Šizofrenija
Šizofrenija
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DOI: 10.4324/9781315152806
Prefacexi
1 What is and is not schizophrenia? 1
2 Assessment of schizophrenia 9
3 Social determinants of health affecting assessment 25
4 Schizophrenia, spirituality and religion 33
5 Putting together the (clinical) pieces 37
6 Talking to patients and families 47
7 Early intervention and prevention for schizophrenia 59
8 Managing symptoms and preventing relapse:
Pharmacological approach 65
9 Psychosocial approaches to improve symptoms
and functional outcomes 77
10 Managing treatment-related complications 91
11 Suboptimal treatment response 99
12 Medication nonadherence 109
13 Managing decompensation and relapse 121
14 Suicide and violence 129
15 Achieving recovery 135
16 History of schizophrenia 143
17 Who gets schizophrenia and why? 149
x Contents
Matcheri S. Keshavan MD
Vinod H. Srihari MD
Ravinder Reddy MD
chapter 1
The term ‘schizophrenia’ was coined almost a century ago by the Swiss
psychiatrist Eugen Bleuler. Because of a long tradition of scientific terms
being derived from Greek, Bleuler combined σχιζω (schizo, split or divide)
and φρενοζ (phrenos, mind) to capture a split between the different ‘psychic
functions’ of perception, thinking and feeling. Schizophrenia does not refer
to a split personality.
Before considering what schizophrenia is, it is important to grasp the
concept of psychosis, because it is central to the definition of schizophrenia.
Psychosis is best thought of as a syndrome, or a collection of symptoms
(subjective experiences) and signs (observable behaviors) elicited by trained
clinicians. Identifying psychosis is analogous to identifying fever. Just as
fever results from an ongoing disturbance of temperature regulation, psy-
chosis results from brain dysfunction. Fever has many causes, and so does
psychosis.
Psychosis is a syndrome characterized by one or more of a variety of
symptoms and signs that can be classified as reality distortion (delusions,
hallucinations) or disorganization (in thought, behavior or expression of
feeling).
All formal definitions of schizophrenia (two of which are widely used –
the Diagnostic and Statistical Manual, 5th edition [DSM-5], and Interna-
tional Classification of Diseases, 11th revision [ICD-11]) require the presence
of psychosis. However, it is important to remember that the presence of
psychosis alone does not make for a diagnosis of schizophrenia. Individuals
with schizophrenia additionally demonstrate a lack of motivation, reduc-
tion in spontaneous speech and social withdrawal (negative symptoms),
DOI: 10.4324/9781315152806-1
2 What is and is not schizophrenia?
Schizophrenia Delirium
Schizophreniform Disorder Dementia
Brief Psychotic Disorder Mood disorders
Schizoaffective Disorder Borderline Personality Disorder
Delusional Disorder Substance-related disorders
Shared Psychotic Disorder
The sufferers
Schizophrenia is a common illness, with a lifetime prevalence near 1%
(Jauhar et al., 2022). Approximately 24 million individuals worldwide suffer
from schizophrenia (WHO statistics). In the USA, there are approximately
2.6 million individuals diagnosed with schizophrenia. It is estimated that
about one-third or more individuals with schizophrenia have not been in
treatment for the past 12 months.
The direct costs of the illness, that is, the cost of caring for these patients,
in the USA alone exceeds $62 billion per year. The total costs, including
indirect costs such as productivity loss, may well exceed $280 billion per
year (Schizophrenia & Psychosis Action Alliance, 2020).
Of approximately 600,000 homeless individuals in the USA, nearly three-
fourths have a substance abuse disorder or mental illness, with a substan-
tial proportion suffering from schizophrenia or related severe mental illness
(Gutwinski et al., 2021).
What is and is not schizophrenia? 3
The myths
Myths are a means of understanding the world and our place in it. Schizo-
phrenia, like epilepsy before it, has been viewed as being ‘un-understandable’,
and therefore evokes myths as explanations. Myths, like ignorance, can lead
to troubling consequences – stigma and denial. The best way to counter
ignorance is by education.
We suggest asking patients and their families about their understanding of
schizophrenia, so that any misunderstanding of schizophrenia can be addressed
directly. In all instances it is our duty to provide education about the best cur-
rent understanding of schizophrenia and its treatment. Some of the common
myths encountered and your potential responses are listed in Table 1.2.
It is ‘split personality’ A very common misunderstanding due to the origin of the word (schizo, split + phrenia, mind). It is
not multiple personality disorder.
It only runs in families It is true that there is a genetic contribution to schizophrenia, but a substantial number of patients
have no family history of the illness.
Patients are violent or dangerous There is some increase in incidence of violent behavior among individuals with schizophrenia,
but this is very variable (Whiting et al., 2022). Individuals with schizophrenia are more likely to be
victims of violence than the general population. However, some individuals with schizophrenia act
aggressively as a result of the psychosis, particularly paranoia.
There is no effective treatment There are very effective treatments, although responses to treatment vary greatly.
It is due to bad parenting, Several decades ago, the so-called schizophrenogenic mother was held responsible. There is no
especially by the mother evidence that bad parenting causes schizophrenia, although parents can play a significant role in
illness management.
It is due to drug abuse Drug abuse is very common in individuals with schizophrenia, particularly at the onset of illness.
There is evidence drug abuse can precipitate psychosis, though it is unclear whether it causes
schizophrenia. Substance abuse can interfere with treatment.
It is their fault It is not the fault of the patient. No one chooses to have schizophrenia!
Children don’t get it Although schizophrenia typically emerges in late adolescence and adulthood, it can appear in early
life (childhood schizophrenia). Treatment is similar to adult schizophrenia.
Marriage ‘cures’ schizophrenia In some cultures it is believed that marriage cures schizophrenia. There is no evidence for this.
While the possibility exists that marriage may have beneficial effects (due to a caring partner), a
dysfunctional marriage can be problematic.
Evil spirits cause schizophrenia In some communities there are strong beliefs about supernatural causes of suffering. It is best to
work with, rather than against, these beliefs. Our approach is to suggest that conventional (modern)
treatments can work alongside efforts to cast off evil spirits, so that patients are not forced to choose
the non-medical approach.
Patients are ‘possessed’ This is analogous to ‘evil spirits’ but not identical. Possession can occur with ‘spirits’ of all sorts –
good, bad or neutral. The same approach as above is recommended.
Past misdeeds cause it In cultures where belief in past lives exists, present suffering is attributed to past actions, usually
‘sins’. Our approach is to suggest to patients and their families that the best we can do is rectify the
suffering in the present.
Only rituals cure schizophrenia This is one of the most challenging myths to deal with because individuals and families who utilize
traditional rituals will try these first before seeking medical help. This results in longer duration of
untreated psychosis, which is a risk factor for poor outcome.
A spell has been cast Similar to other supernatural attributions for schizophrenia, being under a spell is quite common. In
addition to problems of engaging patients into treatment, there is a risk that patients or their families
may retaliate against the spell-caster, if known.
They are stupid The thinking disturbance of schizophrenia can be mistaken for ‘stupidity’. It is important to avoid
Summary
• The term ‘schizophrenia’ was coined to capture the notion of a ‘frac-
tured’ or ‘shattered’ mind, not split mind.
• Psychosis is a state characterized by loss of contact with reality.
• Not all psychosis is schizophrenia, but schizophrenia is a form of psychosis.
• Approximately 50 million individuals worldwide suffer from schizo-
phrenia. The suffering and economic costs are enormous.
• Many homeless individuals are mentally ill, and about half suffer from
schizophrenia.
• Stigma has powerful negative effects and should be combated.
• Myths about schizophrenia are numerous and found worldwide. They
are associated with stigma and denial of illness. Stigma should be com-
bated vigorously by education.
What is and is not schizophrenia? 7
References
Dutta, R., Murray, R. M., Hotopf, M., Allardyce, J., Jones, P. B., & Boydell,
J. (2010). Reassessing the long-term risk of suicide after a first episode of
psychosis. Archives of General Psychiatry, 67, 1230–1237.
Gutwinski, S., Schreiter, S., Deutscher, K., & Fazel, S. (2021, August 23). The
prevalence of mental disorders among homeless people in high-income
countries: An updated systematic review and meta-regression analysis.
PLoS Medicine, 18(8).
Jauhar, S., Johnstone, M., & McKenna, P. J. (2022, January 29). Schizophre-
nia. Lancet, 399(10323), 473–486.
Pescosolido, B. A., Halpern-Manners, A., Luo, L., & Perry, B. (2021, Decem-
ber 1). Trends in public stigma of mental illness in the US, 1996–2018.
JAMA Network Open, 4(12).
Schizophrenia & Psychosis Action Alliance. (2020). Schizophrenia (WHO.
int) Schizophrenia cost the U.S. $281.6 billion in 2020 – Schizophrenia &
Psychosis Action Alliance (sczaction.org).
Whiting, D., Gulati, G., Geddes, J. R., & Fazel, S. (2022, February 1). Asso-
ciation of schizophrenia spectrum disorders and violence perpetration
in adults and adolescents from 15 countries: A systematic review and
meta-analysis. JAMA Psychiatry, 79(2), 120–132.
chapter 2
Assessment of
schizophrenia
Assessing the clinical state of patients with a psychotic disorder can be chal-
lenging, unintuitive and frustrating. This is due to the nature of the illness.
Communication with patients experiencing psychosis can be hampered by
the presence of thinking difficulties, delusions and hallucinations. This is
true, in fact, for all disorders that are accompanied by psychotic phenomena.
Interviewing a patient with psychosis can be an anxiety-provoking expe-
rience for the novice. Patients are frequently uncooperative or outright
hostile. Alternatively, they may be cooperative but unable to communicate
effectively.
Most importantly, remember that the person in front of you is not a ‘psy-
chotic’ or a ‘schizophrenic’, however convenient these labels might be;
rather, you are interacting with an individual suffering from a psychotic dis-
order, just as you or I might suffer from cancer or an intellectual disability.
(We wouldn’t like to be referred to as cancerous or retarded!) Remembering
this will ease the fear and frustrations one may experience while interview-
ing patients with psychosis.
Observe experienced clinicians interviewing patients with psychotic dis-
orders. If possible, interview patients without psychosis a few times prior to
interviewing patients with psychosis. You will feel more practiced in your
interview method.
While interviewing any patient, it is important to:
• be non-judgmental
• be patient
DOI: 10.4324/9781315152806-2
10 Assessment of schizophrenia
Observe behavior.
Listen especially to spontaneous verbalization.
Ask open-ended, leading or follow-up questions as required.
Assessment of schizophrenia 11
Even if the focus of the interview is psychosis, make sure to ask about other
conditions to ensure a comprehensive diagnostic assessment.
Your task is to discover the most salient information relevant to the goal of
the interview. If you anticipate hospitalization, consider what kinds of infor-
mation you’d like to have immediately and what information can be gathered
later. For example, for an acutely suicidal patient, gathering family history may
not be the most important task at this time. If the patient is seeking transfer of
outpatient care, likely you’ll want specific information to assure smooth transi-
tion of care, such as reason for transfer, recent course of treatment and so forth.
That said, at a minimum you need to determine whether the patient is
dangerous to self or others (reviewed in Chapter 14), is using illicit sub-
stances, is adherent with treatment if previously treated and whether there
is any ongoing medical problem.
Have you attempted suicide before? Past suicide attempts are a strong
predictor of suicide.
Is anyone in your family depressed? This gives you an indication that
depression may be familial. It will not necessarily help with estimat-
ing current risk of suicide; instead ask about suicide in relatives, a
better predictor of suicide.
Are the voices commanding you to do something? Auditory hallucina-
tions commanding harm to self can be incessant and patients can
‘give in’ to the voices.
12 Assessment of schizophrenia
Are you taking any medicine? This can tell you about whether the
patient is in treatment, level of medication adherence and whether
there is access to medications with overdose potential.
Do you live alone? Living alone is a risk factor for suicide.
AK, a 17-year-old, comes to the clinic accompanied by his mother. She made this
first appointment because of her concerns that AK is isolating himself, he sometimes
laughs for no apparent reason, his mood is erratic and he stays up all night.
Manner of questioning
There are many techniques and strategies that are available in the service of
eliciting information. With practice one can learn how and when to apply
them appropriately. Conducting lots of interviews and watching experienced
interviewers can greatly enhance one’s skills. The basic types of question are:
Imagining psychosis
I wonder whether you keep a weapon nearby in case the people trying to hurt
you or break into your apartment.
I wonder whether the voices that bother you say really awful things about
you, things that you would never reveal to anyone.
I wonder whether you feel like you don’t fit in because of your illness.
If I thought that others could read my mind, I might be forced to stop having
thoughts that they could pick up. I wonder if you feel that way.
• Appearance
• Behavior
• Conversation – to listen to the form of thinking
• Delusions – to listen to the content of thinking
• Emotions – mood and affect
• Faculties – higher faculties such as attention and orientation
• General intelligence
• Hallucinations
• Insight
• Judgment
Mr. O reports he is concerned that his wife has been having an affair for the past
several months. He thinks this because she doesn’t answer her phone at work and
returns home smelling ‘funny’. He follows her and has hired an investigator to
confirm this. Despite no evidence, he remains convinced that she is unfaithful.
Delusions
Delusions are fixed, false beliefs that are held in spite of evidence to the
contrary, are at odds with the community’s cultural and religious beliefs, are
inconsistent with the level of education of the patient and can be patently
irrational. Overvalued ideas are beliefs which are less firmly held than delu-
sions and tend to be less irrational; they are more easily challenged.
Delusions can be well-organized with ideas connected to each other
(systematized delusions), or non-systematized and fragmented. It is not
uncommon for patients also to have intense preoccupation with esoteric
and vague ideas about philosophical, religious, or psychological themes.
Hypochondriacal thinking about unlikely and bizarre medical conditions
may also occur. Delusions can be about any sort of idea, but the most com-
mon ones are listed in Table 2.1.
Patient: I had to take two buses to get here. You’d think that they’d at least let
me sit down. By the way, can I have bus tokens to get back home? I used my last
tokens on that stupid bus.
Hallucinations
Hallucinations are false perceptions (Table 2.2). These occur in the absence
of a stimulus, and can involve any of the bodily sensations (seeing, hearing,
smelling, tasting and feeling).
Illusions, on the other hand, are misinterpretations of actual stimuli. Illu-
sions are not typically considered psychotic phenomena, although they are
commonly experienced by patients with schizophrenia.
The most common hallucination in schizophrenia is auditory (70–80%
of patients). The presence of visual or olfactory hallucinations alone should
raise suspicion of underlying medical or neurological disorder.
Have you ever heard sounds or voices in your head or even from the outside
that you couldn’t quite figure out? Have you ever heard voices that other
people didn’t hear?
Have you seen things or had visions that didn’t quite fit with what was
going on at the time? Did you ever see things or people that others couldn’t
see at the same time?
What about feelings or sensations in your body that were different from your
usual experiences?
Have you smelled or tasted anything unusual – it could be nice, like per-
fume, or bad, like burning flesh, or some taste like metal?
Thought disturbance
The structure of thinking is reflected in speech and writing and in behavior.
Disordered thinking is common in schizophrenia and takes on many forms.
The end result of thought disorder is impaired communication (see below).
Patient: Fine, doc. But these humanoids really suck. The universe is particulate. I just
wish they’d stop squeezing my intestines. How are you, doc? (Smiling)
Tangentiality Thoughts start off linearly, but quickly veer off into unrelated
areas without returning to the original point. When interrupted,
patients tend to ask what the question was in the first place
Loose There is an apparent disconnection between one thought
associations (usually a sentence) and the next. An indication that
loosening of associations is occurring is when the interviewer
is unable to follow the train of thought (‘huh?’). When severe,
speech becomes incomprehensible
Thought In mid-sentence the patient appears to have lost the train of
blocking thought. However, you need to ascertain whether the patient
actually ‘lost’ the thought – true thought blocking – or was
distracted by competing thoughts
Flight of ideas This represents a combination of thought disorders. Here
a fairly complete idea is followed by another idea with
only a tenuous or no connection between these thoughts.
One experiences it as a zigzagging through conversation
Neologism Coining of new terms with idiosyncratic meanings
(e.g. ‘flushistic’)
Perseveration Persistent repetition of a response to new and unrelated stimuli
Verbigeration Persistent repetition of words or phrases (e.g. ‘I was going
the corrected way. They hadn’t corrected the signs, and now
I was lost and had to get corrected directions’.)
Word salad Complete lack of meaningful connections between words
(e.g. ‘seeing blasts tin hatched flour all along’). This thought
disturbance is quite rare
Was there a time in the past when people complained that they couldn’t
quite follow what you were saying?
Did you ever notice that, in the middle of a thought, it just sort of disap-
peared and you couldn’t recall it?
20 Assessment of schizophrenia
Figure 2.1 A schematic diagram to reflect linear thinking and types of thought
disorder.
Negative symptoms
In addition to psychosis, patients with schizophrenia commonly exhibit
negative symptoms. These are a constellation of signs and symptoms that
are characterized by diminution or loss of functioning (Table 2.4). This is in
contrast to positive symptoms (hallucinations and delusions) which reflect
augmentation or addition of functioning.
Negative symptoms are classified as primary (due to the illness itself) or
secondary (consequence of the illness or its treatment). The importance of
this distinction lies in their treatment (see Chapter 9). Negative symptoms
can be especially bothersome to patients and are often resistant to treat-
ment (Figure 2.1).
Disturbances of emotion
Patients with schizophrenia present with a variety of emotional states – anxi-
ety, perplexity, elation or depression. Expansive mood may present as ecstasy
or exaltation (sometimes confused with religious experiences). Inappropriate
affect, which is the disconnection between the display of emotion and the
Assessment of schizophrenia 21
thought and speech content, is quite common (e.g. the patient may grin
while describing a sad event, or burst into tears while describing an amusing
situation).
Behavioral disturbances
Schizophrenia patients frequently manifest psychomotor and behavioral
abnormalities (Table 2.5). These behaviors are not necessarily a consequence
of underlying delusions or hallucinations.
Cognitive abnormalities
There has been increasing focus on cognition (higher intellectual functioning
including awareness, perception, reasoning, memory and problem-solving)
in schizophrenia. Advances in cognitive neurosciences have significantly bol-
stered our understanding of the nature of cognitive disturbances in schizophre-
nia, and treatments are being developed to remediate these deficits (Table 2.6).
Neurological abnormalities
Patients with schizophrenia can have subtle neurologic disturbances,
referred to as ‘soft signs’, which consist of disturbances in motor coordi-
nation (gait, balance, coordination and muscle tone), sensory integration
(graphesthesia, stereognosis and proprioception) and primitive reflexes
(such as the palmomental, grasp and snout reflexes). While these findings
clearly substantiate the biological basis of schizophrenia, they do not neces-
sarily help us with the diagnosis of this illness.
Social determinants
of health affecting
assessment
Location
Ethnicity
Social determinants of health affecting assessment 27
Gender
Age
Culture
Immigration
Environment
Gender
Sex and gender are not identical. Sex is designated at birth (what you are born
as: biological male, female or intersex) while gender incorporates sex but
involves the assumption of a broader social identity over the course of psy-
chosocial development (what you are born as and become). There are several
important distinctions between men and women with schizophrenia regard-
ing the clinical picture, treatment response and long-term outcome. It has
been theorized that these differences may be due to biological (e.g. estrogen)
and environmental (e.g. better socialization in women) f actors (Table 3.1).
Women Men
Age at onset of Onset five years later than men. Earlier onset, in late teens
illness Late-onset schizophrenia is more and early adulthood
common in women
It was believed in the USA that there were greater rates of schizophrenia
in black persons than white persons. A large study (Robins & Regier, 1991)
in the USA did not find significant differences between the two groups.
It has been thought that schizophrenia has roughly the same prevalence
across the world, though this is increasingly debated. For example, the
rates of schizophrenia in Afro-Caribbean immigrants in the UK appear
to be significantly higher, perhaps due to the stress of emigration. There
also are geographical ‘pockets’ of higher prevalence rates, as in northern
Sweden and Finland, and western Ireland. See additional discussion in
Chapter 17.
Culture
Culture (Latin colere, to inhabit, to cultivate) is a term that has many meanings
and has been used to explain or sometimes obscure the d
ifferences between
individuals. A definition influential in early 20th-century anthropology –
‘knowledge, belief, arts, morals, law, customs, and any other capabilities
and habits acquired by man as a member of society’ – illustrates how diffi-
cult it is to pin down this fluid concept. While a full discussion of the topic
of culture and mental illness is beyond the scope of this chapter, listed in
the Box are several ways in which this concept is invoked in assessments:
CULTURE
• Meanings, values and behavioral norms that are learned and trans-
mitted in the dominant society and within its social groups
• Powerfully influences thinking, feelings and self-concept
• Defines normality and deviance
• Facilitates healthy adaptations
• Has mechanisms that facilitate conflict resolution
• Induces psychopathology by presenting stressors
• Reduces psychopathology by in-built protective factors
• Affects onset, course and outcome of illness, as well as acceptance
of treatments
• Shapes tolerance for certain behaviors and clinical symptoms
• Shapes culture-specific expressions of distress
Immigration
Environment
This category is broadly defined but includes factors that interact with each
other, such as location (urban or rural, industrialized or developing region),
discrimination and socioeconomic status (poverty, housing and food inse-
curity). HOPES is a useful mnemonic to assess social and environmental
factors in each individual (Figure 3.2). We will discuss these factors when
considering the issue of who is at risk for schizophrenia, in Chapter 17.
Summary
• Apart from the illness itself, there are biological, environmental and
cultural factors that modify the clinical presentation (and long-term
outcome).
• Biological factors include sex, race, age and age of onset of illness.
• Environmental factors include, among others, socioeconomic status,
social supports, migration, health-care access, neighborhood safety, and
co-morbid psychiatric and medical conditions.
• There is cultural diversity among patients. Culture has powerful effects
on illness presentation and illness perception, and it affects relation-
ships with health providers; attention needs to be paid to cultural issues
early in assessment and treatment to maximize care of patients.
References
Jester, D. J., Thomas, M. L., Sturm, E. T., Harvey, P. D., Keshavan, M., Davis,
B. J., Saxena, S., Tampi, R., Leutwyler, H., Compton, M. T., Palmer, B.
W., & Jeste, D. V. (2023). Review of major social determinants of health
in schizophrenia-spectrum psychotic disorders: I. Clinical outcomes.
Schizophrenia Bulletin, 49(4), 837–850.
Robins, L. N., & Regier, D. A. (Eds). (1991). Psychiatric disorders in America:
The epidemiologic catchment area study. New York: Free Press.
Sartorius, N., Shapiro, R., & Jablensky, A. (1974). The international pilot
study of schizophrenia. Schizophrenia Bulletin, 1(11), 21–34.
chapter 4
Schizophrenia, spirituality
and religion
Religion is the belief in the supernatural, sacred or divine, and the moral codes,
practices, values and institutions associated with such belief. Or we might say
that religion is a belief in spiritual beings. But most understand religion to
mean organized religion, for example, Buddhism, Christianity, Hinduism, Is-
lam and Judaism.
Faith refers to relational aspects of religion. Among its many meanings are
loyalty to a religion or religious community or its tenets, commitment to a
relationship with God and belief in the existence of God.
Spirituality, often used interchangeably with religion, may or may not include
belief in a personal god and in supernatural beings and powers, as in religion,
but emphasizes experience at a personal level, as in faith. Spirituality can mean
a feeling of connectedness, that life has purpose, and that these perspectives
can facilitate personal development.
DOI: 10.4324/9781315152806-4
34 Schizophrenia, spirituality and religion
For those individuals who have had some sort of religious upbringing,
personal development determines whether they go on to practice that reli-
gion, transform their beliefs or leave behind religion or faith. It is important
to find out the patient’s religious practices, because the superimposition of
a psychotic disorder on pre-existing beliefs can lead to a complicated set of
interactions that need to be sorted out.
Belief in the supernatural (good or evil) is common among people all over
the world, and therefore it is no surprise that religious themes are pres-
ent in psychotic phenomena, as are other elements of culture. Religious
themes in the context of psychosis include belief in personal persecution
by the devil or equivalent; special messages from, or direct communication
with, God; special tasks assigned by the divine; God’s voice; and becom-
ing God or one of the supernatural beings. These presentations, although
recounted in many texts and religious traditions, would not be considered
the norm by most adherents of organized religion. On the other hand, in
many parts of the world there are traditions that are accepting of all of
the above. This, however, does not negate the utility of the definition of a
delusion as a fixed, false belief that is at odds with the community’s cultural
and religious beliefs.
When assessing patients presenting with religious delusions, however,
it is important not to reflexively attribute these beliefs to psychosis, but
to ascertain the cultural context (Table 4.1). If one is not familiar with the
cultural background of the patient, it is the clinician’s responsibility to find
out. Good sources of information include family members, clergy, religious
organizations or academics specializing in religious studies.
It is equally important not to assume that all religious expressions in
an individual with schizophrenia are pathological and should become the
target of treatment! Sometimes a resurgence of faith with the onset of ill-
ness can be beneficial. Faith can help allay fears and even bring the patient
into the orbit of a church or temple community, widening his or her social
network.
Previously held religious beliefs can also become the focus of delusions
or hallucinations. It can become difficult to distinguish pathological from
Schizophrenia, spirituality and religion 35
A clinician’s religious beliefs and practices, or lack thereof, can factor into
the quality of assessment and therapeutic engagement with his or her
patient in this domain. Clinicians must seek supervision in situations where
they feel uninformed or conflicted in their care of patients for whom reli-
gious traditions play an important role in their illness or recovery. Further,
36 Schizophrenia, spirituality and religion
the clinician must respect the patient’s need for spiritual succor and not
proselytize. It is also important not to ‘pathologize’ every form of religious
expression in patients, lest we deny them opportunities for the genuine
uplift and comfort that can be derived from religion or spirituality.
The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) provides
a framework for evaluating spiritual and cultural aspects as part of a psychi-
atric assessment. The DSM-5 cultural formulation includes cultural identity,
cultural conceptualizations of distress (cultural explanations of the indi-
vidual’s illness), psychosocial stressors and cultural features of vulnerabil-
ity and resilience (cultural factors related to psychosocial environment and
functioning), cultural features (elements) of the relationship between the
individual and the clinician and an overall cultural assessment (for diagno-
sis and care).
In order to be sensitive to patients’ concerns about religion or faith, it is
not necessary to become an expert on all the existing religions and tradi-
tions. It is only necessary that the clinician show interest in these matters,
as reflected in the nature of questions they ask (What kinds of religious belief
were you brought up with? What are your thoughts about it now? Do you talk to
anyone about your religion?).
Summary
• Religion, faith and spirituality are important dimensions of quality of
life.
• Psychosis and religious beliefs have complex interactions.
• Religious delusions are common, primarily persecutory and grandiose
delusions.
• Ascertain the cultural context when assessing patients with religious
delusions.
• Do not assume that all religious expressions are pathological.
• Belief can provide comfort and coping skills, be protective (from suicide
or substance abuse), and widen the social network. On the other hand,
religious delusions can be harmful by provoking violence and suicide
and inducing non-adherence to treatment.
chapter 5
Once sufficient current and past psychiatric and medical history has been
gathered and a thorough mental-status examination conducted, these
pieces of information have to be put together to arrive at a ‘working diag-
nosis’. This is the first step in managing the patient’s illness.
It is tempting to assign a diagnosis of schizophrenia, or another diag-
nosis associated with psychosis, when it appears patently obvious based
on the history and mental-status exam. In spite of such certitude, it is
prudent to consider other possible explanations (see Figure 5.1). There
can be serious consequences if a ‘short-cut’ is taken in the diagnostic
process, such as:
DOI: 10.4324/9781315152806-5
38 Putting together the (clinical) pieces
• Alcohol • Inhalants
• Anxiolytics (e.g. diazepam) • Opioids
• Cannabis • PCP and ketamine
• Cocaine • Sedatives
• Hallucinogens (e.g. LSD) • Stimulants
• Hypnotics
Putting together the (clinical) pieces 41
disorders and whether the psychosis is present only in the context of the
mood disorder. In the DSM-5, mood disorders with psychotic features are
major depressive disorder, severe with psychotic features; bipolar I disorder,
severe with psychotic features; bipolar II disorder, severe with psychotic
features.
Distinguishing affective, schizoaffective and non-affective psychotic
disorders can be challenging. A careful history of the chronological rela-
tionship between affective and psychotic features can clarify the diagnosis.
Figure 5.2 provides a useful way for clinicians to think about the differential
diagnosis of psychosis and mood disorders.
Figure 5.3 DSM-5 criteria for schizophrenia (note the HALDOL mnemonic).
The DSM-5 is published by the American Psychiatric Press, USA. For the diagnosis
of schizophrenia, the DSM requires the presence of at least two of the following
symptoms (at least one of which should be 1, 2 or 3) for at least one month:
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Disorganized or catatonic behavior
5. Negative symptoms
Putting together the (clinical) pieces 45
References
Diagnostic and statistical manual of mental disorders. (2022). Text revision
(DSM-5-TR) (5th ed.). American Psychiatric Association Publishing.
Keshavan, M. S., & Kaneko, Y. (2013, February). Secondary psychoses: An
update. World Psychiatry, 12(1), 4–15.
Reed, G. M., First, M. B., Kogan, C. S., Hyman, S. E., Gureje, O., Gaebel, W.,
Maj, M., Stein, D. J., Maercker, A., Tyrer, P., Claudino, A., Garralda, E.,
Salvador-Carulla, L., Ray, R., Saunders, J. B., Dua, T., Poznyak, V., Medi-
na-Mora, M. E., Pike, K. M., . . . Saxena, S. (2019, February). Innovations
and changes in the ICD-11 classification of mental, behavioural and neu-
rodevelopmental disorders. World Psychiatry, 18(1), 3–19.
chapter 6
The foremost goal for communication between clinicians, patients and fam-
ilies is the facilitation and strengthening of the therapeutic alliance. This
bond can help patients and families accept and deal with illness, improve
treatment adherence and manage crises effectively.
Communication with patients and families often begins on a negative
note, commonly when a diagnosis of schizophrenia has been reached and
needs to be conveyed to them. Giving bad news to patients and their fam-
ilies is one of the most onerous tasks for clinicians. Talking to them about
schizophrenia is no different, particularly at the time of initial diagnostic
assessment. Frequently it is complicated by denial on the part of patient
and family.
Reluctance to accept the presence of the illness may be due to:
• fear of stigma
• fear of loss of self-efficacy
• lack of knowledge
• lack of insight
• fear of retaliation by patient or family members
DOI: 10.4324/9781315152806-6
48 Talking to patients and families
You clearly are having difficulties with . . . [symptoms that patient com-
plains about], and I’d like to work with you to help you feel better and also
try to figure out what’s going on.
It seems that you are/were having symptoms such as hearing voices.
What you are experiencing appears to be consistent with a condition called
psychosis. Many conditions can cause psychosis, including mood disorders
and schizophrenia. Have you heard about schizophrenia?
Individualized
Normalizing and non-stigmatizing
Setting-specific
Person-centered
Reassuring
Empathic and empowering
Strategy and next steps
Talking to patients and families 49
Talking to families
Generally, the family is the first to notice changes in the patient and
may even have been involved in bringing the patient to the hospital or
clinic. Nevertheless, the same sensitivity is needed. Families, like patients,
are also dealing with the distress of a relative who is acting abnormally
(incomprehensibly).
Families respond to a relative’s illness in their own unique ways, but
typically early responses are characterized by increased involvement and
concern, whereas, with progression of illness, late responses can include
increased criticism. Both sets of responses, if immoderate, can have negative
consequences for the patient (Figure 6.1).
All families need reassurance regarding:
• being informed and consulted about the care of their relative (‘kept in
the loop’)
• that there are others in the same situation (‘you’re not alone’)
• hope
• What has it been like for you all with what John’s been going through?
• What would be helpful to cope with his illness?
Families often are integral to the care of patients and should be involved
from the beginning and offered support. Schizophrenia is an illness that
strikes young adults, who are likely dependent on their families, and this
dependency increases further with illness onset.
It is very helpful to provide families with the contact telephone numbers
of the treatment team, the hospital emergency number, support groups in
the neighborhood and websites with information about schizophrenia.
Family sessions
It is important to meet with families, with and without the patient, as soon
as possible after initiating treatment. The goals of family sessions are to
allow the sharing of feelings about what is occurring with their relative,
provide them with information about the illness and establish a working
alliance with key family members. Involving the family early in the course
of treatment can actually help to prevent the patient from alienating him-
or herself later. We have found it very useful to insist that initial family
sessions include the patient. This largely mitigates any later communica-
tion problems between patient and family, between patient and clinician
about the family and between clinician and family. During these sessions
we encourage openness, sharing of concerns, discussion of the symptoms
and distress and development of a collaborative spirit. The need for commu-
nication between the clinician and the family, particularly during periods of
crisis, should also be discussed.
When meeting with families, be prepared to answer many, and some-
times difficult, questions. Responses to these questions should be honest,
but with a non-judgmental and hopeful stance. The types of information
that families seek tend to fall into the following categories:
• definition of psychosis
• triggering factors, role of stress
• substance abuse
• denial, compliance issues
• stigma
• impact of illness on family
• prognosis
• dependence and independence issues
• medications, side effects
• difficulties with healthcare system
• depression, suicide
patients will outright forbid contact with family. This is a difficult situation,
but these wishes must be respected, although every effort must be made to
avoid a split between patient and family. We suggest frequently reviewing
the patient’s position on this matter because it may alter during treatment.
For example, conflicts with family may be due to paranoia, and as it resolves
the relations with family may improve. Involving families early in treat-
ment decisions and establishing a spirit of open communication is very
helpful in the longer run.
The chief virtue that language can have is clearness, and nothing detracts from
it so much as the use of unfamiliar words.
Hippocrates
Maintaining hope
There are few good predictive markers in schizophrenia, and the subjective
or ‘gut feeling’ predictions of experienced clinicians can be overly gloomy
compared to careful scientific studies. This ‘clinician’s illusion’ arises from
the experience of spending more time caring for those who are suffering
the worst outcomes. The reality is that outcomes are actually quite variable,
and, for the majority of patients, there are many modifiable prognostic fac-
tors that can be targets for clinical and social intervention. The HOPE mne-
monic (Table 6.2) can be a useful framework to consider while discussing
treatment options and outlook with patients and families.
Talking to patients and families 53
Deegan adds, ‘No one at the time told me boredom and meaninglessness are
profoundly stressful’. Of course, hopeful statements need to be offered with
honesty and humility.
Very often, outcomes are influenced by factors unknown at the begin-
ning, such as response to treatment, treatment adherence, psychosocial
events and circumstances etc. It is important to present possible outcomes
as potentially changeable with the appropriate treatments. It is useful to
suggest alternative options, such as long-acting injectables and clozapine,
early in the course of the illness, so that patients may be willing to con-
sider them later in the event treatment response is unsatisfactory. Develop-
ing a partnership in the context of a positive therapeutic alliance is likely
to improve outcomes in the early course of psychotic disorders (Frank &
Gunderson, 1990). Using a person-centered approach to consider an indi-
vidual’s unique health needs and desired health outcomes is essential for
effective care. Finally, empowering patients and families using a shared
decision-making approach can improve outcomes.
Questions a patient and family may ask when confronted with illness are:
What will happen next?
Will it ever go away?
Why me?
Questions a health provider should ask when confronted with illness are:
How can I help now?
How can I help them plan for the future?
How can I help them cope with the question, ‘why me?’
Summary
• Effective communication between clinicians, patients and families facil-
itates therapeutic alliance, which is essential to good care.
• Talk to patients about treatment with an optimistic stance, particularly
since the rates of resolution of first episodes of psychosis are very high.
• Patients should be provided with as much detail about their treatment as
is tolerable to them.
• Families, like patients, are also dealing with the stress and trauma of the
illness. They also need reassurance that the best is being done for their
relative.
• Meet with families as soon as possible, and have at least a few sessions
with both patient and family together.
• Be mindful of the confidentiality issues involved in sharing information
with family.
• Discussions about prognosis are important. While there are relatively
few reliable predictors of long-term outcome, several indicators (PRE-
DICTS) can help organize support and intervention.
• During the early days of the illness, it is important to maintain a hopeful
stance with the patient and family. The HOPE acronym summarizes the
key principles to consider while discussing the disease outcome with
patients and caregivers.
References
Deegan, P. E. (2022, August). I am a person, not an illness. Schizophrenia
Research, 246, 74.
Duckworth, K. (2022). You are not alone: The NAMI guide to navigating mental
health―with advice from experts and wisdom from real people and families.
NAMI.
Frank, A. F., & Gunderson, J. G. (1990, March). The role of the therapeutic
alliance in the treatment of schizophrenia. Relationship to course and
outcome. Archives of General Psychiatry, 47(3), 228–236.
Keshavan, M. S., Davis, B., FriedMan-Yakoobian, M., & Mesholam-Gately,
R. I. (2022, January). What is my diagnosis, Doc? Discussing psychosis
diagnosis with patients and families. Schizophrenia Research, 239, 92–94.
Mesholam-Gately, R. I., Varca, N., Spitzer, C., Parrish, E. M., Hogan, V.,
Behnke, S. H., Larson, L., Rosa-Baez, C., Schwirian, N., Stromeyer, C.,
Williams, M. J., Saks, E. R., & Keshavan, M. S. (2021, December). Are we
58 Talking to patients and families
Early intervention
and prevention for
schizophrenia
The first three to five years after the onset of psychosis should be viewed as
a ‘critical period’ for intervention. Most of the functional decline from these
illnesses occurs during this time, and several modifiable adverse prognostic
factors emerge in these first few years, including substance misuse, disen-
gagement from treatment and risk for aggression and self-harm (Birchwood
et al., 1998).
Despite the common assumption that schizophrenia is invariably associ-
ated with poor outcome, systematic studies suggest a more hopeful picture
with considerable heterogeneity, and some individuals achieving high lev-
els of recovery. As can be seen in Figure 7.1, patients in groups A and C may
have either an excellent or poor recovery, respectively, after their first epi-
sode. The largest proportion of early course schizophrenia or first-episode
psychosis (FEP) patients (group B) have an uneven course with repeated
episodes of care and successful reduction of symptoms and distress, often
followed by disengagement and relapse (e.g., Srihari et al., 2012). In typical
systems of care, this results in a loss of social function, which reaches a sta-
ble plateau after about five years. Early-intervention services can improve
upon these suboptimal outcomes.
One of the key developments in care for FEP patients has been special-
ized team-based care – or Coordinated Specialty Care (CSC) – wherein
clinicians from several disciplines (e.g., social work, nursing, psychology,
psychiatry) coordinate their efforts to provide a comprehensive package
of empirically based treatments to young individuals with FEP (and their
families) and also address a range of social determinants of outcome (e.g.,
DOI: 10.4324/9781315152806-7
60 Early intervention and prevention for schizophrenia
organize the efforts of the clinical team, but that are nevertheless experi-
enced as a seamless and coordinated journey to and through care by the
patient and family (Figure 7.2).
Early Detection (Module A) includes efforts to reduce DUP and ease the
path to accessing the CSC team. These include efforts to minimize inter-
actions with the criminal justice system and involuntary hospitalizations.
Evaluation and Initiation of Treatment (Module B) includes efforts to
engage FEP individuals into care. While this is a high-risk period for self-
harm, the young individual or family who are disheartened or even angry
about their previous experiences of care often do not acknowledge the pres-
ence of an illness or do not trust the mental healthcare system. A compre-
hensive evaluation of these barriers to engagement will assist with building
an alliance and initiating elements of treatment that will often need to
begin even before a definitive diagnosis and longer-term treatment plan
can be developed.
Coordinated Specialty Care, CSC (Module C) builds on the gains
made in the prior modules. A variety of pharmacological and psychosocial
62 Early intervention and prevention for schizophrenia
Summary
• Psychotic illnesses are distressing, disabling and costly under usual care.
• Outcomes for these ‘chronic illnesses of the young’ can be substantially
improved via Early Intervention Services (EIS).
• Modern EIS should attempt to improve both Access to (reduce DUP and
improve experience of pathway to care) and Quality of (provide Coordi-
nated Specialty Care) care.
64 Early intervention and prevention for schizophrenia
References
Birchwood, M., Todd, P., & Jackson, C. (1998). Early intervention in psycho-
sis. The critical period hypothesis. British Journal of Psychiatry, 172(33),
53–59.
Correll, C. U., Galling, B., Pawar, A., Krivko, A., Bonetto, C., Ruggeri, M.,
Craig, T. J., Nordentoft, M., Srihari, V. H., Guloksuz, S., Hui, C. L. M.,
Chen, E. Y. H., Valencia, M., Juarez, F., Robinson, D. G., Schooler, N. R.,
Brunette, M. F., Mueser, K. T., Rosenheck, R. A.,. . . Kane, J. M. (2018).
Comparison of early intervention services vs treatment as usual for ear-
ly-phase psychosis. JAMA Psychiatry. Published online May 2, 2018.
Keshavan, M. S., Ongur, D., & Srihari, V. H. (2022). Toward an expanded
and personalized approach to coordinated specialty care in early course
psychoses. Schizophrenia Research, 241, 119–121.
Srihari, V. H., Jani, A., & Gray, M. (2016). Early Intervention for psychotic dis-
orders: Building population health systems. JAMA Psychiatry, 73(2), 1–3.
Srihari, V. H., & Keshavan, M. S. (2022). Early intervention services for
schizophrenia: Looking back and looking ahead. Schizophrenia Bulletin,
48(3), 544–550.
Srihari, V. H., Shah, J., & Keshavan, M. S. (2012). Is early intervention for
psychosis feasible and effective? Psychiatric Clinics of North America, 35,
613–631.
chapter 8
These are a diverse group of drugs used to treat the psychosis syndrome.
These drugs do not treat all of the broad range of impairments associated
with schizophrenia, but are quite effective at targeting the positive symp-
toms of psychosis, regardless of cause. Antipsychotic drugs (APDs) used to
be referred to as major tranquilizers (inducing calm) or neuroleptics (from
lepsis, to hold down). These medications can also help manage the symp-
toms of depression and bipolar disorder, and several have been approved
by the FDA as mood stabilizers. This has led to the proposal to replace
the potentially stigmatizing and confusing label ‘antipsychotics’ with one
derived from pharmacological properties (e.g., dopamine antagonists, dopa-
mine serotonin antagonists, dopamine partial agonists, etc.). This neurosci-
ence-based nomenclature has been developed for a variety of medications
used to treat mental illnesses (Zohar et al., 2015).
DOI: 10.4324/9781315152806-8
66 Managing symptoms and preventing relapse
Advantages Disadvantages
The two most common clinical situations that require initiation of APDs
are (1) first-episode psychosis and (2) relapse following discontinuation of
treatment by the patient. Clinicians may switch APDs at any time during
the course of illness in response to intolerable side effects or suboptimal
treatment response.
Initiation of APDs for first-episode psychosis requires consideration of
the clinical presentation, the treatment setting and concerns about specific
side effects. There is no clear data that can help choose among these drugs
based on efficacy. In general, the choice depends on which side effects one
wishes to avoid in a given patient (see Table 8.2). Patients at first episode of
psychosis are particularly prone to side effects. Therefore, the starting dose
should be low, dose increases should be in small increments, and side effects
should be addressed quickly, lest the patient become treatment non-adher-
ent. As indicated by our own and others’ research, patients at first-episode
of psychosis tend to have very good treatment response (>70%).
Drug selection
As noted earlier, there is no convincing research data that can help in choos-
ing one APD over another based on efficacy alone, particularly among the
atypical APDs. One approach is to choose an APD based on side effects one
wishes to avoid (Figure 9.1), along with other considerations such as previ-
ous treatment response, preference, route and frequency of administration
and cost.
Olanzapine
Risperidone
Trade names Risperdal, Risperdal Consta
Available dosing (mg) 0.25, 0.5, 1, 2, 4, 1/ml solution;
Consta IM
Starting dose 1–2 mg daily
Usual daily dose 1–4 mg daily
Maximum daily dose 16 mg
Metabolism CYP450: 2D6; 3A4
Quetiapine
Trade name Seroquel
Available dosing (mg) 25, 100, 200, 300
Starting dose 100 mg daily
Usual daily dose 400–600 mg
Maximum daily dose 800 mg
Metabolism CYP450: 2D6; 3A4
Ziprasidone
Trade name Geodon
Available dosing (mg) 20, 40, 60, 80
Starting dose 20–40 mg daily
Usual daily dose 40 mg
Maximum daily dose 80 mg
Metabolism CYP450: 3A4
Aripiprazole
Trade name Abilify
Available dosing (mg) 5, 10, 15, 20, 30
Starting dose 10–15 mg daily
Usual daily dose 10–15 mg
Maximum daily dose 30 mg
Metabolism CYP450: 2D6, 3A4; poor 2D6
metabolizers have 60% increased
drug exposure
Clozapine
Trade name Clozaril
Available dosing (mg) 12.5, 25, 100
Baseline testing White blood count (WBC), repeated
weekly for six months, then biweekly
Starting dose 12.5–25 mg daily
Usual daily dose 300–600 mg
70 Managing symptoms and preventing relapse
Lurasidone
Brexpiprazole
Cariprazine
Asenapine
Iloperidone
Trade name Fanapt
Available dosing (mg) 1, 2
Starting dose 1 mg twice daily
Usual daily dose 6–12 mg twice daily
Maximum daily dose 12 mg twice daily
Metabolism CYP450: 2D6; 3A4
Lumateperone
When initiating treatment, you should almost always start low, go slow.
The aim of treatment is to arrive at maximal therapeutic benefit using the
lowest effective dose while minimizing side effects. This is best achieved
with the ‘low and slow’ approach. It is also important to educate patients
about likely side effects, giving them a contact number to call in the event
of significant side effects, and promptly address the side effects before they
lead to non-adherence. Decreasing the likelihood of side effects will enhance
treatment adherence, in turn improving treatment response.
Most patients respond to 300–700 mg chlorpromazine equivalents (rel-
ative potency of APDs compared to a standard dose of chlorpromazine).
Table 8.4 provides chlorpromazine equivalents of common APDs; however,
this is not a substitute for careful clinical titration against the response and
side effects of individual patients. Also, while Chlorpormazine equivalents
are better defined for FGAs and are also useful when switching from FGAs
to SGAs, for most SGAs there are now dosing guidelines based on patient
studies that can provide a useful range of doses within which response is
expected to occur (Table 8.5).
72 Managing symptoms and preventing relapse
• How long should the APD be continued at the dose effective for the acute
phase?
• How long is treatment continued when symptoms have remitted?
• How long is an adequate treatment trial?
• Can treatment ever be stopped?
Patients and families tend to be concerned mostly about the last question.
Evidence suggests most patients will need maintenance treatment to prevent
relapses. After remission of an acute episode, the same APD and the dose that
was effective should be maintained for at least a year and probably longer.
Discontinuing treatment at any point increases the risk of relapse. There are
rare patients who have one episode of psychosis that remits completely and
for whom discontinuing APDs may not worsen outcome. However, this is
not predictable in advance, so careful, guided discontinuation should only
be attempted for selected patients who are well educated about relapse, are at
lower risk (based on one or few prior psychotic episodes) and have a support
system that is able to alert them and their prescribers to any re-emergence of
symptoms. More research is needed for determining the duration of main-
tenance after an initial episode of schizophrenia. For now, clinicians should
recommend continuous antipsychotic treatment using the best-tolerated
antipsychotic at minimum effective maintenance doses (Emsley et al., 2016).
Chlorpromazine 100 mg
Haloperidol 2 mg
Fluphenazine 2 mg
Risperidone 2 mg
Olanzapine 5 mg
Quetiapine 75 mg
Ziprasidone 60 mg
Aripiprazole 7.5 mg
Haloperidol decanoate 5 mg every four weeks
Fluphenazine decanoate 10 mg every two weeks
Managing symptoms and preventing relapse 73
Aripiprazole 1.4 mg
Chlorpromazine 38.9 mg
Clozapine 30.6 mg
Haloperidol 0.7 mg
Risperidone 0.4 mg
Ziprasidone 7.9 mg
Insomnia
The quantity, initiation and maintenance of sleep are frequently affected in
schizophrenia, particularly during florid states. Lack of adequate sleep can
contribute to irritability and exacerbation of psychosis. Some APDs have
74 Managing symptoms and preventing relapse
Summary
• APDs are a diverse group of drugs used to treat psychotic symptoms, not
just schizophrenia.
• First-generation APDs are primarily dopamine-blocking drugs. Sec-
ond-generation APDs have different mechanisms of action, affecting
dopamine and serotonin neurotransmission.
• There are no clear data that can help choose among APDs based on effi-
cacy alone. One approach is to choose an APD based on the side effects
one wants to avoid., or dopamine partial agonism.
• When an APD is being restarted, choose an APD that has worked well in
the past.
• SGAs are increasingly used as first-line treatment for first-episode patients
with schizophrenia.
• Start low, go slow when initiating treatment.
• Most patients respond to 300–700 mg chlorpromazine equivalents, but
consult current prescribing guideline for usual ranges for each SGA.
• Maintain the effective APD dose for at least a year, and consider guided
discontinuation only in carefully selected patients.
• Treatment is likely to be continuous and indefinite for most patients
with schizophrenia, but clinicians should use the minimum effective
dose of the best-tolerated APD for maintenance treatment.
References
Emsley, R., Kilian, S., & Phahladira, L. (2016, May). How long should anti-
psychotic treatment be continued after a single episode of schizophre-
nia? Current Opinion in Psychiatry, 29(3), 224–229.
Managing symptoms and preventing relapse 75
Leucht, S., Samara, M., Heres, S., Patel, M. X., Furukawa, T., Cipriani, A.,
Geddes, J., & Davis, J. M. (2015, November). Dose equivalents for sec-
ond-generation antipsychotic drugs: The classical mean dose method.
Schizophrenia Bulletin, 41(6), 1397–1402.
Zohar, J., Stahl, S., Moller, H. J., Blier, P., Kupfer, D., Yamawaki, S., Uchida, H.,
Spedding, M., Goodwin, G. M., & Nutt, D. (2015, December). A review of
the current nomenclature for psychotropic agents and an introduction
to the Neuroscience-based Nomenclature. European Neuropsychopharma-
cology, 25(12), 2318–2325.
chapter 9
Psychosocial approaches
to improve symptoms
and functional outcomes
Psychoeducation
DOI: 10.4324/9781315152806-9
78 Psychosocial approaches to improve symptoms and outcomes
Table 9.1 What approach would you choose for the scenario below?
A. Case management
B. Intensive case management (ICM) or assertive community treatment (ACT)
C. ACT and supported housing
D. Family intervention and psychoeducation
E. Supported employment and ICM
F. Social skills training and case management
Managing symptoms
Mindfulness-based therapies
relapse (ask the patient: Do you think there is a link between you stopping
the medicine and ending back in the hospital?)
• Behavior change. Explore the ambivalence towards treatment; help
patient identify benefits and disadvantages
• Consolidation. Encouraging self-efficacy; reframing medication as a way
to enhance quality of life
Peer support
Improving functioning
Cognitive training
Cognitive dysfunction, now considered a fundamental feature of schizo-
phrenia affecting 40–95% of individuals, contributes significantly to
disability.
Cognitive functions affected in schizophrenia are:
• attention
• working memory (e.g. capacity to keep things in mind long enough for
immediate use, such as a phone number)
• learning
• general memory
• forward planning
• concept formation
• initiating action
• self-monitoring
Verbal and non-verbal skills that aid in communicating with others are
required for socialization (the behavior patterns of the culture). These skills
include the ability to hold a conversation, make ‘small talk’, listen actively,
use appropriate body language including eye contact, pay attention and
express interest. Social skill deficits are a hallmark of schizophrenia. Patients
with schizophrenia often develop these deficits after the emergence of the
illness, while some have these deficits long before the onset of psychosis.
These troublesome deficits are likely due to a combination of positive and
negative symptoms as well as cognitive deficits, and can lead to shrinking
social networks and feelings of loneliness.
Social skills training (SST) is a well-researched and widely used interven-
tion (Kopelowicz et al., 2006). It seeks to improve psychosocial functioning
by helping to improve communication skills needed for interpersonal and
vocational goals. Social skills training is based on behavior therapy princi-
ples. Complex social skills, such as making friends, are broken down into
simpler and smaller steps and then taught using a variety of techniques,
including didactic and Socratic instruction, modeling, corrective feedback
and homework exercises. SST can be conducted in individual and group ses-
sions. Strategies include assessment of barriers to care, role-playing, social
modelling and homework assignments to practice skills in real life situations.
Promoting recovery
Most patients with schizophrenia live in the community, but many are socially
isolated, and few have jobs. Conventional approaches to vocational rehabil-
itation tend not to work well with patients because of the nature of schizo-
phrenia. It is more useful to identify supported worksites that are familiar with
the challenges faced by patients with schizophrenia. Jobs that have flexible
hours, are relatively stress-free and offer privacy are particularly helpful.
Psychosocial approaches to improve symptoms and outcomes 87
Supported employment is based on the view that anyone can gain and
keep competitive employment and pursue academic goals. It takes the
approach of ‘place and train’, as opposed to the traditional vocational reha-
bilitation model of ‘train and place’. Supported employment requires assess-
ment of goals and skills, rapid job search and assistance with placement in a
setting with employers willing to hire patients. Individuals receive support
throughout their period of employment (Table 9.5). Supportive employment,
along with coordinated clinical care, has been found to increase rates of
competitive employment, decrease hospital admissions and improve treat-
ment compliance (Drake et al., 2000).
Supported education, like supported employment, provides support for
individuals with schizophrenia to achieve academic success using one or
more strategies. These include mental-health support on or off the educa-
tional site, integrating school or college health services with ongoing men-
tal-health care and the use of specialized educational services before the
individual moves to integrated classrooms.
In combination with social skills training and/or cognitive remediation,
supported employment or supported education may enhance the individu-
al’s ability to meet the interpersonal demands of the workplace.
Supported housing
Among the many factors that contribute to quality of life, safe and afford-
able housing is particularly important. The type of housing a patient
requires will depend on his or her capacity to attend to housekeeping
chores and general safety. Housing is an evolving ‘process’, in which
88 Psychosocial approaches to improve symptoms and outcomes
Summary
• While antipsychotics are very effective for psychosis, psychosocial treat-
ments are critically important to reduce overall disability.
• Psychoeducational approaches increase patients’ knowledge of, and
insight into, their illness and its treatment.
• Psychotic and affective symptoms can be improved by utilizing a combi-
nation of cognitive behavior therapy and mindfulness-based techniques.
Cognitive behavioral therapy (CBT) focuses on identifying situations
and thoughts that are associated with distress.
• Cognitive remediation and social skills training involve learning strat-
egies that enhance cognition or improve social skills to address func-
tional impairments common in schizophrenia.
Psychosocial approaches to improve symptoms and outcomes 89
References
Drake, R. E., Mueser, K. T., Torrey, W. C., Miller, A. L., Lehman, A. F., Bond,
G. R., Goldman, H. H., & Leff, H. S. (2000, October). Evidence-based
treatment of schizophrenia. Current Psychiatry Reports, 2(5), 393–397.
Hodann-Caudevilla, R. M., Díaz-Silveira, C., Burgos-Julián, F. A., &
Santed, M. A. (2020, June 30). Mindfulness-based interventions for
people with schizophrenia: A systematic review and meta-analy-
sis. International Journal of Environmental Research and Public Health,
17(13), 4690.
Jester, D. J., Thomas, M. L., Sturm, E. T., Harvey, P. D., Keshavan, M., Davis,
B. J., Saxena, S., Tampi, R., Leutwyler, H., Compton, M. T., Palmer, B.
W., & Jeste, D. V. (2023, April 6). Review of major social determinants
of health in schizophrenia-spectrum psychotic disorders: I. Clinical out-
comes. Schizophrenia Bulletin, 49(4), 837–850. https://doi.org/10.1093/
schbul/sbad023
Keshavan, M. S., Vinogradov, S., Rumsey, J., Sherrill, J., & Wagner, A. (2014,
May). Cognitive training in mental disorders: Update and future direc-
tions. American Journal of Psychiatry, 171(5), 510–522.
Kopelowicz, A., Liberman, R. P., & Zarate, R. (2006, October). Recent
advances in social skills training for schizophrenia. Schizophrenia Bulletin,
32(Suppl. 1), S12–S23.
Mander, H., & Kingdon, D. (2015, February 18). The evolution of cogni-
tive-behavioral therapy for psychosis. Psychology Research and Behavior
Management, 8, 63–69.
McFarlane, W. R. (2016, September). Family interventions for schizophrenia
and the psychoses: A review. Family Process, 55(3), 460–482.
Mueser, K. T., & Gingerich, S. (2013). Treatment of co-occurring psychotic
and substance use disorders. Social Work in Public Health, 28(3–4), 424–439.
90 Psychosocial approaches to improve symptoms and outcomes
Scott, J. E., & Dixon, L. B. (1995). Assertive community treatment and case
management for schizophrenia. Schizophrenia Bulletin, 21(4), 657–668.
Solmi, M., Croatto, G., Piva, G., Rosson, S., Fusar-Poli, P., Rubio, J. M., Car-
valho, A. F., Vieta, E., Arango, C., DeTore, N. R., Eberlin, E. S., Mueser,
K. T., & Correll, C. U. (2023, January). Efficacy and acceptability of psy-
chosocial interventions in schizophrenia: Systematic overview and qual-
ity appraisal of the meta-analytic evidence. Molecular Psychiatry, 28(1),
354–368.
chapter 10
Managing treatment-
related complications
Antipsychotic drugs (APDs), like all medicines, can cause side effects. For the
majority of patients these are few and transient and should not prevent con-
tinued treatment. On the other hand, side effects require prompt attention
to alleviate discomfort and prevent rare but more serious adverse reactions.
Additionally, persistent side effects can contribute to treatment non-adher-
ence (see Chapter 12), which increases the risk for decompensation and
relapse. Therefore, one should be familiar with expected and common side
effects, as well as serious and potentially permanent complications.
General principles
Observing the following principles (the ‘10 Cs’ of optimal prescribing) can
improve the chances of a favorable outcome and minimize treatment-re-
lated discomfort (Salzman et al., 2010).
DOI: 10.4324/9781315152806-10
92 Managing treatment-related complications
• Consider cost-effectiveness
• Consultations, as needed, for second opinion or medical reasons
• Chart notes: always provide treatment rationale in progress notes
The general side effects and range of severity for different antipsychotic
medications are summarized Table 10.1, and approaches to management of
common side effects are discussed in Table 10.2.
Table 10.1 General side effects of APDs and range of severity
First generation*
Chlorpromazine + +++ +++ ++ +++ +++ +++
Haloperidol +++ + + +++ +/- - ++ (+++ If IV)
Fluphenazine +++ + + +++ +/- - +/-
Second generation*
Aripiprazole + - + - - - +/-
Treatment-related What to do
problem
QTc prolongation
The QT interval, the Careful cardiac monitoring should be instituted
duration of ventricular with increased QTc interval, particularly in those
depolarization and individuals with a medical history suggestive of heart
repolarization, is disease. It is best to switch APDs to those less likely to
normally 380–420 ms. induce Q – Tc prolongation
QT prolongation >500
ms is associated with the
development of cardiac
dysrhythmias, particularly
torsades de pointes that
can lead to sudden death
Sedation In most instances sedation is transient and lasts about
two weeks. When it interferes with functioning,
change the dosing to all at bedtime, reduce daytime
dosing and, if unsuccessful, switch to a less-sedating
APD. Modafinil may be helpful
Seizures Usually occur with rapid escalation of APD dose, and
in a dose-dependent manner with clozapine. In the
case of clozapine, divided dosing may decrease the
risk. Anticonvulsants may need to be used
Sialorrhea Patients find sialorrhea quite bothersome. It tends to
Drooling or excessive worsen during sleep. A towel over the pillow can help
salivation is the pooling of with the physical discomfort. Anticholinergic agents
saliva beyond the margin (e.g. benztropine, atropine drops) are helpful
of the lip. Common
with clozapine, it is not
transient
Reference
Salzman, C., Glick, I., & Keshavan, M. S. (2010, December). The 7 sins
of psychopharmacology. Journal of Clinical Psychopharmacology, 30(6),
653–655.
chapter 11
Suboptimal treatment
response
DOI: 10.4324/9781315152806-11
100 Suboptimal treatment response
CR is a 26-year-old single mother with three young children who has been
prescribed ziprasidone 40 mg BID, clozapine 50 mg BID, valproate 500 mg q AM
and 250 mg at noon, 500 mg q HS and benztropine 1 mg BID. The severity of
delusions of reference remains unchanged. Her memory is poor, and she often
forgets if she took her medications.
102 Suboptimal treatment response
CR, the patient described above, has had her treatment regimen simplified. She
is now taking clozapine 200 mg BID and valproate 500 mg BID. The delusions of
reference are less bothersome, but she complains of constipation and is gaining
weight.
other reasons why adequate concentrations may not have been reached.
Plasma concentrations depend on both the rate of dosing of a medication
and its clearance by the body, generally by liver enzymes – cytochrome oxi-
dases. The metabolic rate of a given drug may vary from person to person;
some individuals metabolize at a faster rate (rapid metabolizers), others at
a slower rate (slow metabolizers). At a given dose, rapid metabolizers will
have lower plasma levels than slow metabolizers. Genetic factors, as well as
physiological parameters (age, co-morbid illness, concurrent medications,
diet and pregnancy), can affect the pharmacokinetics of medications, lead-
ing to alterations in plasma concentrations even when the dose is constant.
Examining plasma levels of some antipsychotics can inform dosing. The
estimation of plasma levels of clozapine is most common (levels below 350
ng/ml are associated with reduced response and should thus support dose
increase). Higher clozapine levels should suggest close monitoring for side
effects such as seizures. Plasma norclozapine (an inactive metabolite of
clozapine) levels are not correlated with treatment response but are useful
in determining the metabolic rate of clozapine. The optimal ratio of clozap-
ine/norclozapine for non-smokers is around 1.3. Lower ratios suggest more
rapid metabolism, which can be induced by smoking.
Did the drug have the desired effect? Sometimes the desired effect
of the drug is not occurring at specific receptors in the brain, in spite of
adequate plasma concentrations. There are multiple reasons for lack of
effect. Individual genetic differences in receptor affinities may exist, similar
to genetic differences in drug metabolism. It turns out that many of the
abovementioned factors affecting pharmacokinetics can also affect receptor
responsivity to the drug. There is much ongoing research aimed at identi-
fying these genetic variations in order to tailor treatments to the individual
patient.
Clozapine
If two or more antipsychotic medications have been found ineffec-
tive, the appropriate next step is to consider clozapine, if there are no
contraindications.
106 Suboptimal treatment response
Summary
• Suboptimal treatment response is when treatment fails to provide sat-
isfactory resolution of the symptoms. One-third of patients with schizo-
phrenia do not respond satisfactorily to optimal treatment.
• The assessment of therapeutic response in an individual patient is depen-
dent on a combination of factors such as reduction of most symptoms,
acceptance of some residual symptoms and tolerability of treatment.
• Response to treatment occurs along a continuum, ranging from no
response at all to a rapid, complete and sustained resolution of symptoms.
Suboptimal treatment response 107
References
Andreasen, N. C., Carpenter, W. T., Jr., Kane, J. M., Lasser, R. A., Marder, S.
R., & Weinberger, D. R. (2005, March). Remission in schizophrenia: Pro-
posed criteria and rationale for consensus. American Journal of Psychiatry,
162(3), 441–449.
Correll, C. U., & Howes, O. D. (2021, September 7). Treatment-resistant
schizophrenia: Definition, predictors, and therapy options. Journal of
Clinical Psychiatry, 82(5).
Keshavan, M. S., Bishop, D. L., Coconcea, C., & Bishop, J. R. (2022, Octo-
ber). Clozapine, an update. Schizophrenia Research, 248, 168–170.
chapter 12
Medication
nonadherence
Arguably one of the greatest challenges that a clinician will face in caring
for the patient with schizophrenia is nonadherence to antipsychotic medi-
cation. It is paramount that the possibility of nonadherence be considered
from initial treatment contact. Nonadherence is more common early in the
course of schizophrenia. Lack of insight is the most common cause.
General principles
What is adherence?
Treatment adherence or compliance is taking medicine as prescribed,
including at the dose, timing, frequency and duration specified. Treat-
ment adherence also includes prescribed prohibitions, such as on driving
or operating machinery or consuming alcohol, illicit drugs, specified foods
or other substances. Any deviation from the prescribed regimen constitutes
nonadherence.
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110 Medication nonadherence
Why is the patient complaining about ‘meningitis’? What management would you suggest?
Side effects are a very common reason for nonadherence. The clinician
should be familiar with the usual side effects of medications they prescribe,
and should communicate these to the patient with sensitivity and reassur-
ance. Family members should also be informed of side effects so that they
can help monitor the patient, particularly during the early days of treatment.
MK did not show up for his appointment likely because no therapeutic alliance was
established prior to discharge and aggressive follow-up care was not instituted.
To facilitate aftercare, therapeutic continuity should be enhanced, barriers to
treatment should be assessed and letters should be written if phone contact is
unsuccessful.
114 Medication nonadherence
Patients miss appointments for many reasons, but a common one is lack
of alliance with the clinician. It is vital that the patient be a partner in
his or her care. This minimizes the possibility of nonadherence. Patients
who appear not to care about their treatment should be closely monitored.
While there are ‘passive’ patients who go along with treatment, they can
just as easily slip out of treatment.
BA is a 26-year-old woman with three young children who has been prescribed
ziprasidone 40 mg BID, clozapine 50 mg BID, depakote 500 mg q AM and 750 mg
q HS and benztropine 1 mg BID. One day, the police are called mid-day because
she is not answering her door and the children are crying inside.
JL, a 21-year-old college freshman, is admitted for ‘odd’ behavior after trying to
climb the science building and patrolling the neighborhood at night in order to
save lives. He does not believe he is ill and refuses all medications.
Why do you think JL is refusing medications? How would you get him to take
medicines?
JL has no insight into the nature of his behavior or its consequences. First, actively
listen to JL’s concerns. This may help him feel understood and possibly improve the
chances of JL listening to you in return! Elicit support from family and friends who
may be able to influence his decisions. Obtain a second opinion if necessary. As a
last resort, initiate the process for compulsory medication (if legally available) only
if JL is a danger to himself or others.
Medication nonadherence 115
Patients who refuse medications because they lack insight into the nature
or severity of their illness are especially challenging to persuade to partner
in their own care. Every effort should be made to get them to initiate treat-
ment. Sometimes short-acting antianxiety agents can reduce the severity
of the illness enough to permit negotiation regarding antipsychotic medi-
cations. Although there is a continuum of opinions regarding forced treat-
ment, always bear in mind that any intervention must be in the patient’s
best interest.
It appears that the treatment offered has not been effective. Since olanzapine
is associated with some weight gain, its absence raises the possibility of
nonadherence. Assess compliance: if KC has been compliant with treatment,
then titrate the olanzapine dose and ensure an adequate duration of treatment;
if still no response, attempt augmentation strategies or change the antipsychotic
prescribed.
than OAs. LAIs are under-utilized in most clinical settings in the US; rea-
sons may include negative attitudes, misconceptions and lack of knowledge
among clinicians, patients and carers. Practical barriers to LAI use include
acquisition costs and inadequate service structures to administer/monitor
LAI treatment.
Patients often view the suggestion for using depot antipsychotics quite
negatively, because it may indicate to them that:
Recent evidence suggests that LAIs are effective for treating first-episode
psychosis and for early initiation of treatment for schizophrenia (Figure
12.1). LAIs should not be restricted to patients with adherence problems,
but instead should be more widely prescribed. LAIs should systematically
be offered to all patients through shared decision-making. Any patient for
whom long-term treatment is indicated should be considered a candidate
for an LAI. Even if patients initially refuse an LAI, it is helpful to discuss it
further to better understand the potential advantages. A common reason
for non-acceptance of LAI therapy may be that psychiatrists are ambivalent
or unenthusiastic about this option even as they recommend it.
An important barrier to success in addressing nonadherence is clinicians’
tendency to emphasize obedience to medication rather than shared goals
for decision-making toward optimal outcomes. Schizophrenia patients are
Table 12.1 Choosing an LAI antipsychotic: key considerations
Concern è
Long-acting Consider
injectable
Aripiprazole
Summary
• Nonadherence, ranging from partial to total, is common in schizophrenia.
• There are multiple causes of nonadherence, which may be related to the
patient, the treatment or the illness; in most cases, the patient chooses
not to adhere to treatment.
Medication nonadherence 119
References
Haddad, P. M., & Correll, C. U. (1999). Long-acting antipsychotics in the
treatment of schizophrenia: Opportunities and challenges. Expert Opin-
ion on Pharmacotherapy, 24(4), 473–493.
Perkins, D. O. (1999). Adherence to antipsychotic medications. Review Jour-
nal of Clinical Psychiatry, 60(Suppl. 21), 25–30.
Weiden, P. J. (2016, June). Redefining medication adherence in the treat-
ment of schizophrenia: How current approaches to adherence lead
to misinformation and threaten therapeutic relationships. Psychiatric
Clinics of North America, 39(2), 199–216.
chapter 13
Managing decompensation
and relapse
Schizophrenia tends to have a lifelong course. This does not mean that indi-
viduals with schizophrenia cannot have good recovery with a high quality
of life. However, for many patients the course of illness is beset with epi-
sodes of decompensation and relapse. The challenge for the patient and cli-
nician is to minimize the frequency and severity of relapse. It is well known
that each episode of relapse becomes harder to treat than the previous one.
Relapse While there are a variety of research criteria for relapse (e.g. 25% worsening
from baseline), in general it is understood as clinical worsening that requires
active intervention, ranging from adjustment of antipsychotic drug (APD) dose
to increased level of care, such as more frequent emergency room visits or partial
or inpatient hospitalization. About one-fifth of patients develop Breakthrough
Psychosis even while on Antipsychotic Maintenance Medication.
Prediction of relapse
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122 Managing decompensation and relapse
Management of decompensation
The challenge in managing decompensation is deciding when to take a
stance of watchful inaction versus active intervention, because mild wors-
ening of clinical state may simply be normal variation in response to life’s
vicissitudes, and the patient may return to the previous state relatively
quickly. Acting too quickly and aggressively can be demoralizing to the
patient; it engenders a feeling that they are completely at the mercy of the
healthcare system with no capability to manage the illness on their own.
On the other hand, when the rate of decompensation is rapid, it is best to
act quickly.
In patients having multiple relapses, the ‘march’ of clinical worsening
towards relapse tends to be similar from one episode to the next. Thus,
knowing well the psychiatric history of the patient is critical in deciding
when and how to respond to change in clinical state. Also, a good ther-
apeutic relationship with the patient and family is critical to successful
relapse-prevention interventions.
124 Managing decompensation and relapse
Table 13.1 Early warning signs of impending relapse
Sleep difficulty Helpless or useless Thoughts are racing Senses seem sharper
Speech jumbled/odd use of afraid of losing one’s mind Thinking one has special powers Experiencing strange sensations
words sad or low Thinking one can read other’s Hearing voices
Talking or smiling to oneself anxious and restless minds Seeing visions or things others
Acting suspiciously as if being increasingly religious Thinking other people can read cannot see
watched like being watched one’s mind Thinking that a part of body has
Odd behavior Fatigued Receiving personal messages changed shape
Isolative Confused from TV/radio Difficulty concentrating
Neglecting one’s appearance Forgetful Difficulty making decisions Difficulty remembering things
Acting like one is somebody Unusually strong and Preoccupied
else powerful Thinking he/she might be
Not eating Unable to cope somebody else
Not leaving the house like being punished Thinking people are talking
Drinking more Can’t trust others about him/her
Smoking more Irritable Thinking people are against
Movements are slow like you do not need sleep him/her
Unable to sit still Remorseful Bizarre thoughts
Aggressive behavior Thinking one’s thoughts are
controlled
Adapted from: Birchwood M, Smith J, Macmillan F, et al. (1989)
Managing decompensation and relapse 125
Management of relapse
the severity and duration of the relapse. Because each episode of relapse is
more difficult to treat than the previous episode, it is worthwhile to spend
considerable effort in preventing relapses. With each relapse comes the
responsibility of devising an even better program of relapse prevention for
the patient.
Relapse prevention
After the first episode of psychosis, the task of treatment is to keep the
patient well for as long as possible. Thus, preventing relapses is the goal of
maintenance treatment. Everything we have discussed about treatment so
far is applicable to relapse prevention. However, framing these treatments
as a formal program (and giving it a name) helps keep the focus on active
prevention of relapse, not just treatment as usual.
Educating the patient and family about early signs and symptoms asso-
ciated with relapse goes a long way towards relapse prevention. As noted
above, each patient will have a unique pattern of relapse that tends to be
the same for each episode. Table 13.1 contains a very comprehensive listing
of early warning signs, developed by Birchwood and colleagues (1989).
Summary
• The course of schizophrenia illness for many patients involves episodes
of decompensation (transitory clinical worsening) and relapse (clinical
worsening that requires active intervention). The goal of maintenance
treatment is to minimize the frequency and severity of relapse.
• Each episode of relapse becomes harder to treat than the previous one.
• A variety of factors are predictive of relapse and increase its risk: relapse
history, expressed emotion, life events, alcohol and substance abuse,
physical illnesses, stopping medications and emergent side effects.
Discuss these predictors with patients and families at the beginning of
treatment.
• Identify early warning symptoms that are unique to given patient.
• Management of decompensation involves taking a stance of watchful
inaction in the case of mild worsening of clinical state. Act quickly when
the rate of decompensation is rapid. Knowing well a patient’s psychiatric
history can help in deciding when and how to respond to change in
Managing decompensation and relapse 127
References
Birchwood, M., Smith, J., Macmillan, F., Hogg, B., Prasad, R., Harvey, C., &
Bering, S. (1989). Predicting relapse in schizophrenia: The development
and implementation of an early signs monitoring system using patients
and families as observers, a preliminary investigation. Psychological Med-
icine, 19, 649–656.
Emsley, R., Chiliza, B., Asmal, L., & Harvey, B. H. (2013). The nature of
relapse in schizophrenia. BMC Psychiatry, 13, 50.
Henson, P., D’Mello, R., Vaidyam, A., Keshavan, M., & Torous, J. (2021,
January 11). Anomaly detection to predict relapse risk in schizophrenia.
Translational Psychiatry, 11(1), 28.
chapter 14
Suicide
Risk factors
A variety of risk factors are associated with suicide in general and schizo-
phrenia in particular, and the two sets do not necessarily overlap. For exam-
ple, being male is a risk factor for suicide in the general population but a
less robust predictor of suicide in the case of schizophrenia. Predictors of
suicide in schizophrenia include high premorbid IQ and good premorbid
achievement predisposing to failed expectations and early relapse or disabil-
ity leading to a fear of mental deterioration; psychological factors include
hopelessness, perceived loss of control over the illness and experience of
stigma. The risk of a suicide attempt during the first year of treatment is as
high as 10%. The following are established risk factors for schizophrenia
(SADHEART):
DOI: 10.4324/9781315152806-14
130 Suicide and violence
Single
Alcohol and substance abuse
Depressed mood
Hopelessness
Early phase of illness
Achievement (high premorbid)
Recurrent relapses
Treatment nonadherence and treatment resistance
The clinician should be vigilant for subtle and early indications of suicidality,
monitor such patients closely, and institute appropriate interventions. Easy-
to-use scales such as the patient health questionnaires (PHQ-9, item 9) can be
used to identify suicide risk and can help initiate a conversation with patients
to explore suicidal ideation and behavior further in the clinical setting. The
three-digit 988 Suicide and Crisis Lifeline (supported by local and state
sources as well as the Substance Abuse and Mental Health Services Adminis-
tration [SAMHSA]) is now available as a national network of more than 200
crisis centers with confidential 24/7 support to people in suicidal crisis or
mental-health-related distress (www.samhsa.gov/find-help/988). The patient
and family should be made aware of these resources as part of a risk-mitiga-
tion strategy that empowers them to seek help when risk is elevated and also
communicates the clinician’s inability to reliably predict future risk.
This inability to predict risk should be straightforwardly communicated
to families and patients in order to invite their collaboration in an ongo-
ing effort to mitigate risk (Cole-King, 2013), by paying regular attention to
emerging risk and addressing ongoing risk in an open and iterative man-
ner that includes all members of a patient’s community. Clinicians should
Suicide and violence 131
be seen as one, but certainly not the only, resource available to assist the
patient at times of crisis where interventions to delay self-harm (e.g., by
brief admission to an emergency setting) may be all that is required to estab-
lish safety and revise a treatment plan.
Psychosocial interventions play an important role in the management of
suicide risk, especially interventions to help coping with stress, loneliness
and interpersonal/family conflicts. Clozapine in recent years has emerged as
an important tool in the therapeutic armamentarium for suicidal behavior.
Violence
Given the portrayals in the media, one would naturally conclude that
patients with schizophrenia routinely indulge in violent behavior. Although
this is not the case, the data suggests there is an increased risk (Whiting
et al., 2022). Aggression is best conceptualized as an accompaniment to irri-
tability, loss of impulse control and neurological dysfunction, which is seen
with many neurological and psychiatric disorders. However, the enduring
image that patients with schizophrenia are prone to unpredictable violence
has done a great disservice to them. When some patients exhibit aggressive
behavior, it is often a result of bizarre hallucinations or delusions.
It is useful to view violence as either transient or persistent, because such
a classification has management implications.
Transient violence occurs in the context of excitation and hyperarousal,
usually in the midst of an acute episode of psychosis, particularly when
leading up to or during hospitalization. Once the episode of psychosis is
treated, the violence recedes and there is generally no continued aggressive
behavior as long as treatment is continued and effective.
Persistent violence is committed by a very small proportion of patients
with schizophrenia. Unlike transiently violent patients, these patients
remain at high risk for violent behavior, even when receiving adequate
treatment and not in a state of hyperarousal.
Gender – male
Ethanol and drug use
Repeated violence
Management of violence
Violence is a medical emergency. The first order of business is physical safety
of all the parties. Verbal de-escalation and environmental modification are
the first choice of intervention, and physical restraint is to be used only
as last resort. For a detailed approach to managing agitation in psychotic
disorders see Vieta et al. (2017). A quick but careful assessment should
be performed to determine contributors to violence, particularly medical
conditions. With a working diagnosis in hand, appropriate interventions
can be instituted, which may include parenteral benzodiazepines (such as
lorazepam) or antipsychotic drugs (APDs) such as haloperidol. Short-acting
forms of other antipsychotics are also available, such as ziprasidone IM,
asenapine sublingual and risperidone M tabs.
Once the violence has abated and treatment is underway, the episode(s)
of violence should be reviewed in order to determine whether it was tran-
sient or possibly persistent. If transient, then no specific violence man-
agement may be required other than ensuring continued treatment. On
the other hand, if the violence appears to be enduring, review of current
pharmacological treatment and enrollment into a violence-prevention pro-
gram is necessary. Atypical APDs, particularly clozapine, have been found
to reduce violent behavior. Violence-reduction programs vary considerably,
but most have the following components:
• structured environment
• leisure activities
Summary
• Half of all patients with schizophrenia attempt suicide and 2–5% of
patients die from suicide.
• A variety of risk factors are associated with suicide in schizophrenia:
single status, alcohol and substance abuse, depressed mood, hopeless-
ness, early phase of illness, high premorbid achievement, revolving-door
admissions and treatment failure.
• Suicide risk in schizophrenia is greatest early in the course of illness, at
a younger age and during the post-discharge period, and it is associated
with low-level suicidal ideation.
• With regard to violence, patients with schizophrenia are at risk for peri-
ods of transient aggression (often related to untreated or poorly treated
illness or comorbid substance use), that likely accounts for the small
increased population-level risk for violence.
• Aggression is an accompaniment of irritability, loss of impulse control
and neurological dysfunction.
• Violence can be transient or persistent. Transient violence is seen with
excitation and hyperarousal, and with treatment it is controlled. Per-
sistent violence is committed by a very small proportion of patients with
schizophrenia; it can occur even when receiving adequate treatment and
not in hyperarousal state.
• A variety of risk factors are predictive of violence. One of the most
robust predictors is the previous history of violence. Others include
persecutory delusions, lack of insight, substance abuse and treatment
non-adherence; neurologic impairment and antisocial traits are asso-
ciated with persistent violence, and male gender predisposes. There is
no substitute to knowing and intervening on risk factors in or outside
this list for your patient. We are better at preventing violence (towards
oneself or others) with clinical interventions than we are at predicting
the same violence.
• Violence is a medical emergency and management includes seeing to the
physical safety of all the parties, quick but careful assessment and phar-
macological interventions (benzodiazepines, droperidol or haloperidol).
134 Suicide and violence
References
Cole-King, A. (2013). Suicide mitigation: A compassionate approach to sui-
cide prevention. Advances in Psychiatric Treatment, 19(4), 276–283.
Crighton, D. (2011, August). Risk assessment: Predicting violence. Evi-
dence-Based Mental Health, 14(3), 59–61.
Dutta, R., Murray, R. M., Hotopf, M., Allardyce, J., Jones, P. B., & Boydell, J.
(2010, December). Reassessing the long-term risk of suicide after a first
episode of psychosis. Archives of General Psychiatry, 67(12), 1230–1237.
Hor, K., & Taylor, M. (2010, November). Suicide and schizophrenia: A sys-
tematic review of rates and risk factors. Journal of Psychopharmacology,
24(Suppl. 4), 81–90.
Vieta, E., Garriga, M., Cardete, L., Bernardo, M., Lombraña, M., Blanch,
J., Catalán, R., Vázquez, M., Soler, V., Ortuño, N., & Martínez-Arán, A.
(2017). Protocol for the management of psychiatric patients with psy-
chomotor agitation. BMC Psychiatry, 17, 328.
Whiting, D., Gulati, G., Geddes, J. R., & Fazel, S. (2022, February 1). Asso-
ciation of schizophrenia spectrum disorders and violence perpetration
in adults and adolescents from 15 countries: A systematic review and
meta-analysis. JAMA Psychiatry, 79(2), 120–132.
chapter 15
Achieving recovery
All the information in the preceding chapters lays the foundation for
helping patients achieve recovery. The Recovery concept has evolved in
response to the experiences of people with mental illness. It involves a shift
away from traditional clinical definitions, such as avoiding relapse, towards
new priorities of supporting the person in working towards their own goals
and taking responsibility for their own life. There are three types of recovery
(Figure 15.1).
Syndromal recovery occurs when the patient is no longer in the pre-
defined syndromal episode such as psychosis. Functional recovery implies
that the patient will return to his or her most functional period prior to the
onset of the disorder. This type of recovery is often slower and may require
different interventions such as psychosocial and cognitive rehabilitation.
Personal recovery refers to the unique process of changing one’s attitudes,
values, feelings, goals, skills and/or roles toward living a satisfying, hope-
ful and contributing life, despite the limitations caused by serious mental
illness. This aspect of recovery can be summarized in the CHIME frame-
work for personal recovery (Connectedness, Hope, Identity, Meaning and
Empowerment) (Slade et al., 2014).
Having very modest aims for recovery (e.g. absence of positive symp-
toms as the only criterion) can be limiting, because all options for helping
the patient may not have been considered. On the other hand, excessively
rapid or lofty expectations that are not achieved can lead to demoraliza-
tion. The most sensible approach is an individualized one. For each patient
DOI: 10.4324/9781315152806-15
136 Achieving recovery
Co-morbid conditions
Depression
Depressive symptoms are common in schizophrenia and may be part of
the prodrome or the florid phase, or follow the first episode (postpsychotic
depression). Depression occurs in 25–40% of patients and is associated with
increased suicidality and poor outcome.
The relationship between depression and schizophrenia has not been
fully elucidated. Depression in schizophrenia may be due to the appearance
of insight about the nature of illness and its lifetime implications. It may be
integral to the schizophrenia illness or reflect another disorder such as schi-
zoaffective disorder or major depression co-occurring with schizophrenia.
First-episode patients tend to have more severe depression compared with
multi-episode patients. Persistent hopelessness at discharge is associated
with poorer outcome a year later.
Depressive symptoms seen in patients with schizophrenia present a
diagnostic challenge. Depression accompanying psychosis is seen in major
depression and the depressive phase of bipolar disorder. Neuroleptic-in-
duced parkinsonism and primary negative symptoms can be mistaken for
depression.
Co-morbid depression must be treated promptly. Selective serotonin
reuptake inhibitors (SSRIs) are quite effective in treating depression in
schizophrenia, unlike the older antidepressants. In the case of antidepres-
sant-resistant depression, atypical APDs, particularly clozapine, have been
helpful – more so than typical APDs.
Achieving recovery 139
Substance abuse
Substance abuse is very common in patients with schizophrenia; as many
as half of all patients will abuse substances during their lifetime. The most
common are nicotine and alcohol, followed by cannabis and cocaine. Can-
nabis misuse has increased significantly in recent years in the US; our studies
suggest that over three-fourths of young, early-course patients use canna-
bis. Earlier age at first exposure to cannabis is associated with younger age
at prodrome and psychosis onset and worse premorbid functioning (Kline
et al., 2022). Dual diagnosis (substance abuse + schizophrenia) is more com-
mon in young males with lower education. Family history of substance
abuse and conduct disorders further increase the risk for substance abuse.
Substance abuse can precede, accompany or follow the first psychotic epi-
sode. The physiological effects of abused substances tend to occur at much
lower quantities in patients with schizophrenia. The course of substance
abuse in schizophrenia tends to be chronic, with multiple relapses. Sub-
stance abuse has many dire consequences, including:
Smoking
Cigarette smoking by patients with schizophrenia exceeds the rates in
the general US population by two- to threefold (Evins et al., 2019). The
prevalence of cigarette smoking in patients with schizophrenia is between
70% and 90%, compared to 35–55% for all other psychiatric patients and
30–35% for the general population. It is not entirely clear why patients with
schizophrenia smoke at such high rates. Reasons suggested include a genetic
basis, as a method of self-treatment, or an underlying neurobiological cause
(nicotinergic deficit). Many patients start smoking after the first episode of
psychosis. The nature of smoking seems to differ, as well (smoking high-tar
cigarettes and for longer periods, inhaling more deeply).
Smoking offsets the sedative effects from psychotropic medications. It has
been shown that smoking lowers blood levels of many psychoactive agents,
including APDs, by activating hepatic enzyme systems and thereby increas-
ing their metabolism, and may help overcome akathisia, dystonia and
parkinsonism. These findings lend support to the idea of self-medication
– more correctly, self-treatment of side effects. Thus, medication dosing has
to be adjusted to smoking status, and in the event of sudden smoking ces-
sation the blood levels of drugs can rise dramatically, resulting in toxicity.
Dose reduction is often required in such situations.
Regardless of the reasons for high rates of smoking, it is associated with
increased medical morbidity but surprisingly not for lung cancer. Patients
should be referred to smoking cessation programs and coordinate closely
with psychiatric care. Pharmacological aids to smoking cessation include
nicotine patches and gum, bupropion, varenicline and possibly clozapine.
Summary
• Recovery is more than the absence of major symptoms. Functional
recovery involves resumption of social and role functioning. Personal
recovery, which involves adaptive integration of one’s life goals despite
the illness, can occur despite or alongside various levels of symptomatic
or functional losses.
• Recovery assessment and treatment planning should be individualized.
Each patient has a unique set of interacting factors that influence the
extent of recovery.
Achieving recovery 141
• There are at least ten factors important for achieving recovery: access to
care, cognitive abilities, duration of untreated psychosis, family rela-
tionships, initial response to medication, personal history, substance
abuse, social skills, supportive therapy and treatment adherence.
• Co-morbidity can significantly impact treatment and outcome. Depres-
sive symptoms are common in schizophrenia, occurring in 25–40%
of patients. First-episode patients tend to have more severe depression
compared with multi-episode patients. Persistent hopelessness at dis-
charge is associated with poor outcome. Depression accompanying psy-
chosis is seen in major depression, bipolar disorder and parkinsonism,
and primary negative symptoms can be mistaken for depression. SSRIs
and some atypical APDs are quite effective in treating depression in
schizophrenia.
• As many as half of all patients with schizophrenia will abuse sub-
stances during their lifetime; the most common are nicotine and alco-
hol, followed by cannabis and cocaine. Substance abuse has many dire
consequences and treatment is not easy. An integrated approach to
assessment and treatment is required. Treatment consists of psycho-
education, motivational interviewing, cognitive behavior therapy and
pharmacotherapy.
• Patients with schizophrenia in the US have high rates of cigarette
smoking (70%–90%). Patients tend to smoke high-tar cigarettes and
inhale more deeply. Smoking counters the sedative effects from psy-
chotropic medications, lowers blood levels of many psychoactive
agents and may help overcome extrapyramidal side effects. Smoking is
associated with significant medical morbidity and patients should be
referred to smoking cessation programs. Pharmacological aids against
smoking include nicotine patches and gum, bupropion and possibly
clozapine.
References
Evins, A. E., Cather, C., & Daumit, G. L. (2019, July). Smoking cessation in
people with serious mental illness. Lancet Psychiatry, 6(7), 563–564.
Kline, E. R., Ferrara, M., Li, F., D’Souza, D. C., Keshavan, M., & Srihari, V. H.
(2022, March). Timing of cannabis exposure relative to prodrome and
142 Achieving recovery
History of schizophrenia
Texts from Egypt and Mesopotamia from the second millennium BCE, as
well as the Atharvaveda, an ancient Indian scripture (ca. 1000 BCE), con-
tain descriptions of serious mental illness. However, descriptions consistent
with the modern conception of schizophrenia emerge in the 18th century.
Some psychiatric historians suggest that schizophrenia is an ancient disor-
der, while others argue that it is a relatively modern one, no more than two
centuries old (Jeste et al., 1985). This is more than an academic debate. If
schizophrenia is indeed of recent origin, then it suggests that historically
recent changes, likely environmental, may be responsible for the emergence
of schizophrenia.
The history of schizophrenia is the history of keen clinical observation.
Psychiatrists had the opportunity to observe the natural progression of
schizophrenia over the course of years, if not the entire lifetimes of patients.
This allowed careful descriptions of clinical syndromes and their natural
courses. Nosology was in vogue during the 19th century, leading to a variety
of systems of classification of mental disorders. Below is a glimpse of a few
of the luminaries who contributed to the modern concept of schizophrenia
(see Figure 16.1).
In the main, the history of the concept of schizophrenia is the history of
keen clinical observation and classification by psychiatrists during the 19th
and 20th centuries (Table 16.1).
DOI: 10.4324/9781315152806-16
144 History of schizophrenia
In spite of the progress made during the previous century, the early and
mid-20th century was marked by descriptive and diagnostic inconsistency.
Further, the lack of understanding of etiopathology of the illness contrib-
uted to significant variations in the frequency of diagnosis of schizophrenia.
During the 1960s, the World Health Organization (WHO) took the initia-
tive to establish a set of criteria that gradually evolved into the Interna-
tional Classification of Diseases (currently in its eleventh revision, ICD-11).
A multinational study conducted by the World Health Organization, using
History of schizophrenia 147
Summary
• The history of mental illness extends back over two millennia, recorded
in early writings from Egypt, Mesopotamia and India.
• Descriptions of schizophrenia, as defined today, appear in the 18th cen-
tury. The earliest description was provided by John Haslam in 1810.
• Schizophrenia may be a relatively modern disorder, suggesting that the
impacts – probably environmental – of modernity may be responsible
for the emergence of schizophrenia.
• The concept of schizophrenia is still evolving and is best conceptualized
currently as a heterogeneous syndrome that may include multiple psy-
chopathological dimensions and pathophysiological processes.
148 History of schizophrenia
References
Andreasen, N. C., & Olsen, S. (1982, July). Negative v positive schizophrenia.
Definition and validation. Archives of General Psychiatry, 39(7), 789–794.
Carpenter, W. T. Jr, Heinrichs, D. W., & Wagman, A. M. (1988, May). Deficit
and nondeficit forms of schizophrenia: The concept. American Journal of
Psychiatry, 145(5), 578–583.
Clementz, B. A., Sweeney, J. A., Hamm, J. P., Ivleva, E. I., Ethridge, L. E.,
Pearlson, G. D., Keshavan, M. S., & Tamminga, C. A. (2016, April 1).
Identification of distinct psychosis biotypes using brain-based biomark-
ers. American Journal of Psychiatry, 173(4), 373–384.
Crow, T. J. (1980, January 12). Molecular pathology of schizophrenia: More
than one disease process? British Medical Journal, 280(6207), 66–68.
Insel, T., Cuthbert, B., Garvey, M., Heinssen, R., Pine, D. S., Quinn, K.,
Sanislow, C., & Wang, P. (2010, July). Research domain criteria (RDoC):
Toward a new classification framework for research on mental disorders.
American Journal of Psychiatry, 167(7), 748–751.
Jeste, D. V., del Carmen, R., Lohr, J. B., & Wyatt, R. J. (1985, November–
December). Did schizophrenia exist before the eighteenth century? Com-
prehensive Psychiatry, 26(6), 493–503.
Kotov, R., Cicero, D. C., Conway, C. C., DeYoung, C. G., Dombrovski, A.,
Eaton, N. R., First, M. B., Forbes, M. K., Hyman, S. E., Jonas, K. G., Krueger,
R. F., Latzman, R. D., Li, J. J., Nelson, B. D., Regier, D. A., Rodriguez-Seijas,
C., Ruggero, C. J., Simms, L. J., Skodol, A. E., . . . Wright, A. G. C. (2022,
July). The hierarchical taxonomy of psychopathology (HiTOP) in psy-
chiatric practice and research. Psychological Medicine, 52(9), 1666–1678.
chapter 17
Incidence is the number of newly diagnosed cases during a specific time pe-
riod. In any given year, three to six individuals will be newly diagnosed with
schizophrenia out of a population of 10,000 (incidence rate: 30–60 in 100,000).
DOI: 10.4324/9781315152806-17
150 Who gets schizophrenia and why?
Is schizophrenia inherited?
Eugen Bleuler noted that relatives of patients with schizophrenia were often
‘tainted by hereditary mental disease’. In recent years, the genetic basis of
this illness has been well established. In the 1980s, psychiatrists such as
Thomas Szasz held the view that schizophrenia as a disease may be a myth
and that it is caused mainly by problems of living. In response, Seymour
Kety famously said, ‘If schizophrenia is a myth, it is a genetically trans-
mitted myth!’ It is well established that schizophrenia aggregates in fami-
lies. This is the result of interactions between genetic risk and both shared
and non-shared environmental factors, which can begin to act during fetal
development. While the full list and precise mechanism of these gene-en-
vironment interactions are topics of active research, this integrative concept
should replace simple contrasts between nature and nurture.
Family, twin and adoption studies have demonstrated that the chance of
developing schizophrenia increases with biological proximity to the affected
individual, establishing that a significant portion of risk for schizophrenia is
heritable (i.e. explained by genetic factors). The likelihood that an individual will
develop schizophrenia increases from about 0.5% in the general population
to almost 50% if both parents or an identical twin is affected, with risk esti-
mates between the two poles varying with degree of relatedness (Figure 17.1).
Who gets schizophrenia and why? 151
Figure 17.2 There may be multiple etiological factors in what we call schizo-
phrenia.
What is transmitted?
Schizophrenia is a complex disorder that affects multiple domains of higher
level functioning and cannot be tied simply to genes. Rather, what may be
transmitted is a liability for developing the illness. This liability may express
itself as poor psychosocial functioning, unusual behavior or non-affective
psychoses. Biological relatives of individuals with schizophrenia have a
higher prevalence of schizophrenia but also schizotypal personality disor-
der; and these disorders have thus been considered schizophrenia spec-
trum disorders. However, unusual or idiosyncratic thinking and behavioral
disturbances are imprecise indicators of risk.
Endophenotypes (illness traits that are between the phenotype and gen-
otype), such as SPEM (Smooth Pursuit Eye Movement) dysfunction and
sustained attentional deficits (Figure 17.3), may serve as biological vulner-
ability markers and are increasingly being utilized as a detection strategy
in genetic studies.
Who gets schizophrenia and why? 153
Figure 17.4 Genetic factors in schizophrenia overlap with those for bipolar
disorder, autism and ADHD.
Source: Smoller (2013).
result from genetic studies is that many of the genes that confer risk for
schizophrenia are associated with other neuropsychiatric disorders, such
as bipolar disorder, autism and attention-deficit disorder (Smoller, 2013;
see Figure 17.4).
Paternal age Fathers above the age of 45 had a twofold elevated risk, and
fathers above the age of 50 had a threefold elevated risk of
having offspring develop schizophrenia, compared to fathers
at or below the age of 25. Although the mechanisms remain
unclear, accumulation of several point mutations during the
replications of spermatogonial stem cells and epigenetic
changes related to methylation, demethylation and histone
modifications have been proposed.
Trauma Trauma of various kinds (physical and sexual abuse, neglect)
have been associated with the risk for schizophrenia. Overall, a
three- to sevenfold increase in risk for schizophrenia is reported
when the trauma occurred before the age of 16.
Season of In the northern hemisphere, schizophrenia patients tend to
birth be born more frequently between January and April; in the
southern hemisphere, the same is true between July and
September. It has been suggested that viral infections may
account for this correlation.
Cannabis There is increasing evidence that heavy cannabis abuse
abuse during adolescence increases the risk for later schizophrenia
(D’Souza et al., 2022). The greater the dose, and the earlier
the age of exposure, the greater the risk. The liberalization of
cannabis use in USA in recent years is of concern. Delaying
or eliminating exposure to cannabis or cannabinoids could
potentially impact the rates of psychosis related to cannabis,
especially in those who are at high risk for developing the
disorder.
Summary
• Schizophrenia runs in families and has a high degree of heritability.
• Causes of schizophrenia involve a large number of genes and several
environmental factors that may interact to lead to this illness.
• The causal factors of schizophrenia are not specific to this illness and
overlap considerably with other disorders such as bipolar disorder,
autism and neurodevelopmental disorders.
References
D’Souza, D. C., DiForti, M., Ganesh, S., George, T. P., Hall, W., Hjorthøj, C.,
Howes, O., Keshavan, M., Murray, R. M., Nguyen, T. B., Pearlson, G. D.,
Ranganathan, M., Selloni, A., Solowij, N., & Spinazzola, E. (2022, Decem-
ber). Consensus paper of the WFSBP task force on cannabis, cannabinoids
and psychosis. World Journal of Biological Psychiatry, 23(10), 719–742.
Gottesman, I. I. (1991). Schizophrenia genesis: The origin of madness. Freeman.
Jester, D. J., Thomas, M. L., Sturm, E. T., Harvey, P. D., Keshavan, M., Davis,
B. J., Saxena, S., Tampi, R., Leutwyler, H., Compton, M. T., Palmer, B.
W., & Jeste, D. V. (2023, April 6). Review of major social determinants
of health in schizophrenia-spectrum psychotic disorders: I. Clinical out-
comes. Schizophrenia Bulletin. Epub ahead of print. PMID: 37022779.
Schizophrenia Working Group. (2014). Biological insights from 108 schizo-
phrenia-associated genetic loci. Nature, 511(7510), 421–427.
Sekar, A., Bialas, A. R., de Rivera, H., Davis, A., Hammond, T. R., Kamitaki,
N., Tooley, K., Presumey, J., Baum, M., Van Doren, V., Genovese, G., Rose,
S. A., Handsaker, R. E., Schizophrenia Working Group of the Psychiatric
Genomics Consortium, Daly, M. J., Carroll, M. C., Stevens, B., & McCar-
roll, S. A. (2016). Schizophrenia risk from complex variation of comple-
ment component 4. Nature, 530(7589), 177–183.
Smoller, J. W. (2013). Identification of risk loci with shared effects on
five major psychiatric disorders: A genome-wide analysis. The Lancet,
381(9875), 1371–1379.
chapter 18
Neurobiology of
schizophrenia
Neuroanatomical alterations
DOI: 10.4324/9781315152806-18
158 Neurobiology of schizophrenia
It has been known since the early part of the 20th century that schizo-
phrenia patients frequently show enlargement of the cerebral ventricles, as
shown in pneumoencephalographic studies. The advent of CT scanning in
the 1970s confirmed the observations that lateral ventricles are enlarged in
a substantial proportion of schizophrenic patients; these data were repli-
cated with subsequent MRI studies (Figure 18.2).
MRI research has delineated the following structural brain abnormalities:
Neurochemical alterations
The conventional teaching over the past decades has been that psychotic
symptoms are related to excess of dopamine. Supporting this view is the
fact that all effective antipsychotics block dopamine (Figure 18.3), and
the fact that agents that increase dopamine levels, such as amphetamine
and cocaine, can cause psychotic symptoms. Also, there is indirect support
based on observations of increased levels of homovanillic acid, a dopamine
metabolite, in the cerebrospinal fluid of schizophrenic patients. Postmor-
tem studies of dopamine receptor density have yielded inconsistent results.
Recent positron emission tomography (PET) studies, however, support pre-
synaptic alterations of dopamine transmission in schizophrenia.
A more nuanced view of the role of dopamine suggests that negative
and cognitive symptoms in schizophrenia may be related to reduced
activity in the mesocortical dopamine system, while positive symptoms
may be related to a hyperdopaminergic state in the mesolimbic dopamine
system (Weinberger, 1987). The mesolimbic system is normally inhibited
by the mesocortical dopamine system; thus, the mesolimbic over-activity
Neurobiology of schizophrenia 161
may be due to disinhibition from the cortical ‘brakes’. The most recent
articulation of a modified dopamine hypothesis sees hyperdopaminergia
in the mesolimbic system as explaining only the positive symptoms of
the psychosis syndrome. While this makes for a more modest account
of the illness, it remains the most applicable in medication choice and
also offers a useful way to describe or at least speculate about how this
abnormality can lead to a subjective sense of ‘aberrant salience’ in the
patient. This can offer patients and families a way to appreciate that odd
or delusional beliefs and disorganized behavior can be the result of an
illness process rather than a willed choice or personality trait (Howes &
Kapur, 2009).
A variety of other neurotransmitters are likely involved in the patho-
genesis of schizophrenia. It is also possible that more fundamental defects,
perhaps in cellular membranes, may be implicated. For each of these alter-
native hypotheses, varying degrees of evidence are available.
162 Neurobiology of schizophrenia
Glutamate
Glutamate, an excitatory neurotransmitter, is the most abundant neu-
rotransmitter. Phencyclidine, a glutamatergic receptor antagonist, causes
symptoms similar to schizophrenia. Post-mortem studies have suggested
that brains of individuals with schizophrenia may have alterations in glu-
tamatergic receptors.
Neurophysiological alterations
Neuropathological evidence
Over the past several decades it has become clear that the structural, func-
tional and neurochemical brain alterations outlined above are not specific
to schizophrenia, but are seen to varying extent across other disorders, such
as schizoaffective and bipolar disorders.
166 Neurobiology of schizophrenia
Summary
• Schizophrenia is associated with widespread structural and physiologi-
cal alterations, resulting in abnormal connectivity across multiple brain
networks.
• Dopamine is proximately involved, but imbalances in glutamate, GABA
and other molecules underlying synapse function and brain develop-
ment are involved as well.
• Schizophrenia may result from synaptic pruning during adolescence
and a deficit in brain plasticity.
• Brain abnormalities in psychotic disorders may cut across symp-
tom-based diagnoses and may identify distinct biological subtypes of
psychotic illness with distinct treatment targets.
References
Feinberg, I. (1982/1983). Schizophrenia: Caused by a fault in programmed
synaptic elimination during adolescence? Journal of Psychiatric Research,
17(4), 319–334.
Howes, O. D., & Kapur, S. (2009, May). The dopamine hypothesis of schizo-
phrenia: Version III-the final common pathway. Schizophrenia Bulletin,
35(3), 549–562.
Keshavan, M. S. (1999, November–December). Development, disease and
degeneration in schizophrenia: A unitary pathophysiological model.
Journal of Psychiatric Research, 33(6), 513–521.
Stone, W. S., Phillips, M. R., Yang, L. H., Kegeles, L. S., Susser, E. S., & Lieb-
erman, J. A. (2022, May). Neurodegenerative model of schizophrenia:
Growing evidence to support a revisit. Schizophrenia Research, 243,
154–162.
Weinberger, D. R. (1987, July). Implications of normal brain development
for the pathogenesis of schizophrenia. Archives of General Psychiatry,
44(7), 660–669.
chapter 19
Our task in the present is to do the best we can for our patients and
their families. The future, judging from the recent past, looks hopeful. It
is important to maintain an optimistic outlook, for there is good cause.
There continue to be advancements on many fronts – molecular genetics,
integrative biology, refined psychosocial interventions, functional brain
imaging, services research, complementary medicine, prevention studies
and cross-national studies, to name but a few areas. First, advances in our
understanding of the neurobiological features of the illness may enable
development of biomarkers of value for diagnosis, treatment choice and
outcome prediction. Second, neuroimaging studies have enabled identifi-
cation of specific neural circuitry changes that may underlie alterations in
several psychopathological domains. Finally, a better understanding of neu-
rochemical underpinnings of schizophrenia and related illnesses points to
several potential therapeutic targets for psychopharmacological treatments.
These advancements will eventually translate into better-targeted, more-ef-
fective and safer treatments.
Biomarkers
There are relatively few biomarkers in clinical use in psychiatry at this time,
but this is an area of active research (Abi-Dargham et al., 2023). In the area
of schizophrenia, biomarkers may be of value in four settings.
DOI: 10.4324/9781315152806-19
168 What does the future hold?
Phase III trials are large-scale (up to 3000 individuals) and frequently
multi-site studies to confirm efficacy, compare with placebo or stan-
dard treatments and monitor safety.
After the completion of the trials, the data is submitted to the FDA. After
much deliberation about the drug’s safety, efficacy, risk-benefit ratio, man-
ufacturing methods and so on, the FDA may decide to approve the drug or
request additional data. Once approved (which may take up to 12 years from
the initial chemical identification), marketing can begin. There are phase
IV trials for some drugs to continue evaluating effectiveness and safety. The
success rate of getting a potential drug off a laboratory shelf into a patient’s
hands is quite low. It is estimated that for every 5,000 compounds screened,
five make it to clinical trials, and one gets approved (1:5000 = 0.02% chance
of success)!
There are a number of promising compounds in the pipeline, some tak-
ing the well-trodden path of 5-hydroxytryptamine (5-HT)/dopamine (DA)
antagonism, while others have novel mechanisms of action. Table 19.1 is a
partial listing of some compounds at various stages of testing (see Keshavan
et al., 2017 for a detailed review).
Services research
References
Abi-Dargham, A., Moeller, S. J., Ali, F., DeLorenzo, C., Domschke, K., Horga,
G., Jutla, A., Kotov, R., Paulus, M. P., Rubio, J. M., Sanacora, G., Veen-
stra-VanderWeele, J., & Krystal, J. H. (2023, June). Candidate biomark-
ers in psychiatric disorders: State of the field. World Psychiatry, 22(2),
236–262.
Brady, R. O. Jr, Gonsalvez, I., Lee, I., Öngür, D., Seidman, L. J., Schmah-
mann, J. D., Eack, S. M., Keshavan, M. S., Pascual-Leone, A., & Halko, M.
A. (2019, July 1). Cerebellar-prefrontal network connectivity and nega-
tive symptoms in schizophrenia. American Journal of Psychiatry, 176(7),
512–520.
Gandara, V., Pineda, J. A., Shu, I. W., & Singh, F. (2020, January). A system-
atic review of the potential use of neurofeedback in patients with schizo-
phrenia. Schizophrenia Bulletin Open, 1(1).
Guimond, S., Gu, F., Shannon, H., Kelly, S., Mike, L., Devenyi, G. A., Chakra-
varty, M. M., Sweeney, J. A., Pearlson, G., Clementz, B. A., Tamminga,
C., & Keshavan, M. (2021, October 21). A diagnosis and biotype com-
parison across the psychosis spectrum: Investigating volume and shape
amygdala-hippocampal differences from the B-SNIP study. Schizophrenia
Bulletin, 47(6), 1706–1717.
Islam, F., Hain, D., Lewis, D., Law, R., Brown, L. C., Tanner, J. A., & Müller,
D. J. (2022, July). Pharmacogenomics of Clozapine-induced agranulocy-
tosis: A systematic review and meta-analysis. Pharmacogenomics Journal,
22(4), 230–240.
Kapur, S., Phillips, A. G., & Insel, T. R. (2012, December). Why has it taken
so long for biological psychiatry to develop clinical tests and what to do
about it? Molecular Psychiatry, 17(12), 1174–1179.
Keshavan, M. S., & Clementz, B. A. (2023, April). Precision medicine for psy-
chosis: A revolution at the interface of psychiatry and neurology. Nature
Reviews Neurology, 19(4), 193–194.
Keshavan, M. S., Lawler, A. N., Nasrallah, H. A., & Tandon, R. (2017, May).
New drug developments in psychosis: Challenges, opportunities and
strategies. Progress in Neurobiology, 152, 3–20.
Sarpal, D. K., Argyelan, M., Robinson, D. G., Szeszko, P. R., Karlsgodt, K. H.,
John, M., Weissman, N., Gallego, J. A., Kane, J. M., Lencz, T., & Malhotra,
A. K. (2016). Baseline striatal functional connectivity as a predictor of
174 What does the future hold?
When there are several meanings of words, as is often the case, we have cho-
sen the ones that are relevant to the topic at hand, namely schizophrenia.
Professional organizations
Books
Practice guidelines
Note: Page numbers in italics indicate a figure and page numbers in bold
indicate a table on the corresponding page.