Antipsychotic and anticholinergic drugs

Herbert Y. Meltzer

William V. Bobo

Introduction

The discovery by Delay and Denicker in 1953 that chlorpromazine was highly effective in alleviating delusions, hallucinations, and disorganized thinking, was the seminal breakthrough in the treatment of schizophrenia, the first agent to produce sufficient relief of core psychotic symptoms to permit life outside of institutions for many patients with schizophrenia, and even a return to a semblance of function within normal limits. Chlorpromazine and the other related typical antipsychotic drugs which were introduced over the next 30 years have proven to be of immense benefit to vast numbers of people who experience psychotic symptoms as a
component of a diverse group of neuropsychiatric and medical disorders, as well as drug-induced psychoses. These drugs have been invaluable in providing clues to the aetiology of schizophrenia and other forms of mental illness with psychotic features and as tools in understanding fundamental neural processes, especially those involving dopamine, a key neurotransmitter involved in psychosis. This class of drugs has now been supplanted by the so-called atypical antipsychotic drugs, of which clozapine is the prototype. This chapter will describe the various classes of antipsychotic agents, with emphasis on the atypical antipsychotic drugs, their benefits and adverse effects, recommendations for use in clinical practice, and mechanism of action. The drugs used to treat the extrapyramidal side-effects (EPS) produced mainly by the typical antipsychotic drugs are also considered.

The classes of antipsychotic drugs

Antipsychotic drugs have been classified into two broad categories: typical and atypical.⁽¹⁾ Typical antipsychotic drugs are those which (typically) produce EPS at clinically effective doses, including parkinsonism (muscle rigidity, tremor, bradykinesia), acute dystonic reactions, dyskinesias, akathisia (restlessness), and tardive dyskinesia. They are also called neuroleptics because of their inhibitory effect upon locomotion activity. They are sometimes referred to as first generation antipsychotic drugs, but this has multiple problems as a class designation. The prototype of the atyipcal class of agents is clozapine which was first discovered during the early stages of the development of the drugs called first generation agents. The major mode of action of typical neuroleptics is to block dopamine D₂ receptors in the limbic system, which includes the nucleus accumbens, stria terminalis, and amygdala.

The typical antipsychotic drugs are members of a variety of chemical families (Table 6.2.5.1). They vary in affinity for the D₂ receptor, with low affinity drugs such as chlorpromazine, which require high doses for clinical efficacy, to high affinity drugs such as haloperidol, which are effective at lower doses (Table 6.2.5.1). Kapur and Seeman⁽³⁾ have proposed that the rate of dissociation of all antipsychotic drugs from the D₂ receptor provides the basis for the distinction between typical and atypical antipsychotic drugs, with atypical antipsychotic drugs dissociating more rapidly. While this is true for clozapine and quetiapine, the atypical drugs risperidone, sertindole, olanzapine and asenapine dissociate no more rapidly or even slower than haloperidol. As such, ‘fast dissociation’ cannot provide the pharmacological basis for atypicality for most of the drugs that are considered atypical.

Low-potency typical neuroleptic agents are those in which the usual dose range in schizophrenia is equal to or greater than 200 mg/day, while mid- to high-potency agents are those in which the dose range is between 2 and 175 mg/day. In general, the low-potency drugs are more sedative and more hypotensive than the high-potency agents but also have less of a tendency to produce extrapyramidal side-effects. The typical antipsychotic drugs differ from one another with regard to potential for other side-effects, e.g. weight gain and hypotension, but have comparable efficacy as antipsychotic agents.⁽⁴⁾

Atypical antipsychotic drugs are those antipsychotic agents with a significantly lower propensity to produce EPS at clinically effective doses.⁽¹⁾ They are also characterized by a more diverse and complex pattern of pharmacological activity, including serotonin (5-hydroxytryptamine)_2A and dopamine D₂ antagonism as well as a variety of activities at other receptors whose contribution to their mode of action is still being elucidated.⁽²⁾ Substituted benzamides, e.g. amisulpride, also have low EPS at clinically effective doses and may constitute another class of atypical agents. New classes of atypical antipsychotic drugs are emerging from research with considerable frequency at the current time.

The prototypical atypical antipsychotic drug is clozapine, a dibenzodiazepine (Table 6.2.5.1).⁽⁵⁾ Others include aripiprazole,⁽⁶⁾ olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone and zotepine, while iloperidone,⁽⁷⁾ asenapine,⁽⁸⁾ and laurasidone⁽⁹⁾ are in development and have a similar pharmacology to that of risperidone. These drugs are all more potent 5-HT_2A than D₂ receptor antagonists as well as multireceptor antagonists⁽⁹^,¹⁰⁾ except for aripiprazole, which is a dopamine D₂ receptor partial agonist. Bifeprunox is also a partial D₂ agonist. It lacks 5-HT_2A receptor blocking properties, relying instead on 5-HT_1A partial agonism to reduce serotonergic tone. Amisulpride and remoxipride are substituted benzamides. Both are selective D₂/D₃ antagonists.⁽²⁾
Remoxipride was withdrawn shortly after its introduction because of a high rate of aplastic anaemia.

Table 6.2.5.1 Selected antipsychotic drugs and classification schemes

Drug name	Trade name	Chemical class	General class	D2 potency^*
Aripiprazole	Abilify	Dihydrocarbostyril	Atypical
Chlorpromazine	Thorazine	Phenothiazine	Typical	Low
Clozapine	Clozaril	Dibenzazepine	Atypical
Droperidol	Inapsine	Butyrophenone	Typical	Mid
Fluphenazine	Prolixin	Phenothiazine	Typical	High
Haloperidol	Haldol	Butyrophenone	Typical	High
Loxapine	Loxitane	Dibenzazepine	Typical	Mid
Mesoridazine	Serentil	Phenothiazine	Typical	Low
Molindone	Moban	Dihydroindolone	Typical	Mid
Olanzapine	Zyprexa	Thiobenzodiazepine	Atypical
Paliperidone	Invega	9-hydroxy metabolite of risperidone	Atypical
Perphenazine	Trilafon	Phenothiazine	Typical	Mid
Pimozide	Orap	Butyrophenone	Typical	Mid
Promazine		Phenothiazine	Typical	Mid
Quetiapine	Seroquel	Dibenzothiazepine	Atypical
Risperidone	Risperdal, Risperdal CONSTA	Benzisoxazole	Atypical
Thioridazine	Mellaril	Phenothiazine	Typical	Low
Tiotixene	Navane	Thioxanthene	Typical	High
Trifluoperazine	Stelazine	Phenothiazine	Typical	Mid
Ziprasidone	Geodon	Benzisothiazole	Atypical
^*Classification on the basis of potency of D₂ receptor binding for typical antipsychotic drugs only

As will be discussed, the atypical antipsychotic drugs differ not only with regard to side-effects but also with regard to efficacy.⁽¹¹^,¹²⁾ Atypical antipsychotic agents have been shown to have advantages, albeit modest, in treating negative mood symptoms⁽¹³^,¹⁴^,¹⁵⁾ and to improve cognitive dysfunction in schizophrenia and perhaps other psychiatric disorders.⁽¹⁶^,¹⁷^,¹⁸⁾

Pharmacology

There is abundant evidence that dopamine plays a key role in the aetiology of psychosis and the action of antipsychotic drugs.⁽¹⁹⁾ The antipsychotic action of the typical antipsychotic drugs is highly correlated with their affinities for D₂ receptors. Amphetamine and methamphetamine, which increase synaptic concentrations of dopamine, have been found to exacerbate delusions and hallucinations in some patients with schizophrenia This effect is believed to be due to stimulation of a subgroup of D₂ receptors in mesolimbic nuclei.⁽¹⁹^,²⁰⁾ The cell bodies of mesolimbic dopamine neurones reside in the ventral tegmentum, the so-called A10 area, and have terminals in the nucleus accumbens, stria terminalis, and olfactory tubercle. The outflow of these regions to the thalamus and the cortex is believed to mediate psychotic symptoms. The firing rate of the mesolimbic dopaminergic neurones is subject to multiple influences, including stimulatory serotonergic input from the median raphe.⁽²¹⁾ The origin of the dopamine neurones that terminate on cholinergic neurones in the basal ganglia is the substantia nigra, the so-called A9 region.⁽²⁰⁾ Blockade of striatal D₂ receptors in this pathway leads to the extrapyramidal side-effects produced by antipsychotic agents. A group of ventral tegmental dopamine neurones project to various regions of the cortex and comprise the mesocortical dopamine system. There is extensive evidence that these neurones are important for cognition, especially working memory,⁽²²⁾ as well as negative symptoms.⁽²³⁾ Neuroleptic drugs occupy 80 to 95 per cent of striatal D₂ receptors in patients with schizophrenia at clinically effective doses, though a lower blockade threshold of 60 per cent for improving positive symptoms has been identified.⁽²⁴⁾ Extrapyramidal side-effects occur above 80 per cent occupancy of these receptors. Blockade of D₂ receptors in the anterior pituitary gland is the basis for their ability to stimulate prolactin secretion.⁽²⁵⁾

The prefrontal cortex has relatively low concentrations of D₂ receptors and has a higher density of D₁, D₃ and D₄ dopamine receptors.⁽²⁰⁾ The activation of D₁ receptors in prefrontal cortex may be especially critical for normal working memory and other executive type functions subserved by this brain region. However, no D1 agonists are available for treatment at the current time, although several are in development. Drugs which selectively block D₄ receptors have not been found to have an antipsychotic effect.⁽²⁶⁾ There are only limited data regarding the aetiologic or pharmacological significance of D3 receptors in schizophrenia.

The typical antipsychotic drugs vary in their in vitro and in vivo affinities for receptors such as the dopamine D₁, histamine H₁, muscarinic, α-1 and α-2 adrenergic, and serotonergic receptors (Table 6.2.5.2), which mediate effects on arousal, extrapyramidal, cognitive, cardiovascular, gastrointestinal, and genitourinary function (Table 6.2.5.3).⁽²⁷⁾

Thioridazine is a relatively potent antimuscarinic agent. Most of the low-potency antipsychotic agents are potent α₁ and H₁ antagonists. These affinities contribute to hypotension and weight gain, respectively. While some typical antipsychotic drugs have a high affinity for 5-HT_2A receptors, their affinities for D₂ receptors are even higher, which diminishes the beneficial effects of the 5-HT_2A receptor blockade. The specific receptor profile of each atypical antipsychotic is of special interest because it may account for critical differences among these compounds, especially in terms of side effect burden (Table 6.2.5.4). The affinities of the atypical antipsychotic drug have been related to their efficacy and side effect profiles. As noted above, the most important determinant of atypicality for most of the currently available agents of this type is that they are more potent 5-HT_2A than D₂ receptor antagonists. An exception is aripiprazole, which combines potent 5-HT_2A antagonism and 5-HT_1A agonism, with partial D₂ receptor agonism. Another exception is amisulpiride, which is a selective D2/3 antagonist with little pharmacological activity at 5-HT_2A receptors. Combined 5-HT_2A with less potent D2 antagnoism is the most consistent principle yet discovered to produce a separation between antipsychotic action and interference with motor function. This hypothesis arose from showing that it could distinguish clozapine, the prototypical atypical antipsychotic drug, and a series of other atypical antipsychotic compounds from those which have typical properties.⁽²⁸⁾ These studies suggested that the low potential for extrapyramidal side-effects of clozapine, and subsequently, olanzapine, quetiapine, risperidone, iloperidone, ziprasidone, paliperidone and asenapine are due, in part, to their relatively stronger 5-HT₂ antagonist and weak D₂ antagonist properties. The serotonin-dopamine interaction in the nigrostriatal and mesolimbico-cortical pathways appears to be mediated by stimulation of 5-HT_2A receptors, which are located on dopaminergic cell bodies, whereas antagonism of these receptors may release these neurones from tonic inhibition.

The atypical antipsychotic agents have the ability to increase prefrontal cortical dopaminergic activity compared with subcortical dopaminergic activity.⁽²⁹⁾ The ability to increase the release of dopamine in the prefrontal cortex may be important for atypical antipsychotic agents to improve cognition and negative symptoms. It may also contribute to decreasing the release of dopamine in the mesolimbic region, because prefrontal dopamine neurones modulate the activity of corticolimbic glutamatergic neurones that influence the release of dopamine from nerve terminals in the limbic region.⁽²²⁾ Typical neuroleptic drugs do not share this ability to increase dopamine efflux in prefrontal cortex. Clozapine and some of the other atypical antipsychotic drugs that are also potent 5-HT_2A antagonists, but not typical neuroleptics, also produce marked increases in prefrontal cortical and hippocampal acetylcholine efflux.⁽³⁰⁾ These atypical agents also produce marked increases in noradrenaline efflux in the prefrontal cortex which is correlated in time and magnitude with the increase in extracellular dopamine.⁽³¹⁾ It is of interest that in rodents, combining ritanserin (a mixed 5-HT2a/2B/2C antagonist) or M-100907 (a selective 5-HT_2A antagonist) with a selective D_2/3 antagonist resulted in increased prefrontal dopamine release.⁽³²^,³³⁾ The combination of haloperidol and M-100907 also increased prefrontal dopamine release, with the greatest effects observed when lower doses of haloperidol were used.⁽³⁴⁾ Because reduced noradrenergic and dopaminergic function in prefrontal cortex and hippocampus has been associated with negative symptoms and cognitive impairment in schizophrenia,⁽²²^,³⁵⁾ the cortical release of these two neurotransmitters, and possibly also acetylcholine, may provide a pharmacological basis for the advantages of atypical antipsychotics over typical neuroleptic drugs in the treatment of these critical symptom domains. In patients with schizophrenia who were stabilized on typical neuroleptics, the addition of mianserin, a 5-HT_2A/C and adrenergic α-2 antagonist, was associated with improved neurocognitive performance,⁽³⁶⁾ adding further support to a role of 5-HT_2A receptors in the treatment of cognitive dysfunction in schizophrenia.

Table 6.2.5.2 Affinities of selected antipsychotic drugs at various neuroreceptors

Drug name	D₂	5-HT_1A	5-HT_2A	5-HT_2C	α-1	α-2	H-1	M-1
Aripiprazole	0.95	5.6	4.6	181.0	25.0	74.0	29.0	>6K
Chlorpromazine	2.0 >3K	3.2	26.0	0.28	184.0	0.18	47.0
Clozapine	431.0	105.0	13.0	29.0	1.6	142.0	2.0	14.0
Droperidol	0.25 (173)	NA	NA	NA	NA	NA	NA	NA
Fluphenazine	0.54	145.0	7.4	418.0	6.4	314.0	7.3	>1K
Haloperidol	2.0	>1K	73.0	>10K	12.0	>1K	>3K	>10K
Loxapine	10.0	>2K	3.9	21.0	31.0	151.0	2.8	175.0
Molindone	63.0⁽⁴³⁾	>3K⁽⁴³⁾	320.0⁽⁴³⁾	>10K⁽⁴³⁾	>2K⁽⁴³⁾	>1K⁽⁴³⁾	>2K⁽⁴³⁾	NA
Olanzapine	72.0	>2K	3.0	24.0	109.0	314.0	4.9	24.0
9-OH risperidone^*	9.4	637.8	1.9	100.3	2.5	4.7	5.6	>10K
Perphenazine	1.4⁽⁴³⁾	421.0⁽⁴³⁾	5.6⁽⁴³⁾	132.0⁽⁴³⁾	10.0⁽⁴³⁾	810.5⁽⁴³⁾	8.0⁽⁴³⁾	NA
Pimozide	0.65⁽⁴³⁾	650.0⁽⁴³⁾	19.0⁽⁴³⁾	>3K⁽⁴³⁾	197.7⁽⁴³⁾	>1K⁽⁴³⁾	692.0⁽⁴³⁾	800.0(174)
Quetiapine	567.0	431.0	366.0	>1K	22.0	>3K	7.5	858.0
Risperidone	4.9	427.0	0.19	94.9	5.0	151.0	5.2	>10K
Thioridazine	10.0	108.0	11.0	69.0	1.3	134.0	14.0	33.0
Tiotixene	1.4	410.0	111.0	>1K	12.0	80.0	12.0	>10K
Trifluoperazine	1.3⁽⁴³⁾	950.0⁽⁴³⁾	13.0⁽⁴³⁾	378.0⁽⁴³⁾	24.0⁽⁴³⁾	653.7⁽⁴³⁾	63.0⁽⁴³⁾	NA
Ziprasidone	4.0	76.0	2.8	68.0	18.0	160.0	130.0	>10K
All receptor binding affinities are reported as Ki (nM) using National Institutes of Mental Health (NIMH) Psychoactive Drug Screening Program (PDSP) certified data, available online at http://pdsp.cwru.edu/pdsp.php, unless otherwise specified. In general, the lower the Ki (nM) value, the higher the binding affinity for the drug at a given receptor site.
NA = human cloned receptor data not available
^*9-hydroxy (9-OH) risperidone is marketed as paliperidone

Table 6.2.5.3 Hypothesized therapeutic and adverse effects of receptor occupancy by antipsychotic drugs

Target receptor	Pharmacological activity	Therapeutic effect(s)	Adverse effect(s)
Dopamine D2	Antagonism or partial agonist effects	Reduction of positive symptoms	Extrapyramidal effects (EPS) Hyperprolactinemia
Serotonin (5-HT)_1A	Full or partial agonist effects	Cognitive enhancement Reduction of mood and anxiety symptoms
5-HT _2A	Antagonism	Reduction of negative symptoms Reduction of EPS Reduction of mood and anxiety symptoms Increased deep sleep
5-HT _2C	Antagonism	Reduced anxiety symptoms	Weight gain
Adrenergic α-1	Antagonism		Orthostatic hypotension Dizziness
Adrenergic α-2	Antagonism		Reflex tachycardia
Histamine H-1	Sedation	Sedation Drowsiness Weight gain
Muscarinic (cholinergic) M-1	Antagonism	Reduction of EPS	Blurry vision Exacerbation of acute angle closure glaucoma Sinus tachycardia Constipation Urinary retention Memory dysfunction
Adapted from Kelly, D.L. and Love, R.C. Ziprasidone and the QTC interval: pharmacokinetic and pharmacodynamic considerations, Psychopharmacology Bulletin, 35, 66-79, copyright 2001, MedWorks Media Global, LLC.

Table 6.2.5.4 Adverse effects of selected antipsychotic drugs

Typical antipsychotic drugs
	EPS	Tardive dyskinesia	Prolactin elevation	Sedation	Weight gain	Orthostasis	Anti-cholinergic	Diabetes exacerbation & dyslipidemia
Chlorpromazine Fluphenazine Haloperidol Loxapine Mesoridazine Molindone Perphenazine Thioridazine Tiotixene Trifluoperazine	Some (for low potency^* drugs) – +++ (for high-potency^* drugs)	++− +++	++− +++ (risk higher for high-potency drugs)	Some (for high potency drugs) − +++ (for low-potency drugs); ? least for molindone	Some (for high potency drugs) − +++ (for low-potency drugs); ? least for molindone	Some (for high potency drugs) − +++ (for low-potency drugs)	Some (for high potency drugs) − +++ (for low-potency drugs)	+−++
^*See Table 6.2.5.1 for list of low-, mid-, and high-potency (with respect to dopamine D₂ receptor blockade) antipsychotic drugs
Adapted from the International Psychopharmacology Algorithm Project (IPAP) algorithm for the treatment of schizophrenia, available at www.ipap.org, copyright 2008 International Psychopharmacology Algorithm Project (IPAP)

Atypical antipsychotic drugs
	EPS	Tardive dyskinesia	Prolactin elevation	Sedation	Weight gain	Orthostasis	Anti-cholinergic	Glucose dysregulation & dyslipidemia
Amisulpride	+	Rare	+++	+	0 – +	+	0	0
Aripiprazole	0 – +	0 – +	0	0 – +	0 – +	+ – ++	0	0
Clozapine	0	0	Transient	+++	+++	+++	+++	+++
Olanzapine	0 – + (if < 10 mg/day)	Rare	+ (if < 20 mg/day)	++	+++	+	+	+++
Quetiapine	0	Rare	0	++	+- ++	++	0 – +	++
Risperidone	+ (less if < 4 mg/day)	Rare	+++	+	+ – ++	++	0	+
Ziprasidone	0 – +	Rare	0 – +	0 – ++	0	+- ++	0	0
Sufficient data for paliperidone, iloperidone and asenapine are not yet available for inclusion in this table.
Adapted from the International Psychopharmacology Algorithm Project (IPAP) algorithm for the treatment of schizophrenia, available at www.ipap.org, copyright 2008 International Psychopharmacology Algorithm Project (IPAP)

The importance of serotonin receptors other than 5-HT_2A for the action of antipsychotic drugs has received considerable attention. Activation of 5-HT_1A receptors are believed to have a dopamine modulating effect similar to that of 5-HT_2A antagonism.⁽³⁷⁾ Under experimental conditions, 5-HT_1A agonists have been shown to stimulate cortical dopamine release⁽³⁸^,³⁹⁾ and, in schizophrenic patients who were stabilized on haloperidol, the addition of tandospirone, a 5-HT_1A partial agonist, resulted in improved neurocognitive performance.⁽⁴⁰⁾ This effect has also been demonstrated more recently for buspirone, another 5-HT_1A partial agonist.⁽⁴¹⁾ Serotonin-1A receptors may be important for cognitive effects of at least some of the atypical antipsychotic drugs that are active at this receptor site. Activity at 5-HT_1A receptors is not shared by all antipsychotic drugs (Table 6.2.5.2), however. Antagonism of 5-HT_2C receptors also appears to result in cortical dopamine and norepinephrine release, as well as in the nucleus accumbens.⁽⁴²⁾ The cognitive effects of selective 5-HT_2C antagonists added to typical neuroleptic drugs in patients with schizophrenia have not been examined. As is the case with 5-HT_1A activity, not all atypical antipsychotic drugs are active at 5-HT_2C receptors (Table 6.2.5.2). Like antagonism at histamine H1 receptors,⁽⁴³⁾ 5-HT_2C antagonist activity may be related to antipsychotic induced weight gain.⁽⁴⁴⁾

Atypical antipsychotics may display regional selectivity in terms of their dopaminergic activity, relative to typical neuroleptics. For instance, atypical antipsychotic drugs appear to preferentially block cortical D₂ receptors, relative to those located in the striatum.⁽⁴⁵^,⁴⁶⁾ Haloperidol results in proportionally equivalent D₂ blockade in both brain regions.⁽⁴⁷⁾ The atypical antipsychotics also increase the expression of the early intermediate gene c-fos, in the prefrontal cortex and the shell of the nucleus accumbens, while sparing the core of the latter region and the striatum. Typical neuroleptic drugs have the opposite effect on c-fos expression. Sparing the dorsal
striatum is believed to be related to the low potential for extrapyramidal side-effects of these agents.⁽²^,²¹⁾

Clozapine, olanzapine, risperidone, and quetiapine are able to block the interference in prepulse inhibition produced by d-amphetamine, apomorphine, or phencyclidine at doses that do not interfere with locomotor function. Clozapine and M100907 are able to block the effects of phencyclidine, an N-methyl-D-aspartate receptor antagonist, on locomotor activity in rodents. This suggests the ability of rat 5-HT_2A-receptor blockade to block some of the effects of phencyclidine which is one of the more important models for schizophrenia.⁽²^,²¹⁾ In a recent single photon emission tomography (SPECT) study, patients with schizophrenia who received treatment with clozapine evidenced reduced NMDAactive radiotracer binding compared with healthy controls, drug free patients with schizophrenia, and patients with schizophrenia who were treated with typical neuroleptics.⁽⁴⁸⁾ The extent of involvement of other atypical antipsychotic drugs relative to typical antipsychotics at NMDA receptors and other glutamatergic targets is an area of active interest. Other receptor targets that are of special interest in terms of improving cognitive functioning and selected psychotic symptoms include M1 muscarinic, α-7 nicotinic, and α-1 and α-2 adrenergic receptors.

Administration, pharmacokinetics, and dosage

Administration

(a) Typical antipsychotic drugs

The major uses of the antipsychotic drugs are for the treatment of schizophrenia, mood disorders typically with psychotic features, and senile psychoses.⁽⁴^,⁴⁹⁾ Other indications are discussed elsewhere in this book in the consideration of the management of specific disorders, such as Tourette’s syndrome, and aggression. The major advantage of the typical neuroleptic drugs is their ability to improve positive symptoms, i.e. delusions and hallucinations. Administration of typical neuroleptic drugs leads to the complete or nearly complete elimination of positive symptoms and disorganization of thought and affect in about 60 to 70 per cent of patients with schizophrenia and an even higher proportion of those with psychotic mania and psychotic depression.⁽⁴⁹⁾ The antipsychotic response in schizophrenia and mania is sometimes apparent within a few days in many patients but usually takes up to several weeks or months. A reasonable duration for a therapeutic trial with one of these agents is 4 to 6 weeks. It is not appropriate to switch medications after 1 or 2 weeks, even if a response is not apparent, unless side-effects pose a serious problem. Positive symptoms (delusions and hallucinations) do not respond to typical neuroleptic drugs in about 10 per cent of schizophrenic patients even during the first episode.⁽⁵⁰⁾ Another 20 per cent of patients with schizophrenia develop resistance to these agents during the subsequent course of their illnesses.⁽⁵¹⁾ Development of resistance to typical neuroleptic drugs may occur at any time during the course of treatment, even after many years of control of positive symptoms. Such patients are more likely to respond to clozapine⁽⁵¹⁾ or one of the other atypical antipsychotics.⁽⁵⁰^,⁵¹⁾

The average doses of the typical neuroleptic drugs are given in Table 6.2.5.5. The best results with these drugs in terms of efficacy and side-effects may be expected with the lowest dose needed to produce control of positive symptoms with the fewest extrapyramidal side-effects.⁽⁴^,⁴⁹⁾

There are some patients for whom higher doses are indicated, but most controlled studies have failed to find benefits from high-dose strategies of combining two or more of these agents. Increasing the dose of these agents when patients fail to respond rapidly, for example within days, is not recommended. Augmentation with a benzodiazepine may be useful to decrease anxiety until the lower doses of neuroleptic drugs produce adequate control of positive symptoms.⁽⁴^,⁴⁹⁾ Patients who may require higher doses of neuroleptic drugs to respond adequately are at greater risk of hyperprolactinaemic effects, EPS, and tardive dyskinesia and are generally better treated with an atypical antipsychotic drug.

However, the improvement in positive symptoms which is often achievable with the typical antipsychotic drug is only one element in the treatment of schizophrenia and is not sufficient grounds for judging response to be adequate. Additional efficacy factors of major importance are summarized in Table 6.2.5.6.

Tolerability and safety factors, such as compliance, tardive dyskinesia, weight gain, and medical morbidity are also major elements in outcome and are influenced by the choice of a typical or atypical antipsychotic drug. Typical neuroleptic drugs are not as effective for improving primary negative symptoms of schizophrenia in the majority of patients.⁽⁵²^,⁵³⁾ There is a consensus that typical neuroleptic drugs can improve negative symptoms that are secondary to positive symptoms and depression while at the same time possibly causing secondary negative symptoms due to their ability to produce extrapyramidal side-effects.⁽⁵²⁾ Abnormalities in specific domains of cognition (Table 6.2.5.6) are present in first-episode schizophrenic patients at a moderate to severe level and show slight to moderate, rarely severe, deterioration during the course of illness.⁽⁵⁴^,⁵⁵⁾ Approximately 85 per cent of patients with schizophrenia are clinically impaired in one or more domains of cognition.⁽⁵⁵^, ⁵⁾ Cognition has been shown to be perhaps the most critical determinant of functional capacity among patients with schizophrenia, even more so than positive symptoms.⁽⁵⁷⁾ Typical neuroleptic drugs usually do not improve cognitive function.⁽⁵⁸⁾ Those typical neuroleptic drugs such as thioridazine and mesoridazine, which have strong antimuscarinic properties, may produce further impairment in some memory functions.⁽⁵⁸⁾

All of the typical neuroleptic drugs are likely to be equally effective in treating either the initial presentation or recurrent psychosis due to breakthrough of symptoms, despite compliance, or because of having stopped medication⁽⁴^,⁴⁹^,⁵¹⁾ First-episode patients with schizophrenia usually require much lower doses than patients with two or more episodes, suggesting some progression of the disease process or development of tolerance to the mechanism of action of these drugs.⁽⁵⁹⁾ Doses for more chronic patients should be in the range of 5 to 10 mg haloperidol equivalents per day (Table 6.2.5.5) for up to 4 to 6 weeks unless there is a major need for chemical means to prevent harm to self or others, to decrease excitement, or induce sleep.⁽⁶⁰⁾ Auxiliary medications for anxiety and sleeplessness, for example benzodiazepines, may supplement these low doses of antipsychotics.⁽⁶¹⁾

Parenteral injections of haloperidol, chlorpromazine, or other neuroleptics may be needed for patients who refuse oral medication or where very rapid onset of action is needed to control acutely dangerous behaviours if less restrictive means either fail or cannot be utilized safely. Commonly, haloperidol (2-10 mg) with or without lorazepam (2-4 mg) is delivered intramuscularly every 30
to 60 minutes as required, up to three doses. Doses of haloperidol given intramuscularly in such situations generally should not exceed 18 mg per day. Oral medication should be substituted as soon as feasible. If positive symptoms fail to respond to a single trial of a typical neuroleptic drug at adequate doses in patients with schizophrenia, there is evidence that switching to another typical antipsychotic, even of a different chemical class, is unlikely to produce greater control.⁽⁴^,⁴⁹^,⁵¹⁾ This is likely to be true for other indications for the use of antipsychotic agents as well.

Table 6.2.5.5 Oral dosing of antipsychotic drugs

Typical antipsychotic drugs
	Equivalent doses (mg/day)	Starting dose	Titration schedule	Dose range (mg/day)
Chlorpromazine^a	100	15-50 mg BID-QID	As clinically indicated	300-1000 (divided QD-QID)
Fluphenazine^b	2	0.5-10 mg/day (divided Q6-8 hours)	As clinically indicated	5-20
Haloperidol^c	2	0.5-5 mg BID	As clinically indicated	5-20
Loxapine	10	10 mg BID	As clinically indicated	30-100
Mesoridazine	50			150-400
Molindone	10	50-75 mg/day divided TID-QID	As clinically indicated	30-100
Perphenazine^d	10	4-8 mg TID (8-16 mg BID-QID if hospitalized)	As clinically indicated	16-64
Thioridazine	100	50-100 mg TID	As clinically indicated	300-800
Tiotixene	5	2 mg TID	As clinically indicated	15-50
Trifluoperazine	5	2-5 mg BID	As clinically indicated	15-50
For elderly patients, or those with renal or hepatic problems, doses of drug may need to be reduced by one-half or more
^aShort-acting IM formulation may be given 25-50 mg (may repeat after 1-4 hrs as required); may gradually increase dose up to 400 mg IM Q 4-6 hrs (maximum of 2000 mg/day) may be needed for severe cases ^bShort-acting IM formulation may be given 2.5-10 mg/day in Q6-8 hr intervals; Depot IM formulation may be given 12.5-25 mg Q 3 weeks ^cShort-acting IM formulation may be given 2-5 mg Q 1-4 hrs; Depot IM formulation may be given at approximately 10-20 times the stable oral dose Q 4 weeks ^dShort-acting IM formulation may be given 5-10 mg Q 6 hrs (maximum of 30 mg/day)

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Tags: New Oxford Textbook of Psychiatry

Sep 9, 2016 | Posted by drzezo in PSYCHIATRY | Comments Off

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