Schizophrenia and Drug-Induced Psychotic Disorders
Schizophrenia spectrum disorders are among the most expensive illnesses, due to their chronic course, the long periods of in-patient and rehabilitative treatments and a high proportion of chronically disabled and unemployed individuals (Rossler et al., 1998). For developing countries with their very low expenditures for mental health services (Saxena et al., 2003), especially the immense indirect costs, e.g. the loss of productivity through the illness itself and the caretaking, are a high burden for families and communities.
Recent decades brought new insights in its etiology, epidemiology and symptomatology. Today, schizophrenia is conceptualized as a ‚neuro-developmental disorder’, because perinatal brain lesions increase the risk for its onset, which is typically during late adolescence or early adulthood (Laruelle, 2003; Thompson et al., 2004). In recent years, substantial evidence has accumulated that schizophrenic patients develop a dysregulation of dopaminergic neural activity especially of the mesolimbic and mesocortical dopaminergic systems (Laruelle, 2003). This dysregulation is closely related to deficits in glutaminergic, GABAergic and serotonergic activity in limbic structures and prefrontal cortex, which normally modify and down-regulate the dopaminergic response to external stressors (Moggaddam & Krystal, 2003; Thompson et al., 2004). In summary, vulnerability to schizophrenia is expressed as a hyperreactivity of mesolimbic dopamiergic projections to exogenuous stressors, i.e. a dysfunctional down-regulation of
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2003). Although genetic studies revealed a substantial genetic contribution to the vulnerability for schizophrenia, in many cases the genes are not sufficient to explain why a single individual develops schizophrenia (McGue & Gottesman, 1991). Besides complications during pregnancy or birth, certain severe somatic diseases, like Chorea Huntington or Alzheimer’s disease, as well as virus infections of the brain during early childhood increase the risk for schizophrenia substantially (Hafner, 2001).
A number of studies highlight the fact that early drug use be related to the development of schizophrenia. In animal studies, damage imposed on the developing brain, e.g. by drugs, increased the potential of amphetamine-like agents to change neuro-chemical systems and to induce psychotic-like behavior (Lipska et al., 2002; Lipska et al., 1995). In humans, early onset of stimulant abuse might be related to the development of acquired vulnerability (Mueser et al,, 1990) and additional risk factors and particular stressors, such as traumatic experiences, may also contribute to increase it (Mueser et al., 2002).
Most patients develop schizophrenia in their late adolescence and early adulthood with unspecific symptoms, e.g. depressive mood, social withdrawal, loss of motivation, often occuring years before the first hospitatization, These, in turn, may account for poor school performance and other problems. For a long time it was believed that in this period, patients start abusing drugs, like nicotine, alcohol, stimulants or cannabis (Farrell et al., 2002; Hambrecht & Hafner, 2000; Holtmann et al., 2002). While it was assumed that drug use should counteract symptoms (Schneier & Siris, 1987), Hambrecht & Hafner (1996) concluded from a retrospective assessment of a representative sample of 232 first-episode patients that about a third of them each started substance abuse before,
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simultaneously with and after the onset of prodromal symptoms. Moreover, Andreasson et al. (1987) found in a prospective study that among a national cohort of over 45.000 military conscripts cannabis use was related to an increased risk for subsequent schizophrenia, even when predisposing personality traits and the use of other drugs were controlled and a current prodromal phase was excluded (Zammit et al., 2002).
Irrespective of the different ways to determine the onset of the disorder (e.g. first positive symptom, first admission to in-patient treatment, etc.), the onset of schizophrenia is about four years earlier in men than women (Hambrecht & Hafner, 1992). In the above mentioned study, male patients developed their first positive symptom on average at the age of 27.8 years, female patients at the age of 30.9 years (Hafner et al., 1998). The cumulative life-time incidence is similar for both genders because of more frequent late-onset courses in women. At age 60 men had a cumulative lifetime incident rate of 13.1 cases per 100.000 and women 13.2. This is in line with the outcomes of a large international study including ten countries conducted by the WHO (Jablensky et al., 1992; Sartorius et al., 1986), which showed that the cumulative lifetime incidence rates of a narrowly defined schizophrenia (Cathego S+) is about 10 per 100.000. Stimulant abuse during puberty has been found to be related to earlier onset of the disorder and earlier hospitalization (Mueser et al., 1990), as well as to more comorbid behavioral problems (Hambrecht & Hafner, 1996) and poorer treatment outcome (Buhler et al., 2002). Studies in low-income countries show that the course of schizophrenia seems to be more favorable than in western countries (Jablensky et al., 1994; Manton et al., 1994).
However, the recent increased use of cannabis and other drugs in these countries
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(UNODC, 1999, 2004) might produce a different picture by now. Its effect on psychotic disorders have not yet been studied.
In schizophrenia patients, drugs like amphetamines can exacerbate the symptoms or even provoke a relapse (Janowsky & Davis, 1976; Lieberman et al., 1987), which challenges the management of the disorder (Kavanagh et al., 2002). Drug-effects on the course of illness may be attributed to sensitization (Sato et al., 1983; Sato et al., 1992;
Yui et al., 2002) or to lasting neuro-toxic effects of prolonged stimulant intake (Robinson
& Becker, 1986). Many researchers believe that schizophrenic patients under treatment often consume drugs like nicotine, cannabis or amphetamines in order not just to self-medicate the nonspecific physical symptoms but also typical side effects of neuroleptics (Mueser et al., 1998).
Some drugs have circumscribed psychotomimetic properties and neurotoxic effects that can induce temporary or long-lasting psychotic states; examples are Psilocybin, Phencyclin (PCP, ‚Angel Dust’), Ketamin ‚ L-Dopa and amphetamines. In the following we will only focus on amphetamine-like drugs, which include cathinone, the main psycho-active agent of the khat leaves.
Amphetamines, khat and psychotic disorders
Experiments in humans (Bell, 1973) and animals (Robinson & Becker, 1986) have shown that amphetamines and some of its derivatives induce psychotic symptoms. The underlying neurophysiological mechanism is amphetamine-induced dopaminergic hyperactivity of mesolimbic projections (Laruelle et al., 1997; Sharp et al., 1987).
Repeated administration to amphetamines leads to ‘behavioral sensitization’, i.e. the increased dopaminergic reaction and its behavioral correlates to subsequent stimulant
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administrations or stress exposure (Kalivas & Stewart, 1991). Despite the ongoing scientific debate about amphetamine-induced psychosis it remains unclear whether the use of amphetamine-like substances may actually cause disorders of the schizophrenia spectrum in otherwise healthy individuals, or triggers its onset in individual with high vulnerability to the disease (Phillips & Johnson, 2001; Poole & Brabbins, 1996). Several authors suggested that chronic amphetamine use might produce a long-lasting schizophrenia-like disorder (Flaum & Schultz, 1996; Machiyama, 1992; Sato et al., 1992). In the clinical setting, upon admission of a psychotic patient, the possibility of a stimulant-induced psychosis is usually considered when the amphetamine drug screening is positive and the recent use of the drug can be confirmed. The further decision whether or not a drug-induced psychotic disorder is diagnosed largely depends on the time course of the remission. Drug-induced states usually remit very fast, i.e. within two weeks, often without medication, in contrast to disorders of the schizophrenia spectrum, which remit slowly. On the symptom level, the acute picture cannot be easily distinguished between the two disorders, although on a group level there might be differences, e.g. related to whether a clear consciousness is maintained or related to the quality of hallucinatory symptoms (Connell, 1958). The fact that presumed amphetamine psychoses do not fully remit within weeks of abstinence in a substantial percentage of individuals (Sato et al., 1992) may also suggest that those individuals actually had a amphetamine-triggered schizophrenia.
Early, medical researchers visiting Yemen have claimed that khat use can provoke an acute psychotic condition that cannot be distinguished from schizophrenia;
furthermore, they reported that schizophrenic patients are frequently chewers of khat
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(Luqman & Danowski, 1976). According to the currently prevailing opinion, khat-induced psychotic disorders are rare phenomena due to the bulky nature of the drug (Halbach, 1972; Kalix, 1987). However, khat-induced psychopathology might not be detected as caretakers habitually lock-up or chain psychotic patient within their houses due to the lack of psychiatric services. This was reported for Yemen (Luqman &
Danowski, 1976), Ethiopia (Alem & Shibre, 1997) and Somalia (Odenwald et al., 2005b). Psychiatrists from African countries noted khat-induced psychoses in their units (Dhadphale & Mengech, 1987) or hypothesized that many undetected cases exist within communities (Alem & Shibre, 1997).
In summary, we do not know much about the relationship between khat and disorders of the schizophrenia spectrum.
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