Chapter 4
Schizophrenia and Psychosis

Psychosis is not an illness, but a name for a set of symptoms that often occur together, and for which the central characteristic is a major discrepancy between reality and an individual's perception of it. The most familiar symptoms of psychosis are hallucinations (false perceptions) and delusions (false beliefs). A common but less obvious symptom is anosognosia, or the disbelief that anything is wrong with the person's perceptions and thoughts.

Anosognosia greatly complicates the treatment of psychosis. Those whose illness is accompanied by anosognosia are likely to resist treatment that they believe is unnecessary, especially if they suffer from paranoia as well. The combination of anosognosia and paranoia can make treatment impossible, unless enforced involuntarily, on an in-patient basis.

The illness most closely associated with psychosis is schizophrenia, although psychosis can also result from the manic episodes of bipolar disorder, brain injuries, an episode of extreme stress, or psychoactive drugs.

Wikipedia defines psychosis by the following symptoms:

Hallucinations
A hallucination is defined as any sensory perception that is perceived in the absence of an external stimulus. Hallucinations are different from illusions, which are the misperception of external stimuli. Hallucinations may occur in any of the five senses and take on almost any form, which may include simple sensations (such as lights, colors, tastes, smells) to more meaningful experiences such as seeing and interacting with fully formed animals and people, hearing voices and complex tactile sensations.
Auditory hallucinations, particularly the experience of hearing voices, are a common and often prominent feature of psychosis. Hallucinated voices may talk about, or to the person, and may involve several speakers with distinct personas. Auditory hallucinations tend to be particularly distressing when they are derogatory, commanding or preoccupying. However, the experience of hearing voices need not always be a negative one. Research has shown that the majority of people who hear voices are not in need of psychiatric help. The Hearing Voices Movement has subsequently been created to support voice hearers, regardless of whether they are considered to have a mental illness or not.

Delusions and Paranoia
Psychosis may involve delusional or paranoid beliefs. Karl Jaspers classified psychotic delusions into primary and secondary types. Primary delusions are defined as arising out of the blue and not being comprehensible in terms of normal mental processes, whereas secondary delusions may be understood as being influenced by the person's background or current situation (e.g., ethnic or sexual discrimination, religious beliefs, superstitious belief).

Thought disorder
Formal thought disorder describes an underlying disturbance to conscious thought and is classified largely by its effects on speech and writing. Affected persons may show pressure of speech (speaking incessantly and quickly), derailment or flight of ideas (switching topic mid-sentence or inappropriately), thought blocking, and rhyming or punning.

Lack of insight
One important and puzzling feature of psychosis is usually an accompanying lack of insight into the unusual, strange, or bizarre nature of the person's experience or behaviour. Even in the case of an acute psychosis, sufferers may be completely unaware that their vivid hallucinations and impossible delusions are in any way unrealistic. This is not an absolute, however; insight can vary between individuals and throughout the duration of the psychotic episode.
It was previously believed that lack of insight was related to general cognitive dysfunction or to avoidant coping style. Later studies have found no statistical relationship between insight and cognitive function, either in groups of people who only have schizophrenia, or in groups of psychotic people from various diagnostic categories.
In some cases, particularly with auditory and visual hallucinations, the patient has good insight, which makes the psychotic experience even more terrifying because the patient realizes that he or she should not be hearing voices, but is.

Schizophrenia is a serious illness for which the dominant feature, as perceived by the general public, is psychosis. It is schizophrenia that the average person thinks of in connection with terms such as "crazy" or "insane." The Web site for NAMI, the National Alliance for Mental Illness, at www.nami.org, describes schizophrenia as follows:

What is schizophrenia?
Schizophrenia is a medical illness that affects approximately 2.2 million American adults, or 1.1 percent of the population age 18 and older. Schizophrenia interferes with a person's ability to think clearly, to distinguish reality from fantasy, to manage emotions, make decisions, and relate to others. The first signs of schizophrenia typically emerge in the teenage years or early twenties. Most people with schizophrenia suffer chronically or episodically throughout their lives, and are often stigmatized by lack of public understanding about the disease. Schizophrenia is not caused by bad parenting or personal weakness. A person with schizophrenia does not have a "split personality," and almost all people with schizophrenia are not dangerous or violent towards others when they are receiving treatment. The World Health Organization has identified schizophrenia as one of the ten most debilitating diseases affecting human beings.

What are the symptoms of schizophrenia?
No one symptom positively identifies schizophrenia. All of the symptoms of this illness can also be found in other brain disorders. For example psychotic symptoms may be caused by the use of drugs, may be present in individuals with Alzheimer's Disease, or may be characteristics of a manic episode in bipolar disorder. However, when a doctor sees the symptoms of schizophrenia and carefully asseses the history and the course of the illness over six months, he or she can almost always make a correct diagnosis.
The symptoms of schizophrenia are generally divided into three categories, including positive, disorganized, and negative symptoms.⁵

Positive Symptoms, or "psychotic" symptoms, include delusions and hallucinations because the patient has lost touch with reality in certain important ways. "Positive" as used here does not mean "good." Rather, it refers to having overt symptoms that should not be there. Delusions cause the patient to believe that people are reading their thoughts or plotting against them, that others are secretly monitoring and threatening them, or that they can control other people's minds. Hallucinations cause people to hear or see things that are not there.

Disorganized Symptoms include confused thinking and speech, and behavior that does not make sense. For example, people with schizophrenia sometimes have trouble communicating in coherent sentences or carrying on conversations with others; move more slowly, repeat rhythmic gestures or make movements such as walking in circles or pacing; and have difficulty making sense of everyday sights, sounds and feelings.

Negative Symptoms include emotional flatness or lack of expression, an inability to start and follow through with activities, speech that is brief and lacks content, and a lack of pleasure or interest in life. "Negative" does not, therefore, refer to a person's attitude, but to a lack of certain characteristics that should be there.

Schizophrenia is also associated with changes in cognition. These changes affect the ability to remember and to plan for achieving goals. Also, attention and motivation are diminished. The cognitive problems of schizophrenia may be important factors in long term outcome.
Schizophrenia also affects mood. Many individuals affected with schizophrenia become depressed, and some individuals also have apparent mood swings and even bipolar-like states. When mood instability is a major feature of the illness, it is called, schizoaffective disorder, meaning that elements of schizophrenia and mood disorders are prominently displayed by the same individual. It is not clear whether schizoaffective disorder is a distinct condition or simply a subtype of schizophrenia.

While the psychotic and cognitive problems attract the most attention, the negative symptoms of schizophrenia are truly crushing. The emotional flattening (blunted affect) and inability to feel pleasure (anhedonia) rob life of all value.

The treatment of schizophrenia and the treatment of psychosis are almost synonomous, and the medications prescribed for schizophrenia are known as antipsychotic medications, or antipsychotics. These same medications are often used to treat psychosis that arises from other conditions, most notably bipolar disorder. In fact, antipsychotic medications exert a mood-stabilizing effect that makes them effective for treating bipolar mania in general; however, their potential for serious side effects makes them generally less attractive than the standard mood stabilizers for this purpose.

Another, older term for antipsychotic that is often heard is neuroleptic, which means calming. Neuroleptic is less appropriate than antipsychotic, as other calming medications exist that work by different mechanisms than the antipsychotics. However, it is certainly the case that antipsychotic medications can be strongly tranquilizing. The tranquilizing effect varies widely between the different antipsychotics, and can be a benefit or drawback, depending on circumstances.

The challenge for treating schizophrenia lies in treating all categories of symptoms: psychosis, cognitive impairment, and negative symptoms, while at the same time avoiding undesirable side effects. The reality for people who have schizophrenia is that the ideal treatment usually does not happen, and they have to live with a compromise between benefits and drawbacks that is better than the untreated illness, but does not restore their quality of life to the norm.

This chapter will address treatments for schizophrenia and psychosis. The more general term of psychosis will be used with respect to the psychotic symptoms described above, and which may arise from disorders other than schizophrenia. The specific term of schizophrenia will be used only in connection with the illness of that name.

The two major categories of medications used to treat psychosis and schizophrenia are the typical antipsychotics and the atypical antipsychotics. The typical antipsychotics are older medications that have serious drawbacks, and are now seldom used for routine treatment of psychosis, although they are occasionally used for short-term treatment of anxiety or vomiting. The newer atypical antipsychotics are as effective at treating psychosis as the typical antipsychotics, while being less likely to have serious side effects. They also have the additional benefit of treating the negative symptoms of schizophrenia as well, restoring the capacity for emotion.

Because of their superior benefits and reduced drawbacks, the atypical antipsychotics are a major step forward in the treatment of schizophrenia and psychosis. However, they are still relatively dangerous drugs in comparison to medications used for other types of mental illness, such as depression, bipolar disorder, anxiety, and so forth. For this reason, they should be used with caution, and only when needed.

4.1 Causes of Schizophrenia and Psychosis

The causes of psychosis in general, and schizophrenia in particular, remain unknown. Psychotic symptoms can be induced temporarily by drugs, even in a healthy brain, so psychosis by itself probably can be explained in terms of abnormalities of brain chemistry. The illness of schizophrenia, however, is a permanent condition, and if the psychotic symtpoms manifest because of abnormalities in brain chemistry, then presumably the chemical abnormalities are themselves a manifestation of the illness. It seems likely, but has not been proven, that schizophrenia is ultimately a neurological problem, a set of symptoms resulting from damage or malformation of tissues in the brain, either congenital in nature, or caused by head injury or infection.

The following sections describe current theories about the neurochemistry of psychosis. Readers who are interested primarily in treatment, rather than causation, may wish to skip to the medication sections.

4.1.1 The Dopamine Hypothesis

The neurotransmitter dopamine plays the lead role in current theories regarding the neurochemical mechanisms responsible for psychosis. Many neurons in the brain send signals to adjacent neurons, from which they are separated by a synaptic gap, by emitting pulses of dopamine into the synaptic gap. Receptors on the receiving neuron are activated (register a signal) when dopamine molecules attach to them. While there are several dopamine receptors, the D₂ receptor is believed to play the most significant role in psychosis. (There are at least six dopamine receptors, currently labeled D₁, D_2a, D_2b, D₃, D₄, and D₅, of which D₃ and D₄ are subtypes of the more general category D₂.)

Primary evidence for the "dopamine hypothesis" for psychosis comes from the observation that all known effective antipsychotic medications are dopamine antagonists. More specifically, they block the D₂ dopamine receptor. (Each medication usually blocks other receptors, including dopamine receptors, as well, but the common theme among all antipsychotic medications is that all of them block the D₂ receptor.) For this reason, the primary chemical mechanism for treating psychosis is often referred to as "dopamine blockade." The effectiveness of antipsychotics in treating psychosis has led researchers to hypothesize that psychosis is at least partly a consequence of excess dopamine in certain parts of the brain.

The difficulty with treating psychosis, or schizophrenia, by stopping all dopamine-signal transmission (by blocking all dopamine receptors completely) is that it would "fix" the problem by removing the patient from the world of the living. Thus the difficulty faced by psychopharmacologists is to block enough of the undesirable dopamine signalling, while leaving the desirable signalling alone (or bolstering it, if not enough occurs). This is a tall order. The difficulty in achieving this goal is one reason that the current generation of antipsychotic medications, while helpful, is less than ideal in effectiveness. (Another reason is likely that psychosis, and certainly schizophrenia, involve more than the simplified picture of too much dopamine in some parts of the brain.)

4.1.2 The Four Dopamine Pathways

The brain, of course, is not a homogenous organ, but one that possesses a great deal of complexity. Different parts of the brain may respond quite differently to increases or decreases in neurotransmitter concentrations. This local variation in response is particularly important with regards to the treatment of psychosis and schizophrenia, which is tied to the function of four dopamine pathways in the brain.

A pathway is a bundle of nerve fibers that follow a particular path through the brain. The dopamine pathways are pathways for which dopamine-related signalling is especially important. As of this writing, four such dopamine pathways are known. The following sections describe the different dopamine pathways and their relationship to the symptoms of schizophrenia, as currently understood.

4.1.2.1 The Mesolimbic Dopamine Pathway

This pathway is believed to be involved in emotional disorders, delusions, thought disorders, and auditory hallucinations. Hyperactivity of the mesolimbic dopamine pathway is hypothesized to account for the positive symptoms of psychosis, and possibly hostility and excessive aggression as well. It is observed that reduction of dopamine-related signaling in this pathway by the blockade of D₂ receptors does lead to a decrease in the positive symptoms of psychosis.

4.1.2.2 The Mesocortical Dopamine Pathway

There is some evidence that some of the cognitive problems and negative symptoms of schizophrenia are due to an inadequate level of dopamine-related activity in this pathway. Assuming this is the case, it is not clear if the problem arises from low levels of dopamine, or damage to the neurons themselves (possibly due to poisoning from an excess of glutamate). If these hypotheses are correct, then increasing dopamine activity in this pathway could improve cognitive deficits and alleviate the negative symptoms.

4.1.2.3 The Nigrostriatal Dopamine Pathway

This pathway is part of the Extrapyramidal Nervous System. It controls motor movements. Dopamine deficiencies in this pathway produce movement problems (Extrapyramidal Symptoms, or EPS), such as Parkinson's disease. The types of movement problems caused by dopamine deficiencies include akinesia and bradykinesia (lack, or slowing, of movement, respectively), rigidity, tremor, akathisia (restlessness), and dystonia (twisting movements, especially of the face and neck).

Unfortunately, antipsychotic medications that blockade the D₂ receptor in this pathway can produce these movement disorders. If the D₂ blockade continues for an extended period of time, permanent dystonia (which continues even after the medication is stopped) can set in, a condition known as Tardive Dyskinesia.

It is believed that an excess of dopamine in this pathway causes hyperkinetic disorders, such as chorea, dyskinesias, and tics.

4.1.2.4 The Tuberoinfundibular Dopamine Pathway

Dopamine-related activity in this pathway inhibits prolactin release. Not surprisingly, pregnancy and childbirth lead to a reduction of dopamine activity in this pathway, thus increasing prolactin levels, and causing lactation, thus enabling breastfeeding. Undesirable dopamine reductions in this pathway (due to lesions or drugs) will also lead to prolactin increase (hyperprolactinemia), and can cause a variety of problems, such as galactorrhea (breast secretions), amenorrhea, and sexual dysfunction.

Conversely, increasing dopamine activity in this pathway acts to reduce prolactin levels, increase libido, and alleviate sexual dysfunction (see Chapter 5).

Once again, the undesirable consequences of dopamine suppression can occur as a result of antipsychotic medications that blockade dopamine in this area.

4.2 Treatments for Schizophrenia

The symptoms of schizophrenia (and psychosis) can only be alleviated by medical treatment. Therapy alone cannot address the underlying causes, which are neurological in origin. This is in contrast to the case of depression, as some instances of depression arise purely from factors within the capability of the individual to change, with help from a therapist. However, therapy does have a role to play in the overall management of schizophrenia. A good therapist can help a patient develop improved coping strategies for dealing with the illness. This is more important than it might sound, as the delusions and hallucinations severely distort the patient's capacity for judgment. A therapist's input can be of great value, as long as the patient is willing to work with the therapist, and take his input seriously. Unfortunately, the distortion of judgment characteristic of the psychotic experience (especially the anosognosia) may make it impossible for the patient to take the therapist seriously, or see him as other than a hostile and controlling influence.

The only technique, other than medication, that has been found to be effective in treating schizophrenia is that of electroconvulsive therapy, or ECT. This technique, which is described in Section 1.7.2, deserves careful consideration. Rightly or wrongly, ECT is often considered risky as a treatment for mental illness, but the medications used to treat schizophrenia are themselves considerably more dangerous than those used for, say, depression or bipolar disorder. The perceived risks of ECT may look more acceptable when compared to those of antipsychotic medications.

The experimental treatments described in Section 1.8 may be of interest as well, although they have not yet been demonstrated to be effective for schizophrenia.

The standard treatment for schizophrenia, and psychosis in general, is the use of antipsychotic medications, which are described in detail in the following sections.

Finally, one question that is seldom asked is whether schizophrenia should be treated. The question is not as simple it sounds, as the drawbacks of antipsychotic medications can be severe. Those with mild cases of shizophrenia, who are able to recognize and refuse to respond to (if not eliminate) illusory voices, may be better off developing coping strategies that allow them to function normally in the world, rather than taking antipsychotic medication. The patient and physician should consider the relative merits of medical treatment versus coping strategies, and make an educated decision as to which is most appropriate for the patient, instead of assuming that antipsychotic medication is always appropriate.

Similarly, those whose psychotic experiences are episodic, and who have the self-awareness to recognize when an episode is beginning, might choose to take (or increase their dose of) antipsychotic medication for the duration of the episode, instead of on a continuing basis.

4.3 The Dangers of Antipsychotic Medications

Compared to other categories of psychotropic medications, antipsychotic medications are the most dangerous. The possible dangers should not deter those who truly need antipsychotics from taking them, as the untreated illness is itself a very serious problem, but these medications should not be taken by those who have viable alternatives. The author is disturbed at the growing tendency to prescribe even the less dangerous atypical antipsychotics for the treatment of bipolar disorder and depression, when safer mood stabilizers and antidepressants are available.

While all psychotropic medications have undesirable side effects, even dangerous ones, the dangers of antipsychotics are uniquely troubling. The more noteworthy drawbacks are discussed below. The most serious threats to health (in terms of likelihood and severity) are Tardive Dyskinesia and Diabetes, both of which are incurable. Also of concern are the rarer possibilities of sudden death due to Neuroleptic Malignant Syndrome and QT Prolongation.

4.3.1 Tardive Dyskinesia

Tardive Dyskinesia (TD) is a disorder characterized by involuntary movements of the tongue, lips, face, upper body, and extremities.⁶ Although the condition can occur naturally (albeit rarely), it most often occurs as a result of treatment with antipsychotic medications, and can arise from exposure to anticholinergic medications, toxins, illegal drugs, and other dangerous chemicals. Someone who has TD exhibits almost constant involuntary motions such as grimacing, smacking or pursing the lips, and protruding the tongue. Rapid movements of the eyelids (blinking), arms, legs, and upper body are also common, as are impairments to the movement of the hands and fingers. The condition is exceedingly distressing to the person who has it. Part of the distress comes from the condition itself, and part comes from the recoil of others who are appalled by the person's constant and involuntary writhing.

Exactly how antipsychotic medications cause TD is not known. It is clear that dopamine blockade is the ultimate cause, but how dopamine blockade leads to TD is not. Various mechanisms have been proposed, all of which involve modification of dopamine signalling mechanisms in the brain, or damage to brain tissue.

TD is treated by discontinuing or reducing the offending medication. The condition may persist for months or years after the medication is withdrawn, or even be permanent. Aside from medication change, the condition is incurable, and essentially untreatable. A variety of medications have produced ambiguous evidence for some symptomatic relief, including the atypical antipsychotic Clozapine, and benzodiazepines such as Clonazepam.

The extent to which people taking antipsychotic medications will develop TD is unclear, but substantial. There is some evidence to indicate that certain drugs (Haloperidol) are worse than others (Perphenazine), with the atypical antipsychotics being less likely to cause the condition than the typical antipsychotics. Aside from the variation among drugs, some estimates suggest that 15-30% of patients will develop TD on taking antipsychotics for three months or longer, while others suggest that each year of use increases the fraction of a treated population experiencing TD by 5%. The latter estimate in essence states that most people who use antipsychotics over the course of ten or more years will develop TD.

See www.emedicine.com and en.wikipedia.org/wiki/Tardive_dyskinesia for more details regarding Tardive Dyskinesia.

4.3.2 Diabetes

The atypical antipsychotics are thought to have lesser risks of some serious side effects, such as Tardive Dyskinesia or Neuroleptic Malignant Syndrome, and generally have fewer of the less dangerous side effects, as well as providing greater effectiveness at treating both the positive and negative symptoms of schizophrenia. So it comes as something of a surprise to find that they can cause diabetes, a condition not associated with the otherwise more dangerous typical antipsychotics.

The risk of diabetes appears significantly higher with the atypical antipsychotics, especially Clozapine and Olanzapine. One study indicated that 36% of patients treated with Clozapine developed diabetes over a five-year period.

As of this writing, evidence is ambiguous regarding the risk for Risperidone and Quetiapine. Ziprasidone and Aripiprazole are new enough that little information is available, but clinical trial data (pn.psychiatryonline.org/cgi/content/full/39/5/1-a) shows no evidence for diabetes risk at this time. It is likely that the risk varies among the atypical antipsychotics, but insufficient information is available to make an informed assessment at this time. Prudence suggests avoiding Clozapine and Olanzapine in favor of other atypical antipsychotics, and working with a physician to be alert for early warning signs of diabetes.

The mechanism by which these medications lead to diabetes is not known.

4.3.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS) is a rare, but life threatening reaction to antipsychotic medication, consisting of fever, muscular rigidity, altered mental status, and dysfunction of the autonomic nervous system (see www.emedicine.com). It appears to be caused by blockade of the dopamine D₂ receptor in the hypothalamus, nigrostriatal pathway, and spinal cord, which leads to increased muscle rigidity, muscle-cell breakdown, muscle-tissue death and necrosis, tremor, elevated temperature, and dysfunction of the autonomic nervous system. This condition has only been observed in response to the use of antipsychotic medications. Atypical antipsychotics are less likely to produce this condition than the older typical antipsychotics, but the condition can occur with atypical antipsychotics.

The primary treatment of NMS is discontinuation of the antipsychotic medication, combined with supportive measures to alleviate the symptoms. The survival rate is at least 80%, and probably much higher. Unfortunately, resumption of antipsychotic medication is usually a necessity for the patient, in order to treat the original illness, but risks recurrence of NMS. The chance of recurrence can be decreased to below 30% by waiting more than two weeks before resuming the medication, and by switching to a different class of antipsychotic medication (one of the atypical antipsychotics).

Early warning signs that NMS may be developing include rigidity, fever, and changes of consciousness. The patient, family, and friends should be alert to any such signs, and report them to the patient's physician immediately.

4.3.4 QT Prolongation

QT Prolongation is an abnormal lengthening of the QT interval, which is the duration of the electrical activity that controls contraction of the heart muscle. This type of lengthening can occur due to an inherited medical condition (the Congenital Long QT syndrome) or in response to chemistry (medications, or abnormal levels of potassium, magnesium, and so forth). If the QT interval is prolonged too far beyond the norm, it can lead to a type of cardiac arrhythmia (heart malfunction) called Torsades de Pointes, a condition that can cause fainting or sudden death. (See the Arizona CERT Web site at www.arizonacert.org for details.)

Although many medications can cause some prolongation of the QT interval, the typical antipsychotic medications are among the worst offenders. Less is known about the risk of QT prolongation for the atypical antipsychotics, as they are of relatively recent origin, but they should be considered potentially dangerous, though probably less so than the typical antipsychotics.

The symptom of QT prolongation is heart palpitation, i.e., any obvious variation in rhythm or intensity of the heartbeat that is not due to normal causes, such as exercise or strong emotion. Anyone taking a medication known to cause serious QT prolongation should have an EKG test when experiencing an episode of heart palpitation. It is important to perform the EKG during the palpitation episode, which may require advance planning and coordination with your doctor, or even the use of portable heart monitors, if you tend to have short episodes. The EKG test can show whether the palpitations are due to QT prolongation or some other cause, and whether or not they are dangerous. If the EKG test does show significant QT prolongation, you may need to change medications.

4.4 Typical Antipsychotics

The typical antipsychotics are the first-generation treatments for schizophrenia and psychosis. The first typical antipsychotic discovered, in the 1950s, was Chlorpromazine. Many other antipsychotic drugs with similar mechanisms, and with a variety of chemical structures, were discovered in the next few decades. They have largely been replaced by the second-generation, atypical antipsychotics, for these purposes, but remain useful for emergency sedation in cases of severe psychotic episodes, and for uses unrelated to psychosis, such as treatment for severe vomiting, pre-surgical anxiety, Tourette's Disorder, and even hiccups.

4.4.1 Mechanism

The typical antipsychotics work by blocking the dopamine D₂ receptors, a mechanism referred to as dopamine blockade. The blockade occurs throughout the brain, affecting all four dopamine pathways. This indiscriminate blockade not only suppresses psychotic symptoms through its effects on the mesolimbic dopamine pathway (Section 4.1.2.1), but also causes a variety of unpleasant symptoms due to blockading the other dopamine pathways as well (Section 4.1.2).

4.4.2 Benefits

The primary purpose for which these medications were devised is to suppress psychotic symptoms, and they do this with reasonable effectiveness. Their waning use as standard treatments for psychosis and schizophrenia has resulted in greater emphasis on their use in other areas, such as treatment for severe vomiting, pre-surgical anxiety, Tourette's Disorder, and hiccups.

4.4.3 Principal Drawbacks

The drawbacks of chronic use of typical antipsychotics are many. The most serious drawbacks are discussed in Section 4.3, namely Tardive Dyskinesia, Neuroleptic Malignant Syndrome, and QT Prolongation.

Dopamine blockade also produces a variety of movement disorders, namely the Extrapyramidal Symptoms (EPS). Tardive Dyskinesia is one particularly severe type of EPS. Others include Parkinsonism, Dystonia, and Akathisia.

Parkinsonism: is characterized by muscular rigidity, tremor, and impaired motor control (i.e., difficulty grasping and manipulating objects, walking in a straight line, and so forth).
Dystonia: refers to any sustained and involuntary contraction of the muscles, which leads to twisted and distorted posture.
Akathisia: refers to motor restlessness, including quivering and an inability to sit still. In severe cases, akathisia makes resting and sleeping impossible.

EPS symptoms are often treated with beta blockers, benzodiazepines, and anticholinergic medications such as Benztropine, Trihexyphenidyl, and Diphenhydramine (a common, non-prescription allergy medicine, often sold under the name Benadryl).

The dopamine blockade also suppresses positive emotions, leading to anhedonia. (This is a particular and serious problem for people who have schizophrenia, as they are usually troubled by flattened affect to begin with.) Other effects include cognitive impairment (impaired capacity to think and concentrate). In fact, many of the side effects of typical antipsychotics are essentially the same as the negative symptoms of schizophrenia itself, which are exacerbated by the typical antipsychotics.

Other side effects are due to additional blockades, specifically of the muscarinic-cholinergic (M₁), Alpha 1 adrenergic (a₁), and histamine (H₁) receptors. These three mechanisms are also characteristic of the tricyclic antidepressants (TCAs), and are just as undesirable for antipsychotic medications.

The M₁ blockade: can cause dry mouth, blurred vision, constipation, and cognitive impairment.
The Alpha 1 (a₁) blockade: can cause orthostatic hypotension (low blood pressure on standing) and drowsiness.
The H₁ blockade: can cause weight gain and drowsiness typical of antihistamine medications.

The undesirable side effects of typical antipsychotics are distressing at best, and crippling, dangerous, or even fatal at worst. The side effects are so serious that many patients have understandably chosen to skip the medication, and suffer the effects of psychosis as the lesser of two evils.

Danger! Chlorpromazine, Droperidol, Haloperidol, Mesoridazine, Pimozide, Thioridazine, and Zotepine have the highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level are believed to cause QT Prolongation. Medications with lower risk are preferred, and required for anyone who has Long QT Syndrome. If you cannot substitute a medication with lower risk, be alert for heart palpitations. If you experience palpitations, report them to your doctor immediately.

4.4.4 Medications

The largest family of typical antipsychotics is the Phenothiazine family.

Main Brand Name	Chemical Name	Chemical Type	Half Life	Washout Time	On-Label Uses	Off-Label Uses
Compazine	Prochlorperazine	Phenothiazine	6 hours	2 days	Schizophrenia (psychosis); anxiety (non-psychotic); vomiting
Mellaril	Thioridazine	Phenothiazine	23 hours	5 days	Schizophrenia (psychosis)
Prolixin Injection	Fluphenazine Decanoate	Phenothiazine	8 hours	40 days	Schizophrenia (psychosis)
Serentil	Mesoridazine	Phenothiazine	2 days	10 days	Schizophrenia (psychosis)
Sparine	Promazine	Phenothiazine	6 hours	30 hours	Schizophrenia (psychosis)
Stelazine	Trifluoperazine	Phenothiazine	22 hours	5 days	Schizophrenia (psychosis); anxiety (non-psychotic)
Thorazine	Chlorpromazine	Phenothiazine	30 hours	6 days	Schizophrenia (psychosis); vomiting; anxiety (pre-surgical); Porphyria; Tetanus (adjunctive); Bipolar Disorder (Manic phase); Hiccups; explosive hyperexcitability in children; hyperactivity in children	anxiety (used as a sedative)
Trilafon	Perphenazine	Phenothiazine	12 hours	3 days	Schizophrenia (psychosis); vomiting

The second largest family of typical antipsychotics is the Thioxanthene family.

Main Brand Name	Chemical Name	Chemical Type	Half Life	Washout Time	On-Label Uses	Off-Label Uses
Depixol	Flupenthixol	Thioxanthene	35 hours	7 days	Schizophrenia (psychosis)
Navane	Thiothixene	Thioxanthene	30 hours	6 days	Schizophrenia (psychosis)
Truxal	Chlorprothixene	Thioxanthene	10 hours	2 days	Schizophrenia (psychosis); Bipolar Disorder (Manic phase)

The remaining typical antipsychotics are all one-of-a-kind medications.

Main Brand Name	Chemical Name	Chemical Type	Half Life	Washout Time	On-Label Uses	Off-Label Uses
Haldol	Haloperidol	Butyrophenone	21 hours	5 days	Schizophrenia (psychosis); Tourette's Disorder; explosive hyperexcitability in children; hyperactivity in children
Haldol Decanoate	Haloperidol Decanoate	Butyrophenone	3 weeks	15 weeks	Schizophrenia (psychosis)
Loxitane	Loxapine	Dibenzoxazepine	4 hours	1 day	Schizophrenia (psychosis)
Moban	Molindone	Dihydroindolone	90 minutes	8 hours	Schizophrenia (psychosis)

It is worth noting that some medications in the above chemical families, which have the standard antipsychotic mechanisms, are not approved by the Food and Drug Administration (FDA) for schizophrenia. They are used for conditions such as vomiting, anxiety, and Tourette's Disorder.

Medications approved for the control of severe vomiting, or prevention of vomiting in surgical procedures (anti-emetics), include the following:

Main Brand Name	Chemical Name	Chemical Type	Half Life	Washout Time	On-Label Uses	Off-Label Uses
Inapsine	Droperidol	Thioxanthene	2 hours	10 hours	vomiting (in surgical and diagnostic procedures)	anxiety (used as a sedative)

Finally, Tourette's Disorder may be treated by the following:

Main Brand Name	Chemical Name	Chemical Type	Half Life	Washout Time	On-Label Uses	Off-Label Uses
Haldol	Haloperidol	Butyrophenone	21 hours	5 days	Schizophrenia (psychosis); Tourette's Disorder; explosive hyperexcitability in children; hyperactivity in children
Orap	Pimozide	Diphenylbutylpiperidine	55 hours	11 days	Tourette's Disorder

4.4.5 Brand Names

Phenothiazine Antipsychotics

Chemical Name	Brand Names (Principal in Bold)
Chlorpromazine	Thorazine, Aminazin, Aminazine, Ampliactil, Chlordelazin, Chlorderazin, Chlorpromados, Chlorpromanyl, Contomin, CPZ, Fenactil, Fenaktyl, Largactil, Novo-Chlorpromazine, Torazina
Fluphenazine Decanoate	Prolixin Injection, Anatensol, Apo-Fluphenazine, Elinol, Fluorfenazine, Fluorophenazine, Fluorphenazine, Modecate, Moditen, Moditen Enanthate, Moditen Hcl, Omca, Pacinol, Permitil, Perphenazine, Pms Fluphenazine, Prolixin Decanoate, Prolixin Enanthate, Prolixine, Sevinol, Siqualine, Siqualon, Tensofin, Triflumethazine, Valamina, Vespazine, Yespazine
Mesoridazine	Serentil, Calodal, Lidanar, Lidanil, TPS-23, Thioridazien Thiomethyl Sulfoxide, Thioridazine Monosulfoxide Analog, Thioridazine Thiomethyl Sulfoxide, TPS23
Perphenazine	Trilafon, Apo-Perphenazine, Apo Peram Tab, Chlorperphenazine, Decentan, Elavil Plus Tab, Emesinal, Etaperazin, Etaperazine, Ethaperazine, Etrafon, Etrafon-A, Etrafon-Forte, F-Mon, Fentazin, Fluphenazine, PZC, Perfenazina, Perfenazine, Perphenan, Perphenazin, Pms-Levazine, Pms Perphenazine, Proavil, Thilatazin, Tranquisan, Triavil, Trifaron, Trilifan, Triphenot
Prochlorperazine	Compazine, Bayer A 173, Buccastem, Capazine, Chlormeprazine, Chlorperazine, Combid, Compro, Emelent, Emetiral, Eskatrol, Kronocin, Meterazin, Meterazin Maleate, Meterazine, Nipodal, Novamin, Pasotomin, Prochloroperazine, Prochlorpemazine, Prochlorperazin, Prochlorperazine edisylate, Prochlorperazine maleate, Prochlorpromazine, Procloperazine, Proclorperazine, Stemetil, Tementil, Temetid, Vertigon
Promazine	Sparine, AB, Ampazine, Berophen, Elmarin, Esmind, Esparin, Fraction, Liranol, Megaphen, Neo-Hibernex, Novomazina, Phenothiazine, Prazin, Prazine, Proma, Promactil, Promapar, Promazil, Promazin, Promazina, Promwill, Propaphenin, Protactyl, Prozil, Psychozine, Romtiazin, Sanopron, Sinophenin, Sonazine, Tomil, Verophen, Vesprin, Wintermin
Thioridazine	Mellaril, Aldazine, Mallorol, Malloryl, Meleril, Mellaril-S, Mellarit, Mellerets, Mellerette, Melleretten, Melleril, Metlaril, Novoridazine, Orsanil, Ridazin, Ridazine, Sonapax, Stalleril, Thioridazin, Prolongatum, Thioridazinhydrochlorid, Thoridazine Hydrochloride, Tioridazin, Usaf Sz-3, Usaf Sz-B
Trifluoperazine	Stelazine, Apo-Trifluoperazine, Eskazine, Eskazinyl, Fluoperazine, Jatroneural, Modalina, Novo-Trifluzine, PMS Trifluoperazine, Stellazine, Synklor, Terfluzine, Trazine, Trifluoperazin, Trifluoperazina, Trifluoromethylperazine, Trifluoroperazine, Trifluperazine, Triflurin, Trifluroperizine, Triftazin, Triftazine, Triperazine, Triphtazin, Triphtazine, Triphthasine, Triphthazine, Tryptazine

Thioxanthene Antipsychotics

Chemical Name	Brand Names (Principal in Bold)
Chlorprothixene	Truxal, Alpha-Chlorprothixene, CPT, CPX, Chloroprothixene, Chlorprothixen, Chlorprothixine, Chlorprotixen, Chlorprotixene, Chlorprotixine, Chlothixen, Cis-Chlorprothixene, Iaractan, Paxyl, Rentovet, Tactaran, Taractan, Tarasan, Tardan, Tranquilan, Traquilan, Trictal, Truxaletten, Truxil, Vetacalm
Flupenthixol	Depixol, Depixol, Emergil, Fluanxol, Fluanxol Depot, Flupenthixole, Flupentixol, Flurentixol, Fluxanxol, Siplaril, Siplarol
Thiothixene	Navane

Miscellaneous Antipsychotics

Chemical Name	Brand Names (Principal in Bold)
Haloperidol	Haldol, ALDO, Aloperidin, Aloperidol, Aloperidolo, Aloperidon, Apo-Haloperidol, Bioperidolo, Brotopon, Dozic, Dozix, Einalon S, Eukystol, Galoperidol, Haldol Decanoate, Haldol La, Haldol Solutab, Halidol, Halojust, Halol, Halopal, Haloperido, Haloperidol Intensol, Halopidol, Halopoidol, Halosten, Keselan, Lealgin Compositum, Linton, Mixidol, Novo-Peridol, Pekuces, Peluces, Peridol, Pernox, Pms Haloperidol, Serenace, Serenase, Serenelfi, Sernas, Sernel, Sigaperidol, Ulcolind, Uliolind, Vesalium
Haloperidol Decanoate	Haldol Decanoate
Loxapine	Loxitane, Cloxazepine, Dibenzacepin, Dibenzoazepine, Hydrofluoride 3170, Lossapina, Loxapac, Loxapin, Loxapina, Loxapine Succinate, Loxapinum, Loxepine, Loxitane C, Loxitane Im, Oxilapine
Molindone	Moban, Lidone

Anti-Emetics (for control of vomiting)

Chemical Name	Brand Names (Principal in Bold)
Droperidol	Inapsine, DHBP, Dehidrobenzperidol, Dehydrobenzperidol, Deidrobenzperidolo, Dihidrobenzperidol, Dridol, Droleptan, Halkan, Inappin, Inapsin, Innovan, Innovar, Innovar-Vet, Inopsin, Inoval, Leptanal, Leptofen, McN-JR 749, Properidol, Sintodril, Sintosian, Thalamonal, Thalamanol, Vetkalm

Tourette's Disorder Medication

Chemical Name	Brand Names (Principal in Bold)
Haloperidol	Haldol, ALDO, Aloperidin, Aloperidol, Aloperidolo, Aloperidon, Apo-Haloperidol, Bioperidolo, Brotopon, Dozic, Dozix, Einalon S, Eukystol, Galoperidol, Haldol Decanoate, Haldol La, Haldol Solutab, Halidol, Halojust, Halol, Halopal, Haloperido, Haloperidol Intensol, Halopidol, Halopoidol, Halosten, Keselan, Lealgin Compositum, Linton, Mixidol, Novo-Peridol, Pekuces, Peluces, Peridol, Pernox, Pms Haloperidol, Serenace, Serenase, Serenelfi, Sernas, Sernel, Sigaperidol, Ulcolind, Uliolind, Vesalium
Pimozide	Orap, Haldol decanoate, Halomonth, Neoperidole, Opiran, Pimozidum, Primozida

4.5 Atypical Antipsychotics

The atypical antipsychotics are the second-generation treatments for psychosis and schizophrenia. The first atypical antipsychotic discovered, in the 1960s, was Clozapine, which received approval by the Food and Drug Administration (FDA) for use in treating schizophrenia in 1989. Several other atypical antipsychotics followed. Although the number of atypical antipsychotics available at this time is much smaller than the number of typical antipsychotics, these newer medications exhibit such improved effectiveness and decrease in undesirable side effects that they have largely replaced the older typical antipsychotics for the treatment of psychosis.

4.5.1 Mechanism

The standard mechanism for the atypical antipsychotics is a combination of serotonin and dopamine blockade; more specifically, blockade of both serotonin 2A and dopamine D₂ receptors. Many dopamine-producing neurons have serotonin 2A receptors. Their output of dopamine is regulated by signals from their serotonin receptors, with higher serotonin concentration leading to lower dopamine output. The serotonin blockade reduces the serotonin signal, and results in higher dopamine output, while the dopamine blockade suppresses dopamine signalling by blocking dopamine receptors. The two blockades are therefore at odds, simultaneously increasing dopamine concentration and decreasing dopamine effectiveness.

The odd opposition of effects plays out differently among the four dopamine pathways. The net effect, on average, is to reduce dopamine signalling in the mesolimbic dopamine pathway, increase dopamine signalling in the mesocortical and nigrostiratal dopamine pathways, and to fight roughly to a draw in the tuberoinfundibular dopamine pathway.

In more detail, the effects are as follows:

In the Mesolimbic Dopamine Pathway,: the serotonin antagonism loses to the dopamine antagonism. The dopamine D₂ blockade successfully suppresses positive psychotic symptoms, just as the typical antipsychotics do.
In the Mesocortical Dopamine Pathway,: the serotonin antagonism wins quite strongly over the dopamine antagonism, causing a net increase in dopamine activity. Not only does the increase in dopamine activity prevent undesirable side effects of dopamine blockade, but can actually improve the negative symptoms of psychosis, restoring the lost capacity for emotion and pleasure.
In the Nigrostriatal Dopamine Pathway,: the serotonin antagonism wins over the dopamine antagonism, increasing the amount of dopamine available (relative to what a typical antipsychotic would do), and thus reducing the danger or severity of Extrapyramidal symptoms (including tardive dyskinesia).
In the Tuberoinfundibular Dopamine Pathway,: the effects of the simultaneous serotonin and dopamine blockade on prolactin release are mixed. The dopamine blockade acts to increase prolactin, while the serotonin blockade acts, separately, to decrease prolactin. The net effect is that prolactin release is reduced relative to the typical antipsychotics. Compared to the case where no antipsychotic medication is used, the atypical antipsychotics may or may not reduce prolactin emission. The net effect on libido may be positive, negative, or insignificant.

The antipsychotic medication Amisulpride is an exception to the above pattern. It has the reduced side-effect profile of the atpyical antipsychotics, and is therefore categorized with them in terms of its effectiveness, but its mechanism is different. Amisulpride blockades the post-synaptic dopamine D₂ receptor, as do the other atypical antipsychotics, but has no effect on serotonin receptors. At the same time, it blockades D₂ and D₃ pre-synaptic receptors that also regulate dopamine production, causing an increase in dopamine production. Thus Amisulpride demonstrates an alternate approach to the combination of dopamine D₂ blockade and increased dopamine emission, relative to the other atypical antipsychotic medications.

Paliperodine is also the major active metabolite of risperidone, another antipsychotic medication, and thus its effects should be very similar to those of risperidone.

4.5.2 Benefits

These medications suppress psychotic symptoms with reasonable effectiveness. Unlike the typical antipsychotics, the atypical antipsychotics can alleviate the negative symptoms of schizophrenia as well, improving, rather than suppressing, the capacities to think and feel emotion, which is a tremendous benefit. Also unlike the typical antipsychotics, the atypical antipsychotics have less propensity to cause Neuroleptic Malignant Syndrome and extrapyramidal symptoms (movement disorders), including Tardive Dyskinesia.

Paliperodine may have fewer side effects than risperidone, but evidence is too limited to make a definitive statement.

4.5.3 Principal Drawbacks

Unfortunately, the atypical antipsychotics can cause diabetes, something not observed with the older typical antipsychotics (see Section 4.3.2). Also, while the atypical antipsychotics are less likely to exhibit the undesirable side effects of the older typical antipsychotics, less likely does not mean never. Thus all of the drawbacks of the typical antipsychotics described in Section 4.4.3 remain for the atypical antipsychotics as well, but with generally lesser frequency and severity.

It is safe to say that the atypical antipsychotics represent a major step forward in the treatment of psychosis and schizophrenia, but still fall well short of the ideal.

Warning! Clozapine, Quetiapine, Risperidone, and Ziprasidone have the second-highest risk level (of four) for causing QT Prolongation and serious abnormalities of heart rhythm. Medications at this risk level have been associated with QT Prolongation, but not proven to cause it. The risk for QT Prolongation is not considered high, but medications with lower risk are preferred, especially for anyone who has Long QT Syndrome. If you cannot substitute a medication with lower risk, be alert for heart palpitations. If you experience palpitations, report them to your doctor immediately.

4.5.4 Medications

Main Brand Name	Chemical Name	Chemical Type	Half Life	Washout Time	On-Label Uses	Off-Label Uses
Abilify	Aripiprazole	Benzisoxazole	4 days	20 days	Schizophrenia (psychosis)
Clozaril	Clozapine		12 hours	3 days	Schizophrenia (psychosis), treatment-resistant; suicidal behavior
Dolmatil	Sulpiride	Benzamide	8 hours	2 days	Schizophrenia (psychosis)
Geodon	Ziprasidone	Benzisoxazole	7 hours	35 hours	Schizophrenia (psychosis); Bipolar Disorder (Manic phase); agitation in schizophrenic patients
Invega	Paliperidone	Benzisoxazole	1 day	5 days	Schizophrenia (psychosis)
Risperdal	Risperidone	Benzisoxazole	20 hours	4 days	Schizophrenia (psychosis); Bipolar Disorder (Manic phase)	Asperger's Syndrome; Autism; Depression (psychotic)
Serdolect	Sertindole		3 days	15 days	Schizophrenia (psychosis)
Seroquel	Quetiapine	Benzisoxazole	6 hours	30 hours	Schizophrenia (psychosis); Bipolar Disorder (Manic and Depressive phases)
Solian	Amisulpride	Benzamide	12 hours	3 days	Schizophrenia (psychosis)
Zoleptil	Zotepine	Dibenzothiepine	15 hours	3 days	None (Investigational)	Schizophrenia (psychosis)
Zyprexa	Olanzapine		30 hours	6 days	Schizophrenia (psychosis); Bipolar Disorder (Manic phase)	Obsessive-Compulsive Disorder; Autism (for behavioral disorders)

4.5.5 Brand Names

Chemical Name	Brand Names (Principal in Bold)
Amisulpride	Solian
Aripiprazole	Abilify, Abilitat, OPC 31
Clozapine	Clozaril, Asaleptin, Clozapin, Fazaclo ODT, Iprox, Leponex, Lepotex
Olanzapine	Zyprexa, Olansek, Symbyax, Zydis, Zyprexa Intramuscular, Zyprexa Zydis
Paliperidone	Invega
Quetiapine	Seroquel, Quetiapin hemifumarate, Quetiapine fumarate, Quetiapine hemifumarate
Risperidone	Risperdal, Risperdal Consta, Risperdal M-Tab, Risperidal M-Tab, Risperidona, Risperidonum, Risperin, Rispolept, Rispolin, Sequinan
Sertindole	Serdolect
Sulpiride	Dolmatil, Abilit, Aiglonyl, Alimoral, Calmoflorine, Championyl, Coolspan, Darleton, Desmenat, Dobren, Dogmatil, Dogmatyl, Dresent, Eclorion, Eglonil, Eglonyl, Enimon, Equilid, Eusulpid, Fardalan, Fidelan, Guastil, Isnamide, Kylistro, Levobren, Levopraid, Levosulpirida, Levosulpiride, Levosulpiridum, Lisopiride, Mariastel, Meresa, Miradol, Mirbanil, Misulvan, Neogama, Norestran, Normum, Nufarol, Omiryl, Omperan, Ozoderpin, Psicocen, Pyrikappl, Pyrkappl, Restful, Sernevin, Splotin, Stamonevrol, Sulpirid, Sulpirida, Sulpiridum, Sulpitil, Sulpride, Sulpyrid, Suprium, Sursumid, Synedil, Trilan, Valirem, Zemorcon
Ziprasidone	Geodon, Zeldox
Zotepine	Zoleptil

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Chapter 4 Schizophrenia and Psychosis