnosis can include both depressive and manic features.
Irritability, as used in the DSM-IV [43], has a more ominous meaning than irritability as used in ordinary language. During a discussion of depression, the DSM-IV [43] refers to the symptom of "increased irritability (e.g., persistent anger, a tendency to respond to events with angry outbursts or blaming others, or an exaggerated sense of frustration over minor matters)" (p. 321). Many individuals who commit aggression while under the influence of SSRIs will qualify for a substance-induced mood disorder with manic features on the basis of their obvious increase in irritability while taking the drug.
The capacity for SSRIs to induce akathisia - and for akathisia to cause suicidality, aggression, and a worsening mental condition - is also recognized in the DSM-IV [43] and the DSM-IV-TR [44] in the section dealing with neuroleptic-induced akathisia. The DSM-IV-TR observes, "Akathisia may be associated with dysphoria, irritability, aggression, or suicide attempts." It also mentions "worsening of psychotic symptoms or behavioral dyscontrol". It then states, "Serotonin-specific reuptake inhibitor antidepressant medications may produce akathisia that appears identical in phenomenology and treatment response to Neuroleptic-Induced Acute Akathisia" (p. 801).
The APA (1993) [42] practice guidelines, like the DSM-IV [43], attempt to arrive at a consensus among experts. The emphasis, however, is on treatment, rather than diagnosis. Like the DSM-IV, the practice guidelines were published after the SSRIs were in use.
Using several citations from the literature, the practice guidelines state the following:
"All antidepressant treatments, including ECT, may provoke manic or hypomanic episodes. Individuais with a history of mania or hypomania are at particular risk for this untoward effect, although it may occur even in patients with no such history; this complication is estimated to occur in 5%-20% of depressed patients treated with antidepressants." (p. 22)
Recognition of antidepressant-induced maniclike reactions and akathisia in two of the most commonly used manuals of psychiatric diagnosis spanning 1993-2000 has important implications for clinical practice and forensics. Practitioners should be aware that these adverse drug reactions occur and that the patient should be diagnosed with a substance-induced disorder or with akathisia, rather than with a primary psychiatric disorder such as bipolar I disorder or an anxiety disorder. It should alert practitioners to the need to stop antidepressants at the first sign of initial or recurring hypomanic and manic symptoms or akathisia. In forensics, recognition of the existence of these adverse drug reactions can help establish causality in malpractice, product liability, and criminal cases when SSRIs induce abnormal mental and behavior reactions. The body of literature reviewed in this report and the confirmation found in the DSM-IV [43] and DSM-IV-TR [44] help to establish a standard requiring that physicians be aware of the potential for these drugs to cause mania and akathisia with the associated risks of suicidality, violence, and extreme or bizarre behavior.
Many cases of SSRI-induced violent or suicidal behavior involve children or young adults. However, even in regard to cases involving older persons, the literature on children and youth is important. Adverse behavioral effects tend to show up more frequently and severely in children, providing a magnified view of the same or similar effects that the drugs are causing in adults.
As previously noted, Medwar et al. (2002) [913] and Medwar et al. (2003-2004) [912] described numerous public reports involving adults and children that were sent by e-mail to the British TV show Panorama.
An example of Prozac-induced mania with potential violence was presented by Jerome (1991) [679], who described a 10-year-old boy who became depressed when his family moved to a new neighborhood. The youngster was placed on 20 mg of Prozac by his family physician and immediately became "hyperactive, agitated ... [and] irritable," with pressured speech. He gained energy, required less sleep, and developed a "somewhat grandiose assessment of his own abilities". Then he began to make anonymous phone calls, threatening to kill a stranger in the neighborhood. When the telephone calls were traced back to him, the Prozac was discontinued, and all of the hypomanic symptoms resolved within 2 weeks.
A single case study involving paroxetine described a 16-year-old who became manic with angry outbursts after 3 weeks on the drug (Oldroyd, 1997 [1006]). Beech (2000) [117] described an 8-year-old girl who became hypomanic on sertraline. The adverse drug reaction had been originally misdiagnosed as attention-deficit / hyperactivity disorder. Diler and Avci (1999) [362] described three cases of paroxetine-induced mania in children, two aged 9 and one aged 10, who were being treated for obsessive-compulsive disorder. Guile (1996) described a case of activation that fell short of the standards of hypomania in a 15-year-old treated with sertraline. Kat (1996) [744] reported on two teenage girls who became manic on sertraline. One, age 14, developed the mania after two doses and rapidly remitted after stopping the drug.
Heimann and March (1996) [612] reported about a 15-year-old with a long history of "chronic, low grade depression" who became manic after 1 month on sertraline. Her behaviors included "physical aggression toward a peer, intoxication with alcohol, and sexual promiscuity". Behaviors such as this can, unfortunately, ruin a child's life.
Jafri and Greenberg (1991) [661] described the case of a 15-year-old boy who became psychotic "directly related to his receiving fluoxetine". After his medication was stopped, he improved over about 1 week's time. Hersh et al. (1991) [621], physicians from Cornell University Medical College, described an 11-year-old girl who developed a delusional system on Prozac.
In another single case study, a 17-year-old with mild retardation was started on fluvoxamine 50 mg to treat depression and anxiety (Sim, 2000 [1181]). After a single dose, he developed increasing agitation and insomnia, followed in the next 24 hours by auditory and visual hallucinations, a fearful mood, and paranoid delusions about the devil. He required hospitalization and was treated with an antipsychotic drug. The authors believed that fluvoxamine caused the acute psychosis. As a third example of single-case clinical reports, Wilkinson (2000) [1344] described a character change with increased aggression in a 15-year-old boy taking fluoxetine. Uncharacteristically, he struck another youngster in the face. Fluoxetine, was stopped, and within a week, he was no longer aggressive. The author identified blunting, rather than akathisia, as the motivational state.
Koizumi (1991) [773] described a 13.5-year-old boy who developed manic symptoms on 40 mg/day of fluoxetine. These side effects disappeared when the dose was lowered to 15 mg/day. However, after 15 months of fluoxetine treatment, he then developed "explosive, angry outbursts over minor matters, which was totally unlike him" (p. 695). He then experienced a "weird" and ego-alien voice telling him to kill himself. He recovered from these symptoms within 10 days of stopping fluoxetine.
Pravin et al. (2004) [1052] described four patients, age 6-15, who developed mania on citalopram. One child first developed mania when exposed to fluoxetine and then again when given citalopram. Three of the children required additional treatment with lithium or antipsychotic drugs, and the fourth ended up being given ECT.
Chapter 6 described the meta-analyses used by the FDA to determine that the rate of suicidality was doubled in children taking SSRIs in placebo-controlled clinical trials.
Earlier, this chapter reviewed Healy et al.'s (2006) [610] finding that clinical trials in paroxetine for children found an increased number of hostile events and that "the rates were highest in children with obsessive compulsive disorder (OCD), where the odds ratio of a hostile event was l7 times greater (95% confidence interval [CI], 2.22-130.0)".
Numerous epidemiological and clinical study reports confirm that SSRIs cause a high rate of mania in children and youth. Again, as noted earlier in this chapter, Martin et al. (2004) [882] used a national data base of more than 7 million privately insured individuals, aged 5-29 years, and found that the highest risk of manic conversion while taking antidepressants was in the 10- to 14-year-old group.
According to the FDA-approved label for fluvoxamine (Luvox in the Physicians' Desk Reference, 2001 [1036]), the SSRI causes a 4% rate of mania in children under age 18, compared to no cases of mania produced in a similar group of children on placebo. The rate was at least 4 times greater than in adults (see Breggin, 2002a [210], for a more complete analysis of the Luvox label). Moore (2004) [945] analyzed adverse event reports made to the FDA concerning children and adults in association with the six most commonly prescribed antidepressants: Zoloft, Paxil, Prozac, Celexa, Wellbutrin, and Effexor. He reported the following:
A controlled clinical trial found that fluoxetine caused a 6% rate of mania in depressed children and youngsters age 7-17 (Emslie et al., 1997) [408]. The reactions were severe enough to cause the children to be dropped out of the trials. By contrast, none of the depressed youngsters on placebo developed mania. Emslie, as already noted, is closely tied to drug companies and heavily promotes their products. The 6% mania rate is, of course, extremely important and deserved to be mentioned in the abstract, discussion, and conclusion, but it is buried in the discussion of dropouts. I only found it, after a careful search of the article, because I had been alerted in advance by a report he gave to a psychiatric newspaper 2 years earlier (Sherman, 1995 [1171]). In that earlier report, Emslie also mentioned that several children became aggressive on Prozac, but that is nowhere to be found in the published report.
In a most remarkable study, especially given the prodrug bias of the investigative team, Wilens et al. (2003) [1343], of the Clinical and Research Program in Pediatric Psychopharmacology at the Massachusetts General Hospital and Harvard Medical School, systematically evaluated 82 charts of children treated with SSRIs for depressive or OCD symptoms over a mean period of 26.9 months. The drugs included sertraline, paroxetine, fluoxetine, fluvoxamine, and citalopram. The mean age of the children was 12.2 years. Psychiatric adverse events (PAEs) were found in 22%, "most commonly related to disturbances in mood". The onset was typically 3 months after the beginning of treatment. Remarkably, "re-exposure to an SSRI resulted in another PAE in 44% (n = 13) of the group".
The breakdown of PAEs caused by SSRIs in this study was ominous. Of the 82 children, 21% developed mood disorders, including 15% who became irritable, 10% who became anxious, 9% who became depressed, and 6% who became manic. In addition, 4% of the children became; aggressive. Sleep disorders afflicted 35% of the children, including 23% feeling drowsy and 17% experiencing insomnia. Finally, 10% became psychotic!
In a sane medical community, this one study would have raised a hue and cry of concern, leading to the complete abandonment of SSRI antidepressants for children, especially given their lack of efficacy. There is not a hint from this Harvard research team that these findings ought to slow down the drugging of children.
A team at the University of Pittsburgh (Go et al., 1998 [531]) reviewed the cases of 40 youths, age 11-17, treated with SSRIs for OCD. Twenty received SSRIs, and 20 did not. In an open-label clinical treatment regimen, 30% (6 of 20) of the patients treated with SSRIs developed hypomanic or manic symptoms. Five were on fluoxetine and one on sertraline17. According to the authors, "symptoms included impulsivity, grandiosity, pressured speech, and disinhibition". They concluded, "Clinicians are advised to be aware of the risk and to be vigilant in monitoring manic and hypomanic behaviors when using SRIs [sic] to treat OCD in youth, even with low doses and gradual dose elevation."
Jain et al. (1992) [662] made a retrospective examination of the medical charts of children and young men age 8-19 who had taken fluoxetine in a university clinic setting. The researchers found that 23% of fluoxetine-treated young people developed mania or maniclike symptoms. Another 19% developed drug-induced hostility and aggression, including a grinding anger with short temper and increasing oppositional behavior.
Constantino et al. (1997) [309] prospectively studied the course of aggressive behavior in 19 SSRI-treated psychiatrically hospitalized adolescents who were not preselected for potential aggressiveness. They reported symptoms of physical aggression toward self or others in 12 of 19 patients on SSRIs. Of the 19 patients, 13 were assessed both on and off SSRIs. On the SSRIs, there was increased verbal aggression (p = 0.04), increased physical aggression toward objects (p = 0.05), and increased physical aggression toward self (p < 0.02). No increase was observed in physical aggression toward others. The authors warned against using SSRIs to treat aggression in children.
Another study of children and youth age 8-16 in a university setting found that 50% developed two or more abnormal behavioral reactions to fluoxetine, including aggression, loss of impulse control, agitation, and maniclike symptoms (Riddle et al., 1990-1991 [1086]). The effects lasted until the fluoxetine was stopped.
A second research study from the same university setting described a number of youngsters (6 of 42, or 14% in their cohort) who became aggressive and even violent while taking fluoxetine (King et al., 1991 [760]). The researchers hypothesized that fluoxetine caused aggressive behavior by means of drug-induced activation (stimulation) or a specific serotonergic mediated effect.
The report by King et al. (1991) [760] provided a clinical window into the development of obsessive violence and a school-shooter mentality. A 12-year-old boy on fluoxetine developed nightmares about becoming a school shooter and then began to lose track of reality concerning these events. This case occurred in a controlled clinical trial, and the investigators did not know that the child was getting fluoxetine until they broke the double-blind code. The child's reaction occurred long before any of the well-known school shootings had taken place. Therefore his reaction was not inspired by the school shootings - it was not a copycat fantasy:
"Thirty-eight days after beginning the protocol, F. experienced a violent nightmare about killing his classimates until he himself was shot. He awakened from it only with difficulty, and the dream continued to feel `very real'. He reported having had several days of increasingly vivid `bad dreams' before this episode; these included images of killing himself and his parents dying. When he was seen later that day he was agitated and anxious, refused to go to school, and reported marked suicidal ideation that made him feel unsafe at home as well." (p. 180)
The child was hospitalized first for 3 days, and then for 17 days. He gradually improved. Then, 3 weeks after his last hospitalization, his local physician - not one of the clinical investigators - put him back on fluoxetine. The child became acutely suicidal, until the fluoxetine was stopped a second time.
This individual report is important for a variety of reasons:
Reinblatt and Riddle (2006) [1079] stated, "Selective serotonin reuptake inhibitor (SSRI)-induced apathy is characterized by a lack of motivation that is not a result of sedation or symptoms of depression." In a review of 43 participants in a fluvoxamine pediatric research project, the authors identified two (5%) cases of apathy, one in a 9-year-old and the other in a 16-year-old, neither of whom was depressed. They found that "similarities to existing reports included: Lack of insight, delayed onset, dose dependency, and reversibility with SSRI dose reduction or discontinuation".
The 16-year-old girl's personality changed in ways that I witnessed, with more tragic results. Her friends worried that her personality had changed as she became socially withdrawn, began to take unusual risks, and was overly confident with strangers (a grave danger in a teenage girl). Meanwhile, according to Reinblatt and Riddle (2006) [1079], "she was paradoxically simultaneously amotivated to do her usual daily activities". In the case of a 9-year-old boy, when his dose was increased he "presented with extreme amotivation and apathy, not caring about anything; he did not want to go to school and didn't care about typical interests".
Reinblatt and Riddle (2006) [1079] concluded, "SSRI-induced amotivational syndrome is a more important and frequent clinical issue than suggested by the paucity of published reports. It may go undetected in its milder forms owing to delayed onset and variable severity of presentation."
Garland and Baerg (2001) [505] described cases of apathy, one accompanied by disinhibition, in a child and four adolescents. A 14-year-old boy on paroxetine became so flat that his face became masklike, similar to parkinsonism, but without any other signs of that disorder. His parents and the clinician were concerned about his loss of interest, but typical of severe medication spellbinding, "the patient was quite satisfied with his life and did not recognize a problem".
A l5-year-old boy on fluoxetine became "bizarrely" blasé about his participating in competitive sports and lost interest in schoolwork. He began neglecting his chores, losing items of clothing, and was generally criticized as irresponsible by the adults in his life, until the syndrome was recognized. He remained unconcerned. According to Garland and Baerg (2001) [505], "when the parents confronted him about these behaviors, he was calm, unconcerned, and did not seem to perceive a problem". His medication was discontinued, and he gradually returned to normal over a month. However, he then asked to be resumed on the medication at a lower dose to control his anxiety, and "positive benefits returned without the amotivational features". Consistent with the brain-disabling principle, I strongly suspect, however, that the boy was simply experiencing a relatively small induction of apathy that he perceived as reducing his anxiety.
A 14-year old boy taking fluoxetine again demonstrated medication spellbinding (Garland et al., 2001 [505]):
"In a follow up visit 6 weeks after the dose increase, his affect was flat, and he appeared emotionally disconnected and apathetic. However, he reported that he felt `fine' and was not in any way unhappy or distressed about his situation despite a large drop in his grades."
A 10-year-old female taking paroxetine developed disinhibited behavior after a dose increase (Garland et al., 2001 [505]):
"She had interpersonal boundary problems, asking people inappropriate personal questions, having poor judgment and thereby insulting and alienating both peers and adults. This was quite out of character for her, as she previously had been quite polite and sensitive to others. She did not seem to have insight into how inappropriate her statements were at the time. ... When describing her actions to the psychiatrist, she showed no appropriate embarrassment. She appeared unusually unconcerned and flat in affect."
Consistent with the other cases in this section, she showed no signs of mania to account for her disinhibition. She was, instead, apathetic in appearance and affect.
The fifth case, concerning a 17-year-old girl, described how she lost interest in socializing and in sports, even though she was realistically working toward a college athletic scholarship. She appeared apathetic and flat but had few complaints, except for tiredness and mild hypersomnia. Consistent with the brain-disablihg principle, her parents were "far less concerned about her as she was no longer volatile and there was less conflict about curfews as she was less interested in going out with her friends" (Garland and Baerg, 2001 [505]). Fortunately, her psychiatrist became concerned about her and reduced the medication (while adding bupropion). However, according to Garland and Baerg (2001) [505], "her lack of participation in sports during a crucial part of the session had a lasting impact on her career plans". She did not go to college.
As all of the above cases indicate, patients commonly lack insight into how apathetic they have become. In my clinical experience, even when they identify apathy and ask to be withdrawn from their antidepressants, most children and adults are surprised and even mortified as they realize in what an apathetic state they had been when medicated. SSRI-induced apathy is a profound example of the brain-disabling effects of psychiatric medications, including medication spellbinding. The disabling effects occur along a continuum so that a mild degree of apathy is often perceived by others and by the patient as an improvement, while a severe degree will be seen by others, but not necessarily by the patient, as an adverse drug effect. When accompanied by disinhibition, apathy can lead to especially tragic results (Breggin, in press). As in the case of the girl who lost out on her scholarship and never went to college, even without disinhibition, even a relatively brief period of apathy can have lifelong negative results.
As documented in chapter 6, the scientific literature demonstrates, and the FDA admitted at its 2004 hearings, that there is no substantial evidence supporting the usefulness of antidepressants in treating depression in children. What about the treatment of adults? Is it possible that the antidepressants are not antidepressants at all?
At the height of enthusiasm for the older tricyclic antidepressants, Baldessarini (1978) [91] found little scientific confirmation. Spontaneous remission and placebo effect, he concluded, might account for why it usually takes several weeks to obtain a positive response. Even in more severe depressions, he noted, the spontaneous remission rate can exceed 50% in a few months. Similarly, Klerman and Cole (1965) [770], strong drug advocates, recognized that "depressions, on the whole, are among the psychiatric conditions with the best prognosis for symptomatic recovery, with or without treatment". They cited data predating the drug era that show improvement rates of "44% of all patients within the first year and 56% recovery eventually over a longer time period". Like Baldessarini (1978), they observed that the time lapse before the antidepressants are alleged to work may coincide with the period of spontaneous recovery.
Fisher and Greenberg (1989 [448], 1995 [449]) approached the subject of antidepressant efficacy with a systematic analysis of the existing controlled studies. They found that antidepressants were little or no better than placebo. When the placebo had side effects, such as dry mouth or sedation, it convinced the observers and the subjects that the placebo was really an active drug. As a result, in these studies involving a placebo with side effects (an active placebo) there was no difference between the medication and the placebo. Researchers lead by David Antonuccio have reviewed the existing clinical studies and literature concerning antidepressant effectiveness and have found that any positive drug effect is negligible (Antonuccio et al., 1994 [58], 1995 [59]; Antonuccio et al., 2002 [57]). Their research also confirmed that psychotherapy is as good as, or better than, antidepressants. It is obviously much safer.
In 1994, in Talking Back to Prozac, I first brought to light the failure of Prozac to prove its effectiveness in the studies done for FDA approval (see Breggin et al., 1994a [219]). Then, in 2002, a team led by psychologist Irving Kirsch at the University of Connecticut published an analysis of efficacy data submitted to the FDA between 1987 and 1999 for six of the most commonly prescribed antidepressants: Prozac, Paxil, Zoloft, Effexor, Serzone, and Celexa (Kirsch et al., 2002 [765]).
Each of the drugs had been approved based on a drug company submitting two positive studies to the FDA. But all of the companies conducted numerous additional studies before they were able to obtain the required two that seemed positive. So Kirsch et al. looked at all the antidepressant studies - not just the ones submitted for approval.
Kirsch et al. [765] obtained 47 studies, an average of almost eight per drug, conducted as a part of the FDA approval process. After examinig all of the studies, they found that any beneficial or positive effects in comparison to placebo were negligible.
This chapter has emphasized the poor risk:benefit ratio in giving antidepressants to children and adults, but the elderly are probably most vulnerable of all to their adverse effects. The practice of prescribing antidpressants to older patients with dementia is particularly inappropriate since the drugs worsen their cognitive function (Deakin et al., 2004 [341]). In a study of patients over age 55 seen at a day hospital from 1986 to 2005, including 824 patients, 600 of whom received antidepressants, apathy subscales of two depression-rating instruments were significantly correlated with the use of SSRI antidepressants (Wongpakaran et al., 2007 [1362]). Wongpakaran et al. (2007) concluded, "Even though depression was proved in elderly patients receiving antidepressants, the degree of apathy appeared to be greater in patients who were treated with SSRIs than in patients who were not. Frontal lobe dysfunction due to alteration of serotonin was considered to be one of the possibilities."
How do psychiatry and the psychopharmaceutical complex react to the mounting evidence that antidepressants are not only dangerous, but also useless for both adults and children? They generally ignore it. However, the Kirsch et al. (2000) [765] study has received positive recognition from those few professionals brave enough to face the facts, including Angell (2007) [54], the former editor of the New England Journal of Medicine, and Charles Medwar (Medwar et al., 2004, p. 57 [911]), the respected British researcher and public safety advocate.
In 2006, British psychiatrist Joanna Moncrieff and Kirsch [942] published another review and analysis of antidepressant effectiveness in the BMJ. They focused on studies conducted on SSRIs such as Prozac, Zoloft, and Paxil and concluded that these drugs "do not have a clinically meaningful advantage over placebo".
It is a sad, ironic, and tragic tale: It is impossible to prove that antidepressants actually relieve depression, but it is relatively easy to demonstrate that they can worsen depression and cause mania, violence, and suicide. If my colleagues wanted to be scientific about it, they would call them depressants, rather than antidepressants, and take them off the market.
A large percentage of patients suffer from neurological sexual dysfunction as a result of taking the SSRI antidepressants. Estimates vary widely but are way beyond the small percentages suggested on SSRI labels. Baton (2006) [109] noted rates as high as 80% and suggested that a realistic estimate probably lies between 30% and 50%.
In my clinical experience, many, and probably most, patients taking SSRIs suffer from drug-induced sexual dysfunction due to suppressed sexual appetite, inhibited sexual function, and emotional withdrawal, but the SSRIs often make them too apathetic or disinterested to complain to their doctors. They are too medication spellbound to care about their sexual and love life or the effects on their loved ones and partners.
Unfortunately, reports have appeared suggesting that these sexual disorders may remain persistent after termination of the drug, leaving an otherwise recovered individual suffering from lifelong sexual dysfunction (Csoka et al., 2006 [325]).
The risk of causing EPS, another SSRI-induced neurologist disorder, was apparent from early on. The FDA's Kapit (1986) [731] warned, "It is possible that a tardive syndrome related to fluoxetine may exist. It will be necessary to be on the lookout for such events" (p. 32). By January 1993, more than two dozen reports of Prozac-induced tardive dyskinesia had reached the FDA (1993) [462], but the profession has not taken much notice. Numerous case reports confirm that the SSRIs can produce persistent extrapyramidal reactions, including tardive dystonia with painful and disabling spasms of the neck and shoulder musculature.
In his review of the literature published in 1996 [832], Leo already found 42 articles reporting 71 cases of motor symptoms that appeared for the first time during SSRI use. Akathisia was reported in 32 cases, dystonia in 20, parkinsonism in 10, tardive dyskinesia-like movements in 8, and tremors in 7. Several patients had combined disorders.
Gerber and Lund (1998) [509] reviewed the literature and located 127 case reports of SSRI-induced abnormal movements. These included akathisia (agitation with hyperactivity), tardive dyskinesia, parkinsonism, dystonia (mescle spasms), bruxism (tooth grinding), and related disorders. They found many additional case reports from the drug manufacturers, including 516 cases of parkinsonism and 76 cases of tardive dyskinesia. The term tardive dyskinesia is usually reserved for cases that are irreversible.
SSRIs can cause most of the neurological disorders associated with the neuroleptic drugs, including a serotonergic syndrome that resembles neuroleptic malignant syndrome. The similar result is probably due to the capacity of SSRIs to impact the dopaminergic system. Recent studies (e.g., Miura et al., 2007 [936]) continue to confirm the early clinical suspicion that SSRIs were not quite as selective as their name implies and in fact impinge on other neurotransmitter systems.
Theoretically, Prozac is supposed to make more serotonin available in the synapses, but the brain tries to overcome its effects. When an SSRI antidepressant blocks the removal of serotonin from the synapse, the brain senses that too much serotonin is pooling in the region, and it shuts down the production and release of the serotonin into the synapse. Two of Eli Lilly's top researchers, Ray Fuller and David Wong [501], published a paper in 1977 - more than a decade before Prozac reached the marketplace - showing how the brain compensated for SSRI overstimulation by inhibiting the production and release of serotonin and the overall activity of the serotonergic system. When Prozac and similar drugs were given to animals, instead of the anticipated overstimulation, there was a tendency for the system to shut down:
"When fluoxetine or other effective but less specific serotonin uptake inhibitors are given, a rapid decrease in serotonin turnover occurs and the rate of firing of single neural units in the serotonin rich raphe area of the brain is reduced. This decrease in serotonin turnover and release may be a compensatory mechanism in response to an enhanced action of serotonin on the synaptic receptors."
Notice that the actual results are completely contrary to what most health care providers imagine. Prozac and the other SSRIs do not cause an immediate enhancement (e.g., overstimulation) of the serotonergic system; they cause a compensatory shutdown of the system. On the basis of the drug company-sponsored theory that sluggish serotonin causes violence and suicide, this means that an initial dose, and probably dose changes, can cause extreme sluggishness in the system, with the potential for violence and suicide.
Later studies showed that the inhibition lasts about 10 days, but there is evidence that it may last longer in other parts of the brain. Thus, from the start, Eli Lilly knew that it was creating complex, unpredictable biochemical imbalances and a roller-coaster situation in which the drug would block the removal of serotonin and the brain would resist the process.
Then, in 1999 [1317], Wegerer and a team from Germany and the United States discovered that the brain had yet another way of compensating for the SSRI-induced blockade of the transporter system that removes serotonin from the synapse. To envision the chemical transporter system and the antidepressant blockage, imagine a conveyor belt that removes valuable rocks from deep within a quarry. Putting other rocks onto the transporter system (conveyor belt) to take up the space would obviously interfere and slow down the conveyer process. In effect, Prozac, Zoloft, Effexor, and other SSRIs jump onto the transporter system, blocking its function of removing serotonin from the synapse.
SSRIs are potent occupiers (blockers) of the serotonin transporter system (Meyer, 2007 [925]; Meyer et al., 2004 [926]). Meyer et al. (2004) used PET to study the degree of occupancy in normal volunteers and in subjects with mood and anxiety disorders after 4 weeks of exposure to four commonly prescribed SSRIs. They achieved 80% occupancy of the transporter system receptors at "minimum therapeutic doses". They believed that this blockade was important for the "therapeutic effect". But how does the living brain respond to being occupied in this manner?
When antidepressants block the function of the transporter system, Wegerer et al. (1999) [1317] found, the transporter system grows strong in response by increasing in density. This effect was found in young rats after only 2 weeks of exposure to Prozac.
The Wegerer et al. (1999) [1317] study found that the increased transporter system density persisted for at least 90 days into the adulthood of the rats. These abnormalities were found in the most highly developed portions of the rat brain, the frontal lobes. Wegerer et al. were unusually brave and ethical in pointing out that these findings indicated a risk for children taking SSRIs.
After exposure to Prozac and other SSRIs, yet another compensatory biochemical mechanism called down-regulation quickly begins reducing the number of receptors in the brain for serotonin (de Montigny et al., 1990 [339]; Wamsley et al., 1987 [1313]; Wong et al., 1981 [1360]; Wong et al., 1985 [1361]). After weeks or months of exposure, a large percentage of the receptors actually become undetectable; that is, they disappear, resulting in reduced responsiveness to serotonin (subsensitivity). Wamsley et al. (1987) [1313] found that at lower doses, there were both increases and decreases in receptor density in various areas of the brain, indicating the complexity of the brain's response (see also Fuller et al., 1974 [500]).
Down-regulation begins as soon as 2 days after exposure to Prozac in rats. Up to 60% of some subtypes of serotonin receptors can disappear. The reduction in receptors and the resulting down-regulation of serotonergic activity is widespread throughout the brain, involving the frontal lobes and cortex-the centers that regulate the emotional and intellectual life of the individual. In the process, the capacity of the serotonin system for activation is reduced, theoretically producing a sluggish system.
A number of studies show lengthy periods of time-weeks and months - during which receptor loss does not recover, but no systematic attempts have been made to determine if recovery ever occurs. Longer studies would not be hard to conduct. Nonetheless, Ray Fuller, Lilly's head of research, declared in deposition testimony that he knew of no studies concerning recovery of down-regulated serotonin receptors. Asked if he thought these experiments were important, Fuller sounded a little flummoxed as he responded, "I don't see that that would be of any value to know that" (Fuller, 1994, p. 266 [499]). Oblivious of the potential consequences, health care providers too often urge their patients to stay on SSRI antidepressants indefinitely.
Clearly antidepressants do not correct biochemical imbalances in the brain; they cause them. They change the brain for the worse in ways that can persist indefinitely after the drugs are stopped. At no point in time can we know what the exact biochemical imbalance in the brain looks like, and it probably varies in different regions and at different times as the drugs produce their effects and the brain fights back in its varied ways.
Advocates of SSRI antidepressants often assert that depression and suicide, and even violence, may be linked to an underactive serotonin system, and that SSRIs activate the system by blocking the removal of serotonin from the synapse. In reality, the antidepressants produce unpredictable results with an overall impact that cannot be measured in the living brain, even with animal experiments. At times, when the brain's compensatory mechanisms overcome the drug effects, the result of taking SSRIs is likely to be a sluggish serotonergic system. This might account for why so many bizarre and destructive acts are committed shortly after starting the medication, when the initial compensatory shutdown takes place in the serotonin system. All this is speculation, but it is worth underscoring that the biochemical justifications for using antidepressants make no scientific sense.
A group from Wayne State University School of Medicine studied the volume of the thalamus in children diagnosed with OCD before and after being exposed to Paxil and found a loss of brain tissue (Gilbert et al., 2000 [518]). Instead of raising an alarm, the authors tried to justify the use of drugs in children on the grounds that in OCD children, the thalamus is too large, and the drugs correct the problem by shrinking it. This is very similar to the argument that lobotomies killed bad brain cells or dampened an overactive emotion-regulating system, and indeed, the thalamus connects to the frontal lobes through some of the same nerve tracts that are attacked in lobotomy. Shrinking the thalamus of children is very likely to have lobotomy-like effects, an especially dreadful example of the brain-disabling principle of psychiatric treatment.
By contrast, Yale researchers found that Prozac given to rats for a mere 2-4 weeks caused a proliferation of neurons in the temporal lobes (Malberg et al., 2000 [866]; Weaver, 2000 [1316], for the accompanying press release quoting the researchers). While the Wayne State researchers argued that loss of neurons might be good for children, the Yale researchers argued that an abnormal increase in the growth of brain cells might be good for people. To prove their point, the researchers pointed out that shock treatment causes an abnormal growth of cells in the same temporal region. They do not make the obvious connection: The temporal lobe plays a major role in memory function, shock treatment damages the temporal lobe, and postshock patients have devastating, often permanent memory loss (chapter 9). The abnormal growth in the temporal lobes may explain why, in my clinical experience, many patients begin to complain that their memory no longer functions as well after prolonged exposure to SSRI antidepressants.
Another study of the impact of Prozac on the rat brain found grossly suppressed cerebral function as measured by sugar metabolism in the brain (Freo et al., 2000 [491]). In two regions of the brain, metabolism was reduced by 23% and 32%, indicating a substantial compromise of function. Reductions occurred throughout the brain, including the cerebral cortex and basal ganglia. The authors opined that these gross malfunctions may be the source of the so-called therapeutic effect, indirectly confirming the brain-disabling principles of psychiatric treatment.
It is not likely that neurons or other cells will turn out to appear or function normally when they were stimulated to grow by a toxic agent. A study in Brain Research found that single doses of Prozac, Luvox, or the older antidepressant desipramine caused abnormal neuronal growth in the temporal region of rats (Norrholm et al., 2000 [994]). The abnormalities persisted until the end of the study 3 weeks after the last doses. The authors offered the opinion that these effects could disrupt neuronal development into young adulthood. Kalia et al. (2000) [723] found that 4 days of high doses of serotonin-stimulating drugs, including Zoloft and Prozac, caused abnormalities in the body and the axons of neurons. Prozac more often produced a large swelling of the neuronal body. Zoloft caused swollen and truncated axons and, in some cases, made the cells look corkscrew in form. The study raises questions about the survivability of the damaged cells, but there can be no doubt that they were severely injured and malfunctioning. The researchers suggested that their research may reflect on the potential effects of chronic SSRI use in humans.
Meanwhile, researchers and medical publicists continue to spin SSRI-induced abnormal neuronal growth as evidence of a therapeutic mechanism. A December 19, 2005, headline in a promotional bulletin called Johns Hopkins Medicine declared, "Popular Antidepressants Boost Brain Growth, Hopkins Scientists Report." From the university's Office of Corporate Communications, this Johns Hopkins public relations release boasted about a newly published study by the medical center (Zhou et al., 2006 [1382]).
One of the authors, Vassilis Koliatsos, MD, explained, "It appears that SSRI antidepressants rewire areas of the brain that are important for thinking and feeling, as well as operating the autonomic nervous system." It required only 4 weeks for fluoxetine to accomplish this rewiring of the rat's brain. Dr. Koliatsos stated that these abnormal growths of neurons should provide patients "more tangible evidence of a real effect in the brain". Yes, but how many patients would welcome a potentially permanent rewiring of their brains by a toxic drug?
The study itself showed very widespread abnormalities, increasing the density and branching of axons in the dorsal raphe (the origin point for serotonergic nerves) and in the limbic forebrain and neocortex, the most highly evolved areas of the brain. If one were not committed to justifying psychiatric drugs, findings such as these would be viewed as indicators of a widespread, severe disease process with ominous if as yet undetermined implications for the function of the brains and minds of human beings exposed to these drugs. Instead, paralleling the press release, the scientific report suggested that these brain changes caused by the antidepressants "may play a role in their clinical efficacy".
The brain is the focus of this book but it is not the only organ injured by SSRI antidepressants. A recent study of 2,722 older women (mean age 78.5) found that the SSRIs drastically reduced their bone densities (Diem et al., 2007 [360]). The bone mineral density (BMD) decreased by 0.82% per year in SSRI users, compared to 0.47% in nonusers (p < .001). On the other hand, women using tricyclic antidepressants had the same BMD as nonusers. One wonders how this form of SSRI toxicity might be rationalized as therapeutic. Meanwhile, it is yet one more reason not to prescribe the drugs, especially to older people.
Stimulant drugs also impair serotonergic function, contributing to the widespread damage that they also produce in the brain (chapter 11). Particularly in regard to the mood stabilizers and the highly toxic drug lithium, researchers are claiming that the gross neuronal damage found in animals might have a so-called protective function in living, human patients (chapter 8). There is a veritable research industry growing up around this theory, which must prove pleasing to the drug companies, who never want brain damage caused by their drugs to be viewed as harmful.
The tricyclics, such as clomipramine (Anafranil), amitriptyline (Elavil), and imipramine (Tofranil), have been used for several decades. I have previously described their central nervous system toxic effects in some detail (Breggin, 1983b [181]; see also Breggin, 1991b [189]). This section will therefore be abbreviated. A list of some of the older antidepressants can be found in the appendix.
Most of the older antidepressants are called tricyclic because their chemical nucleus has the basic tricyclic structure of the original phenothiazine neuroleptic, chlorpromazine, or Thorazine (Bassuk et al., 1977 [106]; Pauker, 1981 [1021]). Of extreme importance, the antidepressant amoxapine (Asendin) is turned into a neuroleptic in the body, producing the same problems as any other neuroleptic, including tardive dyskinesia (chapters 3 and 4).
Bassuk and Schoonover (1977) [106] noted that tricyclic antidepressants can cause a toxic syndrome similar to the neuroleptics:
"Tricyclics may also cause psychomotor slowing and difficulties in concentration and planning. Although more attenuated than with the phenothiazines, some of these properties are similar to the neuroleptic syndrome. These effects should be explained to the patient if he is in a setting where active physical or mental performance is required. Weakness and fatigue, nervousness, headaches, agitation, vertigo, palsies, tremors, ataxia, paresthesia, dysarthria, nystagmus, and twitching are central symptoms that occasionally occur. Tricyclics also lower the seizure threshold in a manner similar to the phenothiazines."
In discussing animal behavior, Jarvik (1970) [671] noted, "Despite its clinical antidepressant effects, imipramine produces a depression of spontaneous motor activity in laboratory animals." He noted that it produces "difficulty in concentrating and thinking comparable to that experienced during the course of similar treatment with chlorpromazine" and stated that "its effect has been described as a dullness of depressive ideation". Byck (1975) [245] took the same position in a later edition of the same book, including the observation that "imipramine seems to produce greater impairment of cognitive and affective processes and less reduction in physical movement than does chlorpromazine". Other studies of tricyclics indicate that they produce "measurable cognitive impairment in normal subjects following acute or chronic administration" (Judd et al., 1987 [712]).
In my clinical practice, I have occasionally seen otherwise normal patients who were put into states of apathy or lethargy by very small doses of tricyclic antidepressants (e.g., 10 mg to 25 mg of amitriptyline) given to them for nonpsychiatric purposes, especially to treat headache or diarrhea. Depressed patients are frequently made more depressed by these drugs without the spellbound patients or their doctors perceiving that the drug is causing the worsened condition.
As already described, the FDA now requires a broad range of warnings on antidepressant labels. There should no longer be any scientific doubt about the range and frequency of abnormal reactions in children taking SSRIs and other potentially stimulating antidepressants. The older antidepressants are also known to cause a variety of expressions of behavioral toxicity in children. In discussing the use of tricyclic antidepressants in children, Dulcan (1994) [383] observed,
"Behavioral toxicity may be manifested by irritability, worsening of psychosis, mania, agitation, anger, aggression, forgetfulness, or confusion. CNS toxicity may be mistaken for exacerbation of the primary condition." (p. 1222)
Tricyclic antidepressants commonly produce abnormalities in cardiovascular function in children and adults, and there are reports of cardiac arrest and death in children. Cardiovascular function should be carefully monitored in children taking these drugs (Dulcan, 1994 [383]).
Prescribing dangerous, ineffective antidepressants for children is especially tragic because depression in children is almost always a readily identifiable product of their environment. Helping a child overcome depressed feelings involves helping the adults attend better to the needs of the child. Children get depressed because of depressing circumstances in their lives. Sometimes these circumstances may be buried in the past in the form of neglect or physical, emotional, or sexual abuse. Sometimes they are the obvious product of current circumstances.
The so-called therapeutic effect of tricyclics can result from any number of effects that vary from individual to individual, including emotional blunting, sedation, and stimulation. They frequently cause organic brain syndromes, which - as in the case of electroshock treatment - tend to relieve the gross signs of depression by burying them beneath emotional apathy or an artificial high. A study from the Yale University Department of Psychiatry by Davies et al. (1971) [333] indicated that acute organic brain syndromes are very common during routine tricyclic antidepressant therapy (reviewed in detail in Breggin, 1983b [181]). Symptoms included "forgetfulness, agitation, illogical thoughts, disorientation, increased insomnia, and, at times, delusional states".
Especially in earlier decades, many clinicians purposefully administered tricyclics until they produceed toxic reactions. Goodwin and Ebert (1977) [546] advised giving the tricyclics in doses that produce "confusion" and other signs of toxicity. Amphetamine-like toxic effects were considered a good sign. Wells and Mendelson (1978) observed, "In our practice, an adequate trial often constitutes the highest dose that the patient can tolerate."
As described in chapter 1, the patient who experiences drug-induced brain dysfunction and the psychiatrist who induces it collaborate in a mutual denial of what is going on. Both end up denying the patient's drug-induced brain dysfunction and the patient's real-life personal problems. When euphoria is present, it becomes especially easy for the patient and the psychiatrist to deny the reality of what is happening. A drug with sufficient neurotoxicity to produce a mild to severe organic brain syndrome is especially suited to creating the illusion of improvement in depressed patients.
There is no substantial published evidence that any antidepressants, new or old, ameliorate suicidal tendencies. Instead, there is clinical evidence that the tricyclic antidepressants, like the SSRIs, can cause suicide. Baldessarini (1978) [91] warned, "The risk of suicide may even increase with initial improvement, since activity usually increases before mood elevation." Baldessarini's explanation for drug-induced suicidality, formulated many years ago, is oversimplified; but the observation remains correct, that antidepressants cause suicidality, especially early in treatment or during dose changes.
Damluji and Ferguson (1988) [328] reviewed paradoxical worsening of depressive symptomatology caused by antidepressants in an article of the same title and reported four cases of their own caused by the older antidepressants amoxapine, desipramine, nortriptyline, and trazodone. The APA National Task Force on Women and Depression (1990) [39] report on benzodiazepines also cited the problem of depression and suicide from tricyclic antidepressants.
Tragically, while the older antidepressant drugs cannot prevent suicide and can cause it, in relatively small amounts, they can become lethal instruments in the hands of suicidal patients. As little as 1 week's supply of most tricyclics can cause death, often due to cardiac dysfunction. In combination with other drugs, their lethality increases. Thus millions of depressed, suicidal patients are given the tool with which to kill themselves. By 1981, the tricyclics were overtaking the barbiturates as the medications most frequently involved in serious overdoses ("Tricyclics," 1981). The tricyclics remain a major public health problem as agents of suicide (Henry et al., 1995 [617]).
Monoamine oxidase inhibitors such as tranylcypromine (Parnate) for a time went into disfavor because of their extreme toxicity to the central nervous system, their stimulating impact, and their tendency to cause severe hypertension crises when combined with a wide variety of foods and medications. They are reviewed more extensively in the 1997 edition, but in this era of excessive overmedication, they are enjoying something of a comeback.
Several so-called atypical antidepressants are currently on the market in the United States. This brief review is not intended to be comprehensive in regard to their adverse effects.
Venlafaxine (Effexor), approved by the FDA in December 1993, was described in more detail early in this chapter. It is one of the newer antidepressants implicated in causing suicidality. It is a NSRI that also strongly inhibits the reuptake of epinephrine. Its profile is very similar to the SSRIs in producing stimulation, including anxiety, nervousness, insomnia, anorexia, and weight loss. It causes the various emotional and behavioral abnormalities that go along with stimulation, such as agitation and mania, and has been associated with hostility, paranoid reaction, psychotic depression, and psychosis. It can cause hypertension.
Trazodone (Desyrel) and buproprion (Wellbutrin) are somewhat older atypical antidepressants that do not fit the pattern of other groups of agents. Buproprion has an unusually high rate of seizures associated with its use. It can be very stimulating and agitating. Trazodone tends to cause sedation and can also cause dizziness and fainting. It can cause cardiac difficulties for recovering heart patients. It also produces the potentially disastrous side effect of priapism: uncontrolled, irreversible penile erection, sometimes requiring surgical intervention.
In my experience, any of the antidepressants can produce a variety of unexpected and sometimes severe emotional reactions, including apathy, lethargy, and depression, or euphoria, paranoia, and mania. Frequently, these adverse effects are mentioned as possibilities on the FDA-approved label.
Keep in mind that as a group, antidepressants affect diverse neurotransmitter systems in a complex, little understood manner. Even the supposedly selective SSRIs end up producing generalized dysfunction in the brain and hence the mind.
It is counterintuitive that a drug that causes mania would also cause it during withdrawal. However, there are case reports that most types of antidepressants can cause mania during withdrawal, especially the SSRIs, (Goldstein et al., 1999 [541]; Sherese et al., 2003 [1170]). Benazzi (2002) [124] reported on a case of sertraline-induced withdrawal mania. He also summarized some of the problems associated with SSRI withdrawal:
"Discontinuing selective serotonin reuptake inhibitors (SSRIs) may ,induce a syndrome wherein the main neuropsychiatric symptoms are dizziness, shock-like sensations, anxiety, irritability, agitation, and insomnia. These symptoms usually develop 1 to 7 days after abrupt or gradual discontinuation. Antidepressant discontinuation may also induce mania, mainly reported with tricyclics and monoamine oxidase inhibitors but also observed with SSRIs."
Patients with a history of bipolar disorder are probably more vulnerable to this adverse drug reaction. I have observed patients becoming euphoric during withdrawal from SSRIs, but none have become manic. During withdrawal from antidepressants, I advise patients and their families that withdrawal reactions are highly variable and unpredictable and that they should be alert for any significant change in psychological and emotional functioning.
Meanwhile, Benazzi's (2002) [124] brief summary does not capture the severity ar wide variety of withdrawal reactions associated with drugs that block the reuptake of serotonin (SSRIs), especially the overwhelming feelings of depression and despair, with uncontrollable weeping (Shipko, 2002 [1173]; see chapter 15 for more details).
Psychiatry has yet to face the fact that it has trapped millions of patients into taking SSRI and SRI drugs for years on end because they are unable to endure the withdrawal symptoms. Sometimes the brain changes are so persistent or irreversible that the individuals feel compelled to remain on the drugs indefinitely. Often the withdrawal symptoms lead them mistakenly to believe that they suffer from an underlying mental illness that requires medication, when instead they have persistent brain dysfunction caused by medication.
In reality, most patients quickly stop taking the newer antidepressants because of their painful adverse effects, thereby protecting themselves from long-term adverse effects, including withdrawal reactions. Others stay on them mainly because of pressure from their doctors, including the lie that they have so-called biochemical imbalances. The more disturbed or distressed the individual before starting the medication, the more the individual is likely to deteriorate while taking it.
Paxil is probably especially punishing in regard to causing both acute adverse effects and withdrawal. In a double-blind study, Zanardi et al. (1996) administered Zoloft and Paxil to inpatients diagnosed with depression with psychotic features. Within 2 weeks of starting treatment, 41% of the Paxil patients dropped out "because of unpleasant side effects such as anxiety, agitation, and insomnia". Prescribing Paxil is a formula for making psychotic patients even more disturbed.
The older tricyclic antidepressants and monoamine oxidase inhibitors also cause withdrawal mania and a variety of other adverse withdrawal effects, including cognitive. and emotional disturbances and psychosis. Many of them have strong anticholinergic effects and therefore produce severe anticholinergic rebound on withdrawal, including cardiovascular and gastrointestinal symptoms. I have seen patients who have taken tricyclics for many years and then been unable to withdraw from them.
Chapter 15 discusses SSRI withdrawal symptoms in more detail and describes how to successfully withdraw from psychiatric medications.
I have been a medical expert in dozens of criminal, malpractice, and product liability legal cases in which children and adults have developed bizarre, irrational, and violent behavior while taking SSRI antidepressants (Breggin, 2006d [216]; Breggin, in press). In one case in California, a man drowned himself and his two small children in a bathtub a few days after starting on paroxetine (see http://www.breggin.com for this and other legal cases). Also while taking paroxetine, a man in Pennsylvania drove his car into a policeman to obtain the officer's gun to kill himself. In a fourth case involving paroxetine, in Vermont, a 17-year-old boy who had missed one or two doses of paroxetine bludgeoned a close friend for no apparent reason. In Florida, a teenage girl taking Fluoxetine fired a pistol point-blank at another youngster, but the gun fortunately failed to function. None of these individuals had any history of violence prior to taking SSRIs. I have described several dozen cases of SSRI-induced mania, mayhem, murder and suicide in my book Medication Madness (in press).
There is a reluctance to attribute so-called bad behavior or loss of ethical restraint to a psychoactive substance. Western philosophy, religion, and tradition tend to hold human beings responsible for their harmful behaviors and eschew excusing such behavior on the basis of so-called mental illness. Indeed, the concept of mental illness has been subject to challenge by this author and many others. Nonetheless, the weight of considerable evidence indicates that psychoactive substances can play a role in causing suicide, violence, and other forms of disinhibited criminal conduct. The effect should not be attributed to the vague and misleading concept of "mental illness". Instead, the effect is neurological in origin - a genuine brain disorder cause by toxicity. Terms with ethical connotations tend to be expunged from psychiatry as unsciemific, and so the change in ethical restraint caused by medications is referred to by various more neutral terms, such as disinhibition, dyscontrol, or loss of impulse control.
The two chapters on antidepressants and upcoming chapters on stimulants and benzodiazepine tranquilizers provide ample evidence for how medications can cause an adverse change in ethical behavior. In general, the evidence falls into four categories:
First, controlled clinical trials comparing any psychoactive drug to a placebo will typically produce evidence for a pattem of central nervous system adverse drug effects with mental symptoms that are specific for the drug and not for the placebo. For example, SSRI antidepressants and amphetamine-like agents both tend to produce a continuum of central nervous system stimulation. This physical stimulation will be associated with mental manifestations that range from mild euphoria and irritability to depression and mania and ultimately to increased rates of both aggression and suicidality. The studies confirming SSRI-induced suicidality in this chapter should leave no doubt about the capacity of psychiatric medications to disrupt the function and the brain and mind, leading to destructive behavior that would not otherwise have occurred.
Second, pattems of reports made to the FDA's spontaneous reporting system also make apparent that certain drugs are associated with specific patterns of extreme mental and behavioral reactions (for additional examples and an analysis of methodology, see Breggin, 1997a [198], 1998b [201]). Even nonpsychiatric medications have been implicated in causing depression and suicidality. Isotretinoin (Accutane), a medication used to treat severe acne, has been found to produce depression and suicidaly, as demonstrated in numerous clinical reports and in individual case studies. In some clinical cases, "depression subsided with discontinuation of the therapy and recurred with reinstitution of therapy" (Physicians' Desk Reference, 2003, p. 2872 [1036]).
Third, many physical disorders also affect mental attitudes and behavior. Hyperthyroidism as well as overdoses of thyroid hormone can increase anxiety, irritability, and other emotions that the individual would not ordinarily experience and that can lead to behavioral abnormalities. There are, of course, many similar examples involving hormones such as testosterone and cortisone. More to the point, accidental brain injury to the frontal lobes and surgical lobotomy usually impair judgment, ethical restraint, and self-reflection. The character of the injured individual is often viewed as changed and worsened.
Fourth, as an expert in criminal and civil cases, I have studied the lives of many individuals who - under the influence of psychoactive drugs such as SSRIs, nonselective serotonin reuptake inhibitors (NSRIs), and benzodiazepines-have committed acts of aggression that were wholly alien to their character and antithetical to their prior behavior. It is, of course, well known that the illegal use of stimulant drugs, such as methamphetamine and cocaine, can be associated with paranoid reactions and violence.
The example of involuntary intoxication under the law helps elucidate the issue of responsibility while under the influence of psychoactive substances. Under the law, an individual is held responsible for behavior committed under the influence of alcohol or other nonprescription intoxicants because it is presumed that the individual knew that he or she was taking a psychoactive substance that can impair judgment and self-restraint. However, in most states, an individual can claim involuntary intoxication as a mitigating or exonerating factor in a criminal case. For example, if the individual unknowingly drank alcohol from spiked punch, the involuntary nature of the intoxication might become a mitigating or exonerating factor under the law. Similarly, when an individual is prescribed an antidepressant without knowing that it can cause mania, he or she may be exonerated from the consequences of maniclike behavior.
If an individual involuntarily intoxicates another person, the perpetrator trator may be guilty of a crime, and the victim may be absolved of any contributory responsibility. For example, a man can be judged guilty of rape if he has impaired the consciousness and self-restraint of his victim by surreptitiously slipping a sedative into her drink. The victim, even if physically conscious during the sexual act, may be exonerated of seeming acquiescence to the assault on the basis of involuntary intoxication.
The debate over human responsibility will always remain at root ethical and philosophical. However, empirical data must be taken into account. A mountain of experimental and clinical data, some of it reviewed in this report, supports the concept that psychoactive substances are frequently associated with an increased rate of disturbed mental and behavior reactions, causing some individuals to act as if they have lost their customary ethical restraint and self-control.
It may be argued that some individuals will not lose ethical restraint regardless of the nature or intensity of an involuntary intoxication. However, even if some individuals are relatively immune to behaving badly under the influence of drugs, while others seem especially susceptible, this merely reflects human variation, a factor that complicates most research in medicine and behavioral science. The reality of human variation does not undermine the validity of the association between certain drugs and the relatively frequent production of certain kinds of dangerous mental states and behaviors.
I want to reemphasize that drug-induced disturbances in mood or in behavior should be viewed as genuine neurological disorders rather than as vague mental illnesses. The capacity of speculative biochemical imbalances or genetic factors to cause or contribute to mania or depression remains unproven. Nor do we know the specific biochemical or neurological mechanisms whereby psychoactive substances cause mental disturbances. But the capacity for psychoactive substances to disrupt brain fuction and hence mental function is beyond dispute. Furthermore, a great deal of empirical data confirm their capacity to cause disinhibition, mania, depression, and other mental phenomena associated with violence toward oneself and others, as well as other destructive behaviors.
In my clinical experience, including reading innumerable depositions given under oath by psychiatrists in legal cases, I have come to the dismal conclusion that most psychiatrists know little more than what they are told by drug company salespersons who visit their offices and drug company spokespersons who address them at industry-sponsored seminars. At the 2005 annual meeting of the American Psychiatric Association (Strong, 2007 [1222]), a survey was conducted of pediatric psychopharmacologists. The great majority of these professionals are psychiatrists who identify themselves as specializing in prescribing medications to children and adolescents. These are the doctors to whom other doctors refer their more difficult patients. These are the doctors who write papers and teach their colleagues about how to use psychiatric drugs. It was an experienced group who had been in practice on average for approximately 20 years.
Although these specialists knew that the FDA had recently issued a black-box warning about antidepressant-induced suicidality in children and youth, hardly any of them took it seriously. Only 22% thought that any specific medication was more likely to worsen suicidality, with two thirds of them naming the SSRIs. Thus, less than 15% of the experts (two thirds of 22%) thought that SSRIs increased the risk of suicidality in their patients. So much for the impact of research and the black-box warning!
By contrast, 60% continued to believe that some medications were more likely to improve suicidality, with "the vast majority" citing the SSRIs as most helpful in relieving suicidality in children and youth. This flew in the face of evidence from controlled clinical trials and observations by the FDA indicating that antidepressants are no better than placebos in treating childhood depression.
In summary, only a small percentage of the so-called experts thought that the SSRIs increased the suicide risk, while most thought they reduced it. This survey confirmed my experience that the vast majority of specialists and experts in the use of psychiatric medication (psychopharmacologists) are little more than drug-company-inspired drug pushers. Tragically, the medication specialists have become the most dangerous people in regard to the cavalier promoting of drugs for children and youth, as well as for adults.
The newer antidepressants, especially the SSRIs, frequently cause medication spellbinding (intoxication anosognosia) with the associated risk of violence, suicide, mania, and other forms of psychotic and bizarre behavior. Because of the spellbinding effect, the victims of these drug-induced reactions often do not realize that their mental outlook or behavior has been drastically changed. They typically attribute any changes in how they feel to something other than the medication, often blaming themselves or other people. At times they believe they are doing better than ever when they are in reality deteriorating. And in the extreme, they can become driven by suicidal, violent, or bizarre ideas that would otherwise seem alien to them.
Teicher et al. (1993) [1244] suggested nine possible mechanisms for SSRI-induced suicidality: (a) energizing the depressed and suicidal patient, (b) paradoxically worsening the individual's depression, (c) causing akathisia, (d) causing panic and anxiety, (e) causing manic or mixed manic-depressive states, (f) causing insomnia or disturbances in the sleep architecture, (g) causing obsessive suicidal preoccupations, (h) causing borderline states with hostility, and (i) causing alterations in electroencephalogram (EEG) activity. Teicher et al. (1993) [1244] document each of these phenomena in their review of the literature and, as their article indicates, the scientific evidence has grown considerably stronger in the intervening decade.
With the exception of the alteration in EEG activity, the scientific literature and my clinical and forensic work have confirmed that each of the previously mentioned antidepressant-induced phenomena can cause violent and suicidal behavior. However, my clinical and forensic experiences and reviews of the literature indicate that five syndromes encompass most of the phenomena and describe most of the individual cases:
The above syndromes, all of which are medication spellbinding, often appear in combination with each other. Often the syndromes will abate within days after stopping the antidepressant, but sometimes they persist, leading to hospitalization and additional treatment over subsequent weeks or months. Reported rates for these syndromes very widely, but each of them appears to be relatively common. They frequently occur in individuals with no prior history of similar problems or behaviors (Breggin, in press).
In summary, there is incontrovertible evidence that antidepressants cause suicidality, irritability, violence, and mania as well as a wide range of other psychiatric adverse drug reactions often related to overstimulation, such as insomnia, anxiety, agitation, emotional instability, and akathisia. They can also cause apathy and emotional indifference. There is also strong evidence that they cause lasting abnormalities in brain function and even brain anatomy, including abnormal brain cell proliferation, death of brain cells, and shrinkage of brain tissue.
To compound the problem, these drugs can cause severe withdrawal problems, including agitation and a worsening of depression (see 5). A substantial portion of my psychiatric practice involves working with patients who suffered frightening and sometimes agonizing withdrawal symptoms before coming to me for help in stopping the newer antidepressants and, on occasion, the older ones. Sometimes these withdrawal symptoms persist for months, or even years, after stopping the drug.
Furthermore, even the FDA has admitted that these drugs are ineffective in children, and meta-analyses have shown that they are ineffective in adults as well. They are no better than placebo, they cause severe adverse reactions, and they cannot bring about the positive benefits associated with psychotherapy and other life experiences that can truly improve the individual's quality of living.
It bears repeating that antidepressants are dangerous to start taking and dangerous to stop taking as well as ineffective. The best advice is to stay away from them. In 40 years of psychiatric practice, I have never started a patient on an antidepressant, although I do prescribe them during the withdrawal process or if the patient is unable to go through withdrawal. Although good fortune undoubtedly plays a role as well, I believe that my refusal to start patients on these drugs has contributed to my success in never having a suicide in my practice. In addition to preventing antidepressant-induced suicidality, by not giving the medications I encourage myself and my patients to work together to find more effective and hope-inspiring ways of living.