The tardive syndromes: Phenomenology, concepts on pathophysiology and treatment, and other neuroleptic-induced syndromes

Dopamine and serotonin (5HT) receptor antagonism

Although drugs that are labeled as atypical antipsychotic agents block dopamine D2 receptors, they also block serotonin 5HT _2A receptors, and some investigators attribute their antipsychotic effect to this mechanism and recommend research and drug development of newer agents that block other 5HT receptors (Meltzer, 1999).

How tightly drugs to bind to the D2 receptor (their occupancy rate) is currently considered to be important in the propensity of the drug to cause drug-induced side effects such as parkinsonism and TD. Seeman and Tallerico (1998) found that the atypical antipsychotic drugs bind more loosely than classic antipsychotic drugs (neuroleptics) to the D2 receptors. Kapur and colleagues (1999) measured D2 and 5HT ₂ receptor occupancies by positron emission tomography (PET) scan for patients receiving clozapine, risperidone, or olanzapine. Clozapine showed a much lower D2 occupancy (16%–68%) than risperidone (63%–89%) and olanzapine (43%–89%); all three showed greater 5HT ₂ occupancy than D2 occupancy at all doses, although the difference was greatest for clozapine. In their PET study, Moresco and colleagues (2004) found that striatal D2 receptor occupancy was significantly higher with olanzapine than with clozapine. All of these studies support the relationship between receptor occupancy and the clinical observations that clozapine and quetiapine are the most “atypical,” with the least propensity to cause parkinsonism, tardive syndromes, or other neuroleptic drug reactions.

Despite interest in the 5HT _2A receptor, it is the D2 receptor that is associated with the antipsychotic effect (Seeman, 2010). Antipsychotic clinical doses correlate with their affinities for this receptor. The receptor has high- and low-affinity states. Clozapine and quetiapine do not elicit parkinsonism and rarely result in TD because they are released from D2 within 12 to 24 hours. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to TD. Glutamate agonists that treat schizophrenia have affinity for the dopamine D2(High) receptor and the D3 receptor (Seeman and Guan, 2009).

A comparison of the receptor-binding profiles of quetiapine, clozapine, olanzapine, and risperidone is presented in Table 17.5 . Both quetiapine and clozapine have poor affinity for the dopamine D2 receptor, which probably accounts for the low incidence of inducing parkinsonism and tardive syndromes. Risperidone has the highest affinity for the D2 receptor, resembling haloperidol ( Table 17.6 ), and is therefore more of a typical than an atypical antipsychotic.

In one PET study, striatal D1 and D2 receptor occupancies were evaluated (Tauscher et al., 2004). D1 occupancy ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D2 occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D1/D2 occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31). In a [ ¹²³ I]epidepride single-photon emission computed tomography (SPECT) study involving clozapine-, olanzapine-, and haloperidol-treated schizophrenia patients, drug-naive patients, and healthy controls, midbrain D(2/3) receptor occupancy was studied. Of those on medication, occupancy was least for those on clozapine (5%), next for those on olanzapine (28%), and greatest for those on haloperidol (40%); no significant differences were observed in the temporal poles (Tuppurainen et al., 2009). All imaging studies are compatible with the clinical results in that clozapine and quetiapine, with the least neuroleptic features, have the lowest D2 receptor occupancy rate.

Clozapine

Clozapine was the first agent to be labeled as an atypical antipsychotic and deservedly so, although rare case reports do exist of drug-induced parkinsonism (Kurz et al., 1995), but it has been reported not to induce rigidity and it rarely induces parkinsonian tremor (Gerlach and Peacock, 1994). It has also caused rare cases of acute akathisia (Friedman, 1993; Safferman et al., 1993), acute dystonic reaction (Kastrup et al., 1994; Thomas et al., 1994), tardive syndromes (Dave, 1994), tardive dystonia (Bruneau and Stip, 1998; Molho and Factor, 1999a, van Harten et al., 2008b), tardive akathisia (Kyriakos et al., 2005), tardive oculogyria (Uzun and Doruk, 2007), and NMS (Sachdev et al., 1995; Benazzi, 1999; Lara et al., 1999; Gambassi et al., 2006). Parkinsonian features are also seen with clozapine. In a prospective study, 7 of 25 patients on clozapine developed TD (Bunker et al., 1996). In a retrospective study, comparison of clozapine and typical antipsychotics showed no lower prevalence of TD in the clozapine group (Modestin et al., 2000). But it is not clear that the patients in the clozapine group had not been previously exposed to typical antipsychotics and had not developed TD while receiving them. What is clear from this study is that the conversion to using clozapine has not markedly reduced the prevalence of extrapyramidal syndromes; this finding supports the realization that clozapine does not effectively treat TD once it has developed. How effective its use would be in preventing TD in the first place still needs to be verified. For patients with PD, the low propensity to augment existing parkinsonism makes clozapine very useful in treating patients who have dopaminergic drug-induced psychosis (Factor and Friedman, 1997; Friedman et al., 1999).

A SPECT study measuring dopamine D2 receptor binding reveals lower binding with clozapine than with typical neuroleptics (Broich et al., 1998). In animal studies, rats that have been pretreated with haloperidol for 4 weeks develop vacuous chewing movements (VCMs) after treatment with a dopaminergic, whereas rats that have been pretreated with clozapine do not (Ikeda et al., 1999).

A problem with clozapine is the side effect profile. Common side effects associated with clozapine include sedation, weight gain, seizures, sialorrhea, orthostatic hypotension, and blood dyscrasias. Up to 2% of treated patients can develop at least transient neutropenia that can progress to agranulocytosis ( ). Currently, complete blood counts are required weekly until 6 months, every 2 weeks for 6 to 12 months, and monthly thereafter. If neutropenia occurs (less than 1000/μL), discontinuation of the drug with more frequent monitoring is required until recovery. Uncommon adverse effects include metabolic syndrome, delirium, and NMS. Myocarditis associated with clozapine has been reported (Hill and Harrison-Woolrych, 2008).

Quetiapine

After clozapine, quetiapine is the most favorable in being least likely to induce parkinsonism, NMS (Stanley and Hunter, 2000), or tardive syndromes. In a prospective, head-to-head comparison with risperidone treatment in schizophrenia, quetiapine had far fewer extrapyramidal adverse effects, but more orthostasis (Perez et al., 2008). D2 receptor antagonism is relatively selective for limbic rather than striatal receptors for clozapine and sertindole, followed by quetiapine, ziprasidone, olanzapine, and remoxipride, whereas risperidone in many respects has a profile that resembles that of haloperidol (Arnt and Skarsfeldt, 1998). In primates, quetiapine and clozapine were equally less likely to induce oral dyskinesias compared with standard antipsychotics (Peacock and Gerlach, 1999). Like clozapine, quetiapine easily induces drowsiness, so when it is used to treat dopa-induced psychosis, it should be taken at bedtime. The major advantage over clozapine is that it does not require blood tests because it does not induce agranulocytosis. However, there may be a rare risk that quetiapine can cause agranulocytosis (Ruhe et al., 2001). Since its introduction, there have been reports of acute dystonic reactions (Jonnalagada and Norton, 2000; Desarker and Sinha, 2006), acute akathisia (Prueter et al., 2003), NMS (El-Gaaly et al., 2009; Gortney et al., 2009), and TD (Ghaemi and Ko, 2001). In 367 patients treated for 12 months with quetiapine (mean dose 720 mg/day), parkinsonism was seen in 10%, akathisia in 3%, dystonia in 1.4%, and “hyperkinesia” in 1.7% (Perez et al., 2008).

In a SPECT study using the D2/D3 ligand [ ¹²³ I]-epidepride the percent occupancy of receptors in the limbic system (temporal lobe) and striatal receptors while patients were receiving quetiapine was 60% and 32%, respectively, which is similar to that for clozapine (Stephenson et al., 2000). In another SPECT study, quetiapine was shown to occupy 5HT _2A receptors in the frontal and temporal cortex (Jones et al., 2001). A PET study using [ ¹⁸ F]fallypride showed similar results (Vernaleken et al., 2010).

A patient with oculogyric crisis, who failed to improve after withdrawal of antipsychotic medication, was successfully treated with quetiapine (Gourzis et al., 2007). Drug-induced parkinsonism and acute akathisia caused by other neuroleptics can be reduced by switching patients to quetiapine (Cortese et al., 2008). Drowsiness and weight gain are common; postural hypotension is not infrequent. A rare complication of quetiapine is hepatotoxicity (Shpaner et al., 2008).

Olanzapine

In contrast to clozapine and quetiapine, olanzapine more readily increases parkinsonian symptoms in patients with PD (Jimenez-Jimenez et al., 1998; Granger and Hanger, 1999; Molho and Factor, 1999b), but does so less readily than risperidone and conventional antipsychotics. Drug-induced parkinsonism, including the rabbit syndrome, is seen with olanzapine (Durst et al., 2000), but less than with haloperidol (Peuskens et al., 2009). It can induce acute akathisia (Kurzthaler et al., 1997; Jauss et al., 1998) and TD but less so than haloperidol (Tollefson et al., 1997; Wood 1998). It can also induce NMS (Filice et al., 1998; Moltz and Coeytaux, 1998; Burkhard et al., 1999; Levenson, 1999; Margolese and Chouinard, 1999; Sierra-Biddle et al., 2000; Abu-Kishk et al., 2004; Zaragoza Fernandez et al., 2006), TD (Herran and Vazquez-Barquero, 1999), and tardive dystonia (Dunayevich and Strakowski, 1999). Acute dystonic reactions also occur (Beasley et al., 1997; Landry and Cournoyer, 1998; Vena et al., 2006).

A direct comparison with chlorpromazine showed similar parkinsonism and acute akathisia for the two drugs (Conley et al., 1998). A double-blind comparison with haloperidol by Beasley and colleagues (1999) showed a much lower risk for developing TD with olanzapine. After 1 year of exposure, 0.52% of patients developed TD with olanzapine and 7.45% developed TD with haloperidol. An open-label comparison with conventional antipsychotics after a 9-month follow-up after discharge from the hospital favored olanzapine, with TD being present in 2.3% for olanzapine (2/87), and 16.7% (12/72) for the conventional treatment (Mari et al., 2004). There are case reports of agranulocytosis induced by olanzapine (Meissner et al., 1999; Naumann et al., 1999; Tolosa-Vilella et al., 2002), including in a patient who had previously had agranulocytosis with clozapine (Benedetti et al., 1999). This has been attributed to some similar structural and pharmacologic properties of clozapine. A case of restless legs syndrome with periodic movements in sleep has been attributed to olanzapine (Kraus et al., 1999).

Olanzapine has relative regional mesolimbic dopaminergic selectivity and a broad-based binding affinity for serotonin (all 5HT ₂ receptor subtypes and the 5HT ₆ receptor), dopamine (D2, D3, and D4 receptors), muscarinic, and alpha-1 adrenergic receptors (Bymaster et al., 1999). A PET study in schizophrenic patients being treated with olanzapine revealed that this drug is a potent 5HT ₂ blocker, but also a blocker of D2 dopamine receptors similar to risperidone and less so than clozapine (Kapur et al., 1998). Patients on olanzapine were also studied with [ ¹²³ I]iodobenzamide (IBZM) SPECT; the D2 receptor was occupied 60% and 83% of the time at doses of 5 mg/day and 10 mg/day, respectively (Raedler et al., 1999). Such high rates of occupancy probably account for olanzapine’s tendency to worsen parkinsonism and induce DRBA complications, because, as was noted earlier, D2 receptor occupancy rates are directly related to neuroleptic potential.

Risperidone

With the success of clozapine, there is a commercial advantage for pharmaceutical companies to tout other antipsychotics as atypical. Such has been claimed for risperidone, but this drug can readily induce parkinsonism, including the rabbit syndrome (Levin and Heresco-Levy, 1999), tardive syndromes (Haberfellner 1997; Silberbauer 1998; Hong et al., 1999; Ananth et al., 2000), and NMS (Newman et al., 1997; Norris et al., 2006). The prevalence of parkinsonism from risperidone is usually considered to be less than that with conventional neuroleptics, but it was observed in 42% compared with 29% in those on haloperidol (Knable et al., 1997). TD and tardive dystonia occurred in a patient who was exposed only to risperidone (Bassitt and Garcia, 2000). The annual incidence of TD in patients taking risperidone has been estimated to be 0.3%, compared with an annual incidence in patients taking conventional neuroleptics of 5% to 10% (Gutierrez-Esteinou and Grebb, 1997). However, in an open-label prospective study of 255 institutionalized patients with dementia who were treated with risperidone, the 1-year cumulative incidence of TD was 2.6% (Jeste et al., 2000).

Like conventional neuroleptics, risperidone induces acute dystonic reactions in marmosets, in contrast to clozapine, which does not (Fukuoka et al., 1997). In a report of an open-label comparison with haloperidol, Rosebush and Mazurek (1999) found the two drugs to have a similar side effect profile. In a prospective follow-up of first-episode schizophrenic patients treated with risperidone, movement disorders developed in more than one-third of these patients, who had previously never been exposed to antipsychotic drugs (Lang et al., 2001). When risperidone is compared with low-potency antipsychotics, such as thioridazine, no difference was discerned in the rates of developing movement disorders (Schillevoort et al., 2001).

In a SPECT study, dopamine receptor binding with IBZM showed risperidone to have effects between those of haloperidol and clozapine, with a dose–response curve for risperidone showing greater similarity to that of haloperidol (Dresel et al., 1998). A PET study showed dopamine D2 receptor occupancies of about 70% and 60% in the striatum and extrastriatum, respectively (Ito et al., 2009). Clearly, risperidone is not an atypical antipsychotic agent. Risperidone’s occupancy of the 5HT ₂ receptors is about 90%, and its occupancy of the D2 receptors is between 50% and 80%, but the latter correlates with the extrapyramidal side effects (Yamada et al., 2002).

Ziprasidone

This benzisothiazole was approved by the FDA in 2001. There are already case reports of acute dystonic reactions (Weinstein et al., 2006; Yumru et al., 2006, Rosenfield et al., 2007), NMS, rhabdomyolysis, and pancreatitis (Murty et al., 2002; Yang and McNeely, 2002; Gray 2004). It has been reported to cause TD (Mendhekar, 2005) and tardive dystonia (Papapetropoulos et al., 2005; Tsai et al., 2008). Although it is a potent 5HT _2A antagonist (like risperidone, olanzapine, and clozapine), it is also a D2 antagonist in humans as detected by PET scan (Bench et al., 1993, 1996). But in-vitro studies reveal much lower affinity for the D2 receptor than for the 5HT _2A receptor (Seeger et al., 1995), and ziprasidone also binds less tightly to the D2 receptor than dopamine (Seeman, 2002). Ziprasidone has two other unique features compared with other antipsychotic agents: (1) it is a potent 5HT _1A agonist and thus inhibits dorsal raphe serotonergic cell firing (Sprouse et al., 1999) and increases cortical dopamine release (Rollema et al., 2000), and (2) it inhibits neuronal uptake of 5HT and norepinephrine in a manner comparable to that of the antidepressant imipramine (Schmidt et al., 2001). What these unique actions might contribute to antipsychotic activity or to propensity for or against extrapyramidal reactions is unclear. Ziprasidone has been reported to induce a case of oculogyric crisis in an adult (Viana Bde et al., 2009).

Aripiprazole

This quinolinone has a novel mechanism of action. Like a number of other atypical antipsychotics, it is an antagonist at the 5HT _2A receptors. It is also a 5HT _1A partial agonist (Jordan et al., 2002). What is novel is that it is a partial agonist at the dopamine D2 receptor. It has a higher affinity for the presynaptic autoreceptor than for the postsynaptic receptor. Hence, it reduces dopamine synthesis and release through an agonist action at the dopamine autoreceptor (Tamminga and Carlsson, 2002). Because of its novel action as a partial D2 agonist, it was anticipated that it might cause fewer extrapyramidal adverse effects, and clinical trials reported favorable results (Kane et al., 2002). However, D2 ligand–binding PET revealed a dose-related high occupancy state of 71.6% at 2 mg/day to 96.8% at 40 mg/day (Kegeles et al., 2008). With wider use, it has been shown to worsen PD (Friedman et al., 2006; Wickremaratchi et al., 2006), and there are already reports of it causing parkinsonism (López-Torres et al., 2008), NMS (Chakraborty and Johnston, 2004; Hammerman et al., 2006; Palakurthi et al., 2007), acute dystonic reactions (Desarkar et al., 2006; Fountoulakis et al., 2006), and TD (Zaidi and Faruqui, 2008; Abbasian and Power, 2009; Friedman, 2010).

Amisulpride

Amisulpride, a substituted benzamide, is a highly selective antagonist for dopamine D2 and D3 receptors in the limbic region, which would predict potent antipsychotic activity with a low potential to cause extrapyramidal symptoms (Lecrubier, 2000). It binds less tightly to the D2 receptor than do the typical antipsychotics (Seeman, 2002). Using the full range of recommended amisulpride dosage, striatal occupancies up to 90% can be measured (Vernaleken et al., 2004). It is not yet commercially available in the United States. It has already been reported to induce tardive oculogyric crisis (Mendhekar et al., 2010).

Metoclopramide

After the introduction of metoclopramide for gastrointestinal disorders, reports of acute dystonic reactions in children and TD in adults began to appear (Cochlin, 1974; Kataria et al., 1978; Lavy et al., 1978). Today, metoclopramide has become a common cause of TD, and the legal profession has found such cases ripe for lawsuits. The annual incidence of TD from metoclopramide has been reported to be between 4.5% and 23% per year (Grimes, 1981; Ganzini et al., 1993), about the same as that for haloperidol of approximately 5.7% per year (Tollefson et al., 1997; Beasley et al., 1999; Csernansky et al., 2002), but higher than those for risperidone at about 1.8% per year (Lemmens et al., 1999; Davidson et al., 2000; Jeste et al., 2000; Csernansky et al., 2002) and olanzapine at approximately 1.2% per year (Tollefson et al., 1997; Beasley et al., 1999). Because antipsychotic drugs have an affinity for brain neuromelanin (Seeman, 1988), Chen and colleagues (2010) examined the amount of metoclopramide and antipsychotic drugs binding to postmortem human SN. They found that in clinical conditions the amount of metoclopramide that would bind to nigra is much higher than the amount of raclopride, haloperidol, or olanzapine that would be expected to be bound and suggest that this binding might explain the higher annual incidence of TD induced by metoclopramide.

Acute dystonia

The earliest abnormal involuntary movement to appear after initiation of dopamine receptor antagonist therapy is an acute dystonic reaction. In about half of the cases, this reaction occurs within 48 hours, and in 90% of cases, it occurs by 5 days after starting the therapy (Ayd, 1961; Garver et al., 1976). The reaction may occur after the first dose (Marsden et al., 1975).

Dystonic movements are sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures (Fahn, 1988). In a series of 3775 patients, Ayd (1961) found that acute dystonia is the least frequent side effect, affecting about 2% to 3% of patients, with young males being most susceptible. The incidence rate increases to beyond 50% with highly potent dopamine receptor blockers such as haloperidol (Boyer et al., 1987). In one prospective study, Aguilar and colleagues (1994) reported that 23 of 62 patients developed acute dystonia after haloperidol was introduced, that anticholinergic pretreatment significantly prevented this, and that younger age and severity of psychosis were risk factors. In the prospective study by Kondo and colleagues (1999), 20 (51.3%) of 39 patients placed on nemonapride had dystonic reactions, onset occurring within 3 days after the initiation of treatment in 90%. As in other series, the incidence of acute dystonia was significantly higher in males than in females (77.8% versus 28.6%, P < 0.05), and younger males (30 years or younger) had an extremely high incidence (91.7%). The incidence is much lower with the atypical antipsychotics; Raja and Azzoni (2001) observed only 41 cases in 1337 newly admitted patients treated with antipsychotics, which included 8 treated with risperidone, 1 with olanzapine, and 1 with quetiapine. A meta-analysis compared intramuscular injections of SGAs to haloperidol injections (Satterthwaite et al., 2008). SGAs were associated with a significantly lower risk for acute dystonia (relative risk [RR], 0.19) and acute akathisia (RR, 0.25) compared with haloperidol alone.

All agents that block D2 receptors can induce acute dystonic reactions, including risperidone (Brody, 1996; Simpson and Lindenmayer, 1997) and clozapine (Kastrup et al., 1994). One child developed an acute dystonic reaction after ingestion of a dextromethorphan-containing cough syrup (Graudins and Fern, 1996). Dextromethorphan has several different known pharmacologic actions, but D2 receptor blockade is not one of them. A case of acute dystonia after abrupt withdrawal of bupropion (DA reuptake blocker) was reported (Wang et al., 2007). A case of acute dystonia after abrupt withdrawal of dexamphetamine in a patient taking risperidone was also reported (Keshen and Carandang, 2007). Serotonergic agents also have been reported to induce acute dystonic reactions (Lopez-Alemany et al., 1997; Madhusoodanan and Brenner, 1997; Olivera, 1997). The mechanism could relate to inadequate release of dopamine from the nerve terminals in the striatum owing to the inhibitory effect of serotonin on dopamine neurons in the SN pars compacta (SNc). The opioid σ ₁ and σ ₂ receptors also have been implicated (Matsumoto and Pouw, 2000).

Acute dystonic reactions most often affect the ocular muscles (oculogyric crisis), face, jaw, tongue, neck, trunk, and less often the limbs. Oculogyric crisis has previously been noted to occur as a common feature of postencephalitic parkinsonism (Duvoisin and Yahr, 1965). A typical acute dystonic reaction may consist of head tilt backward or sideways with tongue protrusion and forced opening of the mouth, often with arching of trunk and ocular deviation upward or laterally (Rupniak et al., 1986). The forcefulness of the muscle contractions can be extremely severe and led to auto-amputation of the tongue in one patient (Pantanowitz and Berk, 1999).

Mazurek and Rosebush (1996) studied the timing in the development of an acute dystonic reaction in 200 patients who were taking a neuroleptic medication for the first time. The neuroleptic was given twice daily, and over 80% of the episodes of acute dystonia occurred between 12 noon and 11 pm .

Reserpine and alpha-methylparatyrosine, which deplete presynaptic monoamines, have not been associated with acute dystonic reactions (Duvoisin, 1972; Marsden et al., 1975; Walinder et al., 1976). However, another dopamine depleter, TBZ, has been reported to induce acute dystonic reactions (Burke et al., 1985). One possible explanation for this difference is that in addition to depleting dopamine, TBZ blocks dopamine receptors (Reches et al., 1983).

It is important to mention the case described by Wolf (1973) of a patient who developed an oral dyskinesia while taking reserpine. Fig. 17.1 in his paper clearly shows a dystonic phenomenon and not the complex, rapid, stereotypic movements of classic TD. This development appeared too late after initiation of reserpine to be considered an acute dystonic reaction, however. Whether this could be an example of tardive dystonia is not clear, because the phenomenology of tardive dystonia is identical to that of naturally occurring primary dystonia; therefore, the patient could have had a coincidental case of spontaneous, idiopathic oromandibular dystonia (Fahn, 1984b). Thus, there is no absolute evidence that reserpine induces acute dystonic reactions, classic TD, or tardive dystonia. In fact, symptoms of these three tardive syndromes can be suppressed by reserpine, and eventually reserpine can be withdrawn successfully in many patients without exacerbation of the symptoms (Fahn, 1983). Furthermore, the long time that reserpine has been available without a clear-cut case of tardive syndromes can be compared with the much shorter duration of use of metoclopramide, in which there are already cases of acute dystonic reactions, classic TD, and tardive dystonia as a consequence of its use (Casteels-Van Daele et al., 1970; Gatrad, 1976; Pinder et al., 1976; Reasbeck and Hossenbocus, 1979; Miller and Jankovic, 1989; Lang, 1990).

Of 452 patients given high-dosage oral metoclopramide to control emesis, Kris and colleagues (1983) observed 14 who developed acute dystonic reactions. However, there was a distinct preponderance of the reactions occurring in children (6/22) compared with adults (8/430). Intravenous metoclopramide is more likely to induce it than oral administration (Pinder et al., 1976). In a study at a Veterans Administration hospital, comparing patients treated with metoclopramide and controls, the relative risk for TD was 1.67, and the relative risk for drug-induced parkinsonism was 4.0 (Ganzini et al., 1993).

The available biochemical explanations for the acute dystonic reaction are unsatisfactory, but several observations contribute to the understanding of the phenomena, relating it to dopamine, muscarinic, and sigma receptors. Acute neuroleptic administration produces sudden increase of dopamine release and increased turnover lasting for 24 to 48 hours after a single dose (O’Keefe et al., 1970; Marsden and Jenner, 1980). This effect is blocked by anticholinergics consistent with their efficacy in treatment of acute dystonic reactions (O’Keefe et al., 1970). Moreover, in baboons that were pretreated with reserpine and alpha-methylparatyrosine, which markedly reduces presynaptic dopamine concentration, haloperidol-induced acute dystonic reaction is abolished or greatly reduced (Meldrum et al., 1977). On the other hand, blockade of the postsynaptic receptor fades in about 12 hours after a single dose of antipsychotics, and supersensitivity of receptors begins to develop. Therefore, presynaptic dopaminergic excess in combination with the emerging supersensitive postsynaptic dopamine receptors could result in markedly increased striatal dopaminergic activity at about 20 to 40 hours after a neuroleptic dose. This period corresponds to the critical time for acute dystonic reactions in human subjects who were given a single dose of butaperazine (Garver et al., 1976). However, extrapolating the data from experimental animals to the clinical situation has limitations, including the fact that rats do not develop acute dystonic reactions. Further data on human cerebrospinal fluid (CSF) dopamine metabolites as an indicator of presynaptic function might prove to be of value in pursuing the hypothesis. Jeanjean and colleagues (1997) suggested that the σ ₂ receptors could be involved in the acute dystonic reaction. They found a correlation between the clinical incidence of neuroleptic-induced acute dystonia and binding affinity of drugs for the sigma receptor.

Another animal model of acute dystonia is the common marmoset that is treated with haloperidol (Fukuoka et al., 1997). But it takes at least 6 weeks of such treatment to develop this reaction. The dystonia subsides only to reappear when haloperidol treatment is restarted; other neuroleptics, including risperidone, can also make the dystonia reappear, but clozapine was without such an effect. In this animal model, the anticholinergic agent trihexyphenidyl inhibited the induction of acute dystonia.

In patients with acute dystonic reactions, symptoms can be relieved within minutes after parenteral anticholinergics or antihistaminics (Paulson, 1960; Waugh and Metts, 1960; Smith and Miller, 1961). Diphenhydramine 50 mg, benztropine mesylate, or biperiden 1 to 2 mg is given intravenously and can be repeated if the effect is not seen in 30 minutes. Intravenous diazepam also has been shown to be effective and can be used as an alternative therapy (Korczyn and Goldberg, 1972; Gagrat et al., 1978; Rainer-Pope, 1979). If untreated, the majority of cases still resolve spontaneously in 12 to 48 hours after the last dose of the dopamine receptor antagonists. Dopamine receptor antagonists with high anticholinergic activities have low incidence rates of acute dystonic reactions (Swett, 1975). Therefore, prophylactic use of anticholinergics (Arana et al., 1988) and benztropine (Goff et al., 1991) has been studied and reported to be helpful in reducing the risk for acute dystonic reactions, especially in young patients on high-potency drugs. Three cases of recurrent episodes of acute dystonia and oculogyric crises despite withdrawal of the offending DRBAs (haloperidol in two cases, metoclopramide in one) have been reported, responding to anticholinergics each time (Schneider et al., 2009). The response of acute dystonic reactions to anticholinergics is so characteristic that it is difficult to explain the report of a few cases apparently caused by amitriptyline, which has considerable anticholinergic activity and no known DRBA activity (Ornadel et al., 1992).

A case of an acute dystonic reaction occurring in an elderly person with bipolar disorder taking the serotonin uptake inhibitor paroxetine has been reported (Arnone et al., 2002). Speculation about the risk because of previous exposure to neuroleptics was raised. This class of drug can reduce firing rate of nigral dopaminergic neurons owing to their inhibition by serotonin.

Acute akathisia

The term akathisia, from the Greek, meaning unable to sit down, was coined by Haskovec in 1901 (cited by Mohr and Volavka, 2002), long before antipsychotic drugs were introduced. Akathisia was seen in some patients with advanced parkinsonism, and in others it was frequently thought to be functional. Akathisia refers to an abnormal state of excessive restlessness, a feeling of the need to move about, with relief of this symptom on actually moving. Today, it is most frequently encountered as a side effect of neuroleptic drugs.

Two major issues of akathisia remain in confusion. First, there is no consensus about diagnostic criteria. Some authors consider akathisia to be an abnormal subjective state and regard the movements as an expression of the subjective state but not a necessary feature for the diagnosis (Van Putten, 1975). Others recognize the characteristic patterns of restless movements and consider presence of movements to be sufficient for the diagnosis (Munetz and Cornes, 1982; Barnes et al., 1983; Gibb and Lees, 1986). A second point of confusion is that akathisia occurs not only in an early-onset, self-limited form (acute akathisia), but also as a late-onset, persistent form (tardive akathisia). Much of the literature on akathisia does not distinguish between acute and tardive akathisia, which makes the interpretation of the literature difficult. The recognition of tardive akathisia as a distinct subsyndrome of tardive syndromes has been more recent (Fahn, 1978, 1983; Braude and Barnes, 1983; Weiner and Luby, 1983). For the discussion of the clinical features of akathisia, acute and tardive akathisia are lumped together because they are similar but their treatments and most likely their pathophysiologies are distinct.

The subjective aspect of akathisia is characterized by inner tension and aversion to remaining still. Patients complain of vague inner tension, emotional unease, or anxiety with vivid phrases such as “jumping out of my skin” or “about to explode.” Subjective descriptions, however, can be nonspecific. Inner restlessness and inability to remain still can be present in a significant number of psychiatric patients without akathisia and in control subjects without psychiatric problems (Braude et al., 1983). In an attempt to clarify the issue, Braude and colleagues (1983) systematically surveyed the frequency of various complaints and found that inability to keep the legs still was the most characteristic complaint and was present in over 90% of patients with akathisia in contrast to about 20% of those with other psychiatric disturbances. Others noted more conservative estimation of the frequency of complaints related to the legs from 27% (Gibb and Lees, 1986) to 57% (Burke et al., 1989). Various authors also described atypical features such as “acting out,” suicidal ideation, disruptive behaviors, homicidal violence, sexual torment, terror, and exacerbation of psychosis as akathitic phenomena (Van Putten and Marder, 1987). Evaluation of the subjective aspect also depends on patients’ ability to describe their feelings. Those with psychosis, dementia, or learning disability are often unable to provide useful descriptions for diagnosis. Although akathisia may manifest as subjective feeling alone, lack of specific subjective feeling and variable expression by patients pose a diagnostic dilemma. Therefore, the presence of the motor phenomenon is very helpful for the diagnosis.

Akathisia can manifest as focal pain or burning, usually in the oral or genital region (Ford et al., 1994). The symptom of moaning may be a verbal expression of the subjective feeling of akathisia. Some patients may moan as part of a generalized akathitic state and have other motor evidence of akathisia, such as marching in place, inability to sit still accompanied by associated walking about, inability to lie quietly with writhing and rolling movements, and making stereotypic caressing or rocking movements. The differential diagnosis of moaning includes parkinsonism, akathisia, levodopa usage (Fahn et al., 1996), dementia, pain, and other syndromes of phonations, such as tics, oromandibular dystonia, and Huntington disease (HD), as discussed by Fahn (1991).

The motor aspect of akathisia (akathitic movements) is generally described as excessive movements that are complex, semipurposeful, stereotypic, and repetitive. Braude and colleagues (1983) found that rocking from foot to foot, walking on the spot, and coarse tremor and myoclonic jerks of the feet were characteristic of akathitic movements. Others agree that various leg and feet movements are more common in patients with akathisia than in those with TD (Gibb and Lees, 1986; Burke et al., 1989). However, they also noted that these did not distinguish akathisia from the group that did not meet criteria for akathisia (Gibb and Lees, 1986), and movements involving other parts of the body such as trunk rocking, respiratory grunting, face rubbing, and shifting weight while sitting were also frequent (Burke et al., 1989). Although there are not enough data and no consensus on the diagnostic movements of akathisia, these movements seem to be characteristic enough to be recognized by different authors who have independently documented similar phenomena.

Akathisia is seen in patients with PD (Lang and Johnson, 1987), in patients abusing cocaine (Daras et al., 1994), and as an adverse effect of selective serotonin uptake inhibitors (Poyurovsky et al., 1995). Acute akathisia occurs not only as an adverse effect of DRBAs but also fairly commonly as an acute adverse effect of the dopamine depleters reserpine, TBZ, and alpha-methyltyrosine (Marsden and Jenner, 1980).

In Ayd’s review (1961), half of the cases of acute akathisia occurred within 25 days of drug treatment and 90% occurred within 73 days. Acute akathisia was the most common side effect of DRBAs, occurring in 21.2% of patients in that study (Ayd, 1961). In a more recent study by Sachdev and Kruk (1994) of 100 consecutive patients placed on neuroleptics, mild akathisia developed in 41% and moderate to severe akathisia in 21%. In a literature review, Sachdev (1995b) reported that incidence rates for acute akathisia with conventional neuroleptics vary from 8% to 76%, with 20% to 30% being a conservative estimate. Sachdev stated that preliminary evidence suggests that the newer atypical antipsychotic drugs are less likely to produce acute akathisia. Using the criterion that both subjective and objective phenomena are required for the diagnosis of acute akathisia, Miller and colleagues (1997) found an incidence rate of 22.4%, 75% of which occurred within the first 3 days of exposure to a neuroleptic. Muscettola and colleagues (1999) found a prevalence rate of 9.4%.

The potency of neuroleptics has been associated with incidence of akathisia, ranging from 0.5% for reserpine (Marsden and Jenner, 1980) to 75% for haloperidol (Van Putten et al., 1984). Other risk factors are neuroleptic dose, the rate of dosage increase, and the development of drug-induced parkinsonism (Sachdev and Kruk, 1994). Akathisia has occurred with FGAs and SGAs (Kane et al., 2009).

As with acute dystonic reactions, akathisia also has been induced by serotonergic agents (Chong, 1996; Lopez-Alemany et al., 1997). The mechanism was discussed in the earlier section on acute dystonia.

As was noted previously, akathisia needs to be distinguished from other conditions such as agitated depression; restless legs syndrome, in which similar subjective sensations may be described by patients but are mainly localized to legs and are present particularly at night (Blom and Ekbom, 1961); complex motor tics with preceding aura, which show more variety of abnormal movements; and complex vocal tics (Jankovic and Fahn, 1986). Akathisia also can be obscured by other psychiatric disorders, or it could be mistaken for a psychiatric disease. For example, when patients with psychosis develop akathisia after withdrawal from antipsychotic drugs, it may be mistaken for recurrence of psychosis. Paradoxical dystonia (see Chapter 11 ) in which dystonic movements are relieved by movement can be mistaken for akathisia.

The pathophysiology of acute akathisia remains poorly understood. On the basis of the observation in rats that show increased locomotor activity after blockade of the mesocortical dopamine system (Carter and Pycock, 1978), reduction of this dopaminergic projection was suggested to be responsible for akathisia (Marsden and Jenner, 1980). However, tardive akathisia cannot be explained by this hypothesis because dopamine depleters can ameliorate those symptoms. The observation that acute akathisia can occur with a serotonin uptake inhibitor (Altshuler et al., 1994) indicates that inhibiting dopamine neurons in the SN by such drugs could link the dopamine system with akathisia. These types of drugs have been reported to increase parkinsonism in patients with PD (Meco et al., 1994). One attractive possibility is that akathisia might reflect an alteration of the dopaminergic mesolimbic system.

Because propranolol has been reported to be beneficial in treating acute akathisia, another suggestion is that acute akathisia results from alterations in the cingulate cortex, the piriform cortex, or area 1 of the parietal cortex based on effects of propranolol in these regions in haloperidol-treated rats (Ohashi et al., 1998).

Ayd (1961) noted that acute akathisia is self-limited, disappearing on discontinuation of neuroleptics, and is well controlled by anticholinergics despite continuation of neuroleptics. Others have noted that only patients with concomitant parkinsonism improve significantly with anticholinergics (Kruse, 1960; Braude et al., 1983). Amantadine may also help, but patients can develop a tolerance (Zubenko et al., 1984a). Beta-blockers at relatively low doses, below 80 mg of propranolol per day, have been noted to be effective in many studies, including one with a double-blind design (Lipinski et al., 1984; Zubenko et al., 1984b; Adler et al., 1986; Dupuis et al., 1987). Nonlipophilic beta-blockers that have poor penetration to the central nervous system (CNS) are not as effective (Lipinski et al., 1984; Dupuis et al., 1987). Selective beta-blockers might not be as effective as nonselective ones (Zubenko et al., 1984b); however, when two equally lipophilic beta-blockers, propranolol and betaxolol, were compared, they were equally effective in treating acute akathisia (Dumon et al., 1992), although the former is a beta-2-blocker and the latter is a beta-1-blocker. In a rat model of acute akathisia (neuroleptic-induced defecation), a lipophilic beta-1-blocker was found to be effective in reducing the phenomenon (Sachdev and Saharov, 1997).

Clonidine also reduces central noradrenergic activity by stimulating central alpha-2 receptors and has been noted to be effective in a small number of studies. The sedating effect is pronounced, however (Adler et al., 1987). Nicotine patches have been reported to reduce akathisia (Anfang and Pope, 1997). Weiss and colleagues (1995) found cyproheptadine, an antiserotonergic agent, to be effective in ameliorating akathisia. In a small placebo-controlled trial, mianserin, a 5HT ₂ antagonist, was found to reduce the severity of acute akathisia (Poyurovsky et al., 1999). Trazadone also has been reported to be beneficial (Stryjer et al., 2003). Poyurovsky and Weizman (2001) discuss the potential of serotonin agents in akathisia. A literature search revealed mirtazapine to be effective and superior to propranolol (43.3% versus 30.0%) (Hieber et al., 2008).

Parkinsonism

Neuroleptic-induced parkinsonism (usually referred to as extrapyramidal syndrome (EPS) by psychiatrists and as drug-induced parkinsonism by neurologists) is a dose-related side effect and is indistinguishable phenomenologically from idiopathic PD, including high frequency of tremor and asymmetrical signs (Hardie and Lees, 1988). SPECT imaging of the dopamine transporter (DAT), however, may be helpful in determining whether the neuroleptic-induced parkinsonism is entirely drug-induced or an exacerbation of subclinical PD (Lorberboym et al., 2006). It develops with use of both DRBAs and dopamine-depleting drugs such as reserpine and TBZ. Some authors have noted perioral tremor and termed this rabbit syndrome, which is a localized form of parkinsonian tremor (Decina et al., 1990). The incidence of parkinsonism varies. Korczyn and Goldberg (1976) found 61%, and Muscettola and colleagues (1999) found 19.4%. Women are affected almost twice as frequently as men, which is the reverse of the ratio in idiopathic PD. Neuroleptic-induced parkinsonism also occurs increasingly with advanced age (Ayd, 1961; Hardie and Lees, 1988) in parallel with the incidence of idiopathic PD.

Blockade of dopamine receptors by antagonists or depletion of presynaptic monoamines by drugs such as reserpine mimics the deficient dopamine state in PD. All DRBAs can induce parkinsonism, except clozapine (there are only rare reports with clozapine) (Factor and Friedman, 1997). Risperidone can do so (Gwinn and Caviness, 1997; Simpson and Lindenmayer, 1997), as can olanzapine and only rarely quetiapine. Parkinsonism from neuroleptics is typically reversible when the medication is reduced or discontinued. Sometimes, the reversal can take many months; an interval of up to 18 months has been noted in the literature (Fleming et al., 1970).

Some patients show persisting parkinsonism despite prolonged discontinuation of neuroleptics (Stephen and Williamson, 1984; Hardie and Lees, 1988), giving rise to consideration of a proposed condition of tardive parkinsonism. A study of 8-week exposure of rats to haloperidol found a highly significant 32% to 46% loss of tyrosine hydroxylase (TH)-immunoreactive neurons in the SN, and 20% contraction of the TH-stained dendritic arbor (Mazurek et al., 1998). Perhaps such pathologic changes account for some cases of prolonged drug-induced parkinsonism in humans. Several cases in the literature had initial resolution of parkinsonism and later reappearance of the symptoms without reexposure to neuroleptics (Hardie and Lees, 1988). Two cases that had complete resolution of drug-induced parkinsonism after withdrawal of neuroleptics showed evidence of mild PD at autopsy (Rajput et al., 1982). Although one assumes that these patients had subclinical PD, the effect of neuroleptics on the disease progression is unknown. The use of the term “tardive parkinsonism” to refer to cases of persistent parkinsonism remains an enigma. Some cases are due to concurrent development of progressive PD, and there are no autopsied proven examples of non-PD in any example. Therefore, this suggests that there is as yet no evidence of tardive parkinsonism.

With the introduction of selective serotonin reuptake inhibitors (SSRIs) to treat depression, it has been noticed that these drugs can sometimes worsen parkinsonism in patients with PD (Meco et al., 1994) and occasionally can induce parkinsonism in patients who never had symptoms of PD (Coulter and Pillans, 1995; DiRocco et al., 1998). In an intensive monitoring program in New Zealand of the SSRI drug fluoxetine over a 4-year period, there were 15 reports of parkinsonism in 5555 patients who were exposed to the drug (Coulter and Pillans, 1995). Of these 15 patients, 4 were also on a neuroleptic and 1 was on metoclopramide. In a literature search, parkinsonism was found with different classes of antidepressants, is not dose related, and can develop with short-term or long-term use (Madhusoodanan et al., 2010). The explanation for inducing or enhancing parkinsonism is that increased serotonergic activity in the SN will inhibit dopamine-containing neurons, thus causing functional dopamine deficiency in the nigrostriatal pathway (Baldessarini and Marsh, 1992).

The possibility of the existence of tardive parkinsonism comes up from time to time because some patients have continued parkinsonism despite long-term discontinuation of the DRBA (Melamed et al., 1991). However, there is always the possibility that the patient had preclinical PD before developing drug-induced parkinsonism. Then, when the DRBA is withdrawn, the parkinsonism persists because of progressively worsening PD. One would need to show that there are no Lewy bodies or that the PET scan shows no loss of fluorodopa uptake in patients thought to have tardive parkinsonism.

Anticholinergics can be effective in reducing the severity of the parkinsonism induced by DRBAs, whereas dopaminergic drugs (that activate the dopamine receptors) are ineffective, probably because they are not able to displace the DRBA from its binding to the receptor. Levodopa up to 1000 mg in combination with a peripheral dopa decarboxylase inhibitor had no significant effect (Hardie and Lees, 1988), nor did apomorphine, a dopamine receptor agonist (Merello et al., 1996). On the other hand, levodopa can effectively reverse parkinsonism induced by dopamine depleters, such as reserpine. In fact, the discovery of the dopamine hypothesis for parkinsonism was based on this observation (Carlsson et al., 1957; Carlsson 1959). Treatment is usually initiated with anticholinergics or amantadine (Mindham et al., 1972; Johnson, 1978; Konig et al., 1996).