GENERAL CNS DEPRESSANTS: neuroleptics, tranquilizers, sedatives. Lithium preparations (Aminazinum, Triftazinum, Droperidolum, Haloperidolum, Closapinum, Chlorprotixenum, Sulpiridum, Phtorphenasinum, Chlozepidum, Sibasonum (Diasepanum), Phenazepamum, Medazepamum, Litii carbonas)

ACTIVATING CNS DRUGS: analeptics, antidepressants, metabolic cerebral protectors and adaptogens (Imisinum, Amitriptillinum, Pyrazidolum, Fluoxetinum, Sydnocarbum Coffeinum-natrii benzoas, Piracetamum, Cavintonum, Pentoxyphylline, Natrii oxybutiras, Cinarisinum, Vinpocetinum, Nicergolin, Pentoxiphyllini, papaverini hydrochloridum, Sermionum, Tinctura Ginseng, Tinctura Schisandrae, Extract Eleuterococci, Pantocrinum, Bemetilum, Cordiaminum, Sulfocamphocainum, Camphora, Bemegridum, Aethymisolum)

 

General CNS depressants: neuroleptics, tranquilizers, sedatives. Lithium preparations

Central nervous system depressants slow down the operation of the brain. They first affect those areas of the brain that control a person’s conscious, voluntary actions. As dosage increases, depressants begin to affect the parts of the brain controlling the body’s automatic, unconscious processes, such as heartbeat and respiration.

Alcohol is the most familiar and most widely abused depressant. With some exceptions, all depressants affect people in much the same way as do alcohol.

Most depressant users ingest these drugs orally. However, a few abusers will inject their drugs intravenously. The injection paraphernalia used by barbiturate abusers are similar to those used by heroin addicts, although a wider gauge hypodermic needle is used, because the barbiturate solution is thicker than the heroin solution. The injection sites on the skin of a barbiturate abuser exhibit large swellings, and may develop ulceration’s resembling cigarette burns.

The affects of depressants are once again compared to those of alcohol – reduced social inhibitions, impaired ability to divide attention, slow reflexes, impaired judgment and concentration, impaired vision and coordination, slurred, mumbled or incoherent speech, a wide variety of emotional effects, such as euphoria, depression, suicidal tendencies, laughing or crying for no apparent reason, etc.

Depressants vary in the amount of time it takes the user to feel the effects and also the amount of time the effects are felt. Some depressants act very quickly, and begin to affect their user within seconds. Others act more slowly, sometimes taking one-half hour or more to begin to exert an influence. The quick-acting depressants also tend to be relatively short acting: in some cases their effects wear off in a matter of minutes. The slow-acting depressants, on the other hand, tend to produce longer-acting effects.

Overdoses of depressants produce effects that are the same as alcohol overdoses. The person becomes extremely drowsy and passes out. Their heartbeat slows and respiration will become shallow. Their skin may feel cold and clammy, and death may result from respiratory failure.

Neuroleptic: synonym for antipsychotic drug; originally indicated drug with antipsychotic efficacy but with neurologic (extrapyramidal motor) side effects

Typical neuroleptic: older agents fitting this description

Atypical neuroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effects

The neuroleptic drugs (also called antipsychotic drugs, or major tranquilizers) are used primarily to treat schizophrenia, but they are also effective in other psychotic states, such as manic states with psychotic symptoms such as grandiosity or paranoia and hallucinations, and delirium. All currently available antipsychotic drugs that alleviate symptoms of schizophrenia decrease dopaminergic and/or serotonergic neurotransmission. The traditional or “typical” neuroleptic drugs (also called conventional or first-generation antipsychotics) are competitive inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blocking of dopamine receptors. These drugs vary in potency. For example, chlorpromazine is a low-potency drug, and fluphenazine is a high-potency agent. No one drug is clinically more effective than another. In contrast, the newer antipsychotic drugs are referred to as “atypical” (or second-generation antipsychotics), because they have fewer extrapyramidal adverse effects than the older, traditional agents. These drugs appear to owe their unique activity to blockade of both serotonin and dopamine (and, perhaps, other) receptors. Current antipsychotic therapy commonly employs the use of the atypical agents to minimize the risk of debilitating movement disorders associated with the typical drugs that act primarily at the D2 dopamine recep tor. All of the atypical antipsychotics exhibit an efficacy that is equivalent to, or occasionally exceeds, that of the typical neuroleptic agents. However, consistent differences in therapeutic efficacy among the individual atypical neuroleptics have not been established, and individual patient response and comorbid conditions must often be used as a guide in drug selection. Neuroleptic drugs are not curative and do not eliminate the fundamental and chronic thought disorder, but they often decrease the intensity of hallucinations and delusions and permit the person with schizophrenia to function in a supportive environment.

Dopamine-blocking actions of neuroleptic drugs.

TYPICAL NEUROLEPTICS:

PHENOTHIAZINES:

Chlorpromazine (Thorazine ® )

Thioridazine (Mellaril ® )

Fluphenazine (Prolixin ® )

THIOXANTHENE

Thiothixene (Navane® )

OTHER

ATYPICAL  NEUROLEPTICS:

Risperidone (Risperdal ® ; most frequently prescribed in U.S.)

Clozapine (Clozaril ® )

Olanzapine (Zyprexa ® )

Quetiapine (Seroquel ® ) Haloperidol (Haldol ® )

The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system.

Typical neuroleptics block the dopamine-2 receptor.  

 

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS

Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence

Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension with reflex tachycardia, sedation

Antihistamine effect: sedation, weight gain

EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).

Dystonia

Neuroleptic  malignant syndrome

Parkinsonism

Tardive dyskinesia

Akathisia

Other side effects

Increased prolactin secretion (common with all; from dopamine blockade)

Weight gain (common, antihistamine effect?)

Photosensitivity (common with phenothiazines)

Lowered seizure threshold (common with all)

Leucopenia, agranulocytosis (rare; with phenothiazines)

Retinal pigmentopathy (rare; with phenothiazines)

Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).

Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

Blockade of alpha-1 adrenergic receptors

Blockade of muscarinic cholinergic receptors

Blockade of histamine-1 receptors

Clozapine is a prototype ‘broad-spectrum’ antagonist. Its binding profile is quite different from other anti-psychotics both within and outside the dopaminergic system. It has relatively low affinity for D2 receptors in the striatum, while its in vitro affinity for the D4 receptors is approximately ten times greater than that for D2 receptors, and it has also been shown to bind to the D1, D3 and D5 receptors. Since D4 density is highest in the frontal cortex and amygdala but relatively low in the basal ganglia, this may be the explanation for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra-pyramidal side-effects. Clozapine has been recognised to show significant activity at a broad range of receptors outside the DA system. Of particular interest is its high affinity for 5-HT receptors, including 5-HT2, 5-HT3, 5-HT6 and 5-HT7 subtypes. Clozapine has high affinities for muscarinic A1 and A2 receptors, while it also has significant effects on GABA-ergic and glutamatergic mechanisms.

Pharmacokinetics and Metabolism

After oral administration the drug is rapidly absorbed. There is extensive first-pass metabolism and only 27-50% of the dose reaches the systemic circulation unchanged.

Its plasma concentration has been observed to vary from patient to patient. Various individual factors may vary response such as smoking, hepatic metabolism, gastric absorption, age and, possibly, gender. Clozapine is rapidly distributed. It crosses the blood-brain barrier and is distributed in breast milk. It is 95% bound to plasma proteins. Steady-state plasma concentration is reached after 7-10 days. The onset of the anti-psychotic effect can take several weeks, but maximum effect may require several months. In treatment-resistant schizophrenia, patients have been reported to continue to improve for at least two years after the start of clozapine treatment. Clozapine metabolises into various metabolites, out of which only norclozapine (a desmethyl metabolite) is pharmacologically active. The other metabolites do not appear to have clinically significant activity. Its plasma concentration declines in the biphasic manner, typical of oral anti-psychotics, and its mean elimination half-life ranges from 6 to 33 hours. About 50% of a dose is excreted in urine and 30% in the faeces.

 

Cautions and Contra-indications

These include patients with myeloproliferative disorders, a history of toxic or idiosyncratic agranulocytosis or severe granulocytopaenia (with the exception of granulocytopaenia/agranulocytosis from previous chemotherapy). Clozapine is contra-indicated in patients with active liver disease, progressive liver disease and hepatic failure. Other contra-indications include severe CNS depression or comatose state, severe renal and cardiac disease, uncontrolled epilepsy, circulatory collapse, alcoholic/toxic psychosis and previous hypersensitivity to clozapine.

The most serious of clozapine’s side-effects is agranulocytosis. Other important side-effects include postural hypotension and tachycardia, sedation, seizures, weight gain and rebound psychosis.

Clozapine can also cause:

• Nausea, vomiting and constipation.

• Elevation of liver enzymes (frequency up to 10%).

• Hypersalivation (frequency 12-40%).

• Confusion or delirium.

• Incontinence frequency/urgency, hesitancy, urinary retention, or impotence (6%).

• Benign hyperthermia (5-15%).

Isolated reports have been documented of clozapine-associated emergence of obsessive compulsive symptoms^[46,47] , priapism^[48,49] , allergic complications^[50,51] . pancreatitis^[52] , toxic hepatitis^[53] , elevation in creatinine kinase levels^[54] and diabetes-like symptoms^[55,56] .

There have also been a handful of papers and case reports linking clozapine with raised triglyceride levels. Ghaeli and Dufresne^[57] found that elevated serum triglycerides in four patients resolved when they were switched to risperidone. In two of these patients clozapine was re-introduced and again serum triglycerides increased. They called for serum triglyceride levels to be monitored in clozapine patients with additional cardiac risk factors. Dursun et al.^[58] looked at cholesterol and related lipids in eight patients on clozapine treatment over 12 weeks. Serum triglyceride levels were found to increase, but not cholesterol levels.

 

The therapeutic armamentarium for the treatment of schizophrenia has grown and diversified in the half century since the advent of chlorpromazine and the beginning of the pharmacologic era in psychiatry. Over the past decade, much of our attention regarding the treatment for schizophrenia and related psychotic disorders has focused on a new class of antipsychotic medications. The reintroduction of clozapine represented a major step forward, and led to the proliferation of ‘atypical’ or second-generation antipsychotics (SGAs), including risperidone, olanzapine, quetiapine, ziprasidone, sertindole and zotepine. In fact, there is growing evidence that most of the new medications can offer some advantages over ‘typical’ or first-generation antipsychotics (FGAs) such as greater improvement iegative symptoms, cognitive impairment, relapse prevention, functional capacity, and quality of life with fewer extrapyramidal symptoms (EPS), and less tardive dyskinesia (TD) (for a review, see Miyamoto et al¹). Accordingly, many clinicians are prescribing these new antipsychotics as first-line agents for acute and maintenance therapy for schizophrenia.^{2, 3, 4, 5} However, these advantages, thus far, have been regarded as incremental and not necessarily substantial. In addition, concerns about side effects such as EPS have been replaced by other distressing side effects, including weight gain, hyperglycemia and dyslipidemia. At present, we are still in the process of defining fully the clinical profiles of new agents in terms of the extent of their therapeutic efficacy and adverse effects, on a variety of other outcomes including cognition, affect, suicide, subjective response, social and vocational function, cost effectiveness, etc.⁶

Table. Relative neurotransmitter receptor affinities for antipsychotics at therapeutic doses (adapted from Miyamoto et al ¹ and modified)

Receptor	Clozapine	Risperidone	Olanzapine	Quetiapine	Ziprasidone	Sertindole	Sulpiride	Amisulpride	Zotepine	Aripiprazole	Haloperidol
D1	+	+	++	–	+	++	–	–	+	–	+
D2	+	+++	++	+	+++	+++	++++	++++	++	++++	++++
D3	+	++	+	–	++	++	++	++	++	++	+++
D4	++	–	++	–	++	+	–	–	+	+	+++
5-HT1A	–	–	–	–	+++				++	++	–
5-HT1D	–	+	–	–	+++					+	–
5-HT2A	+++	++++	+++	++	++++	++++	–	–	+++	+++	+
5-HT2C	++	++	++	–	++++	++	–	–	++	+	–
5-HT6	++	–	++	–	+				++	+	–
5-HT7	++	+++	–	–	++				++	++	–
1	+++	+++	++	+++	++	++	–	–	++	+	+++
2	+	++	+	–	–	+	–	–	++	+	–
H1	+++	–	+++	++	–	+	–	–	++	+	–
m1	++++	–	+++	++	–	–	–	–	+	–	–
DA transporter	++		++							–
NA transporter	+		++		++				++	–
5-HT transporter					++					–

 -=minimal to none; +=low; ++=moderate; +++=high; ++++=very high.

First-generation antipsychotic agents

The effect that is common to all FGAs is a high affinity for dopamine D₂ receptors,¹⁷ and there is a strong correlation between the therapeutic doses of these drugs and their binding affinity for the D₂ receptor.^{18, 19, 20, 21} In vitro data show that FGAs such as haloperidol bind ‘tightly’ to the D₂ receptor and dissociate slowly.²² In vivo positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies have further demonstrated the importance of dopamine receptor occupancy as a predictor of antipsychotic response and adverse effects (for a review, see Remignton and Kapur²³). Such studies have demonstrated that antipsychotic effects are associated with a striatal D₂ receptor occupancy of 65–70%,^{24, 25, 26, 27} and D₂ occupancy greater than 80% significantly increases the risk of EPS.²⁴ Recent imaging studies have also shown that therapeutic doses of FGAs produce high blockade of D₂-like receptors equally in limbic cortical areas and the striatum.^{28, 29} Thus, a threshold between 65 and 80% D₂ occupancy appears to represent the therapeutic window to minimize the risk of EPS for FGAs.^{23, 27, 30} However, this is not absolute as some patients can respond below this threshold, and nonresponders can be seen in spite of adequate D₂ receptor blockade reflecting the limitations of the receptor occupancy model.^{27, 31} Interestingly, low doses of haloperidol (2–5 mg/day) would be expected to induce 60–80% dopamine D₂ receptor occupancy,^{25, 32} while dosages five to 20 times as high are often prescribed in current clinical practice.³³ This may be partly accounted for by the fact that long-term treatment with FGAs induces upregulation in D₂ receptors in both animals^{34, 35} and humans,^{36, 37} which appears to be associated with dopamine D₂-mediated supersensitivity,^{38, 39} thus theoretically, increments in dose may be needed to produce the same effect on dopaminergic transmission for chronic patients.^{27, 31}

It is important to acknowledge that the gradual and time-dependant onset of therapeutic efficacy is not consistent with the rapid striatal D₂ receptor blockade induced by antipsychotics. Preclinical studies demonstrating that chronic treatment of rodents with FGAs can decrease the number of spontaneously active dopamine neurons in both the substantia nigra pars compacta (A9) and the ventral tegmental area (A10) have given rise to the ‘depolarization inactivation (or block) hypothesis’.^{40, 41, 42} Mereu et al,^{43, 44, 45} however, have suggested that the depolarization inactivation of dopamine neurons may be an artifact produced by the use of general anesthetics, and thereby questioned the validity of this phenomenon and whether it would occur in the intact nonanesthetized unrestrained animals.^{43, 44, 45} Nevertheless, a number of studies have demonstrated that FGA-induced dopamine cell depolarization block does occur ionanesthetized animals^{40, 41, 46, 47} (for a review, see Grace et al⁴⁸).

Benzamides

Amisulpride, a substituted benzamide analogue of sulpiride, is a highly selective anatagonist of D₂ and D₃ receptors with little affinity for D₁-like or nondopaminergic receptors (Table ).^{49, 50} Its congener, sulpiride, demonstrates a generally similar pharmacological profile. Preclinical studies suggest that low doses of amisulpride (and probably sulpiride) preferentially block presynaptic D₂-like autoreceptors, and thus lead to an increase in dopaminergic release and neurotransmission, while higher doses reduce certain postsynaptic dopamine receptor-mediated behaviors that predict antipsychotic efficacy, but with little or no induction of catalepsy that predicts low EPS liability.^{31, 50, 51} Several PET and SPECT studies in schizophrenia demonstrated that amisulpride selectively binds to temporal cortical D₂/D₃ receptors in a dose-dependent fashion, but this extra-striatal selectivity is lost at higher doses as striatal D₂/D₃ receptor occupancy increases.^{52, 53, 54} Another PET study found no significant binding to 5-HT_2A receptors in amisulpride-treated patients.⁵⁵ It is also characterized by the rapid dissociation from the D₂ receptor similar to clozapine.⁵⁶ Amisulpride is essentially devoid of 5-HT_2A antagonism, thus its moderate affinity for striatal D₂ receptors and preferential occupancy of limbic cortical D₂/D₃ receptors may be reasons for its therapeutic efficacy and low liability to induce EPS.⁵⁴

Second-generation antipsychotic agents

The serotonin–dopamine antagonism theory

The ‘serotonin–dopamine (S₂/D₂) antagonism theory’ promulgated by Meltzer et al⁵⁷ suggests that a higher ratio of a drug’s affinity for serotonin 5-HT_2A receptor relative to dopamine D₂ receptor affinity can predict ‘atypicality’ and will explain the enhanced efficacy and reduced EPS liability of SGAs (for reviews, see Miyamato et al,¹ Lieberman,⁵⁸ Duncan et al⁵⁹).

PET studies showing that therapeutic doses of risperidone, olanzapine and ziprasidone produce greater than 70% occupancy of D₂ receptors suggest that a specific threshold of D₂ receptor antagonism could be important in producing antipsychotic effects of these drugs.^{60, 61, 391} Clozapine and quetiapine, however, exhibit lower levels of D₂ receptor occupancy (less than 70%) at therapeutically effective doses (Table),^{24, 61, 62, 63} suggesting that a threshold level of D₂ receptor occupancy (and possibly antagonism) alone cannot fully explain the greater therapeutic efficacy of clozapine⁵⁹ or for that matter serve as a model to predict antipsychotic efficacy. The low occupancy of striatal D₂ receptors by clozapine and quetiapine could account for its low EPS liability.^{30, 62, 63, 64} Interestingly, ziprasidone exhibits high levels of D₂ occupancy at doses of 20–40 mg,^{65, 66} doses that are substantially below the therapeutically effective dose range (120–200 mg/day).^{67, 68} Thus, pharmacological properties other than a threshold level of D₂ receptor antagonism (at least as reflected by receptor occupancy levels) may account for the clinical efficacy of ziprasidone.

Clozapine, risperidone, olanzapine and ziprasidone occupy more than 80% of cortical 5-HT_2A receptors in the therapeutic dose range in humans (Table 1).^{24, 60, 61, 63, 69, 70} Although 5-HT_2A receptor antagonism is likely to be associated with the low EPS liability of SGAs, risperidone at higher doses produces EPS,⁷¹ indicating that high levels of D₂. antagonism cannot be completely ameliorated by even maximal 5-HT_2A receptor antagonism. Moreover, at this point, it is unclear what clinical effects 5-HT_2A antagonism confers, beyond mitigating the adverse effect of striatal D₂ antagonism, and propensity to cause EPS.⁷² In particular, the role of 5-HT_2A antagonism in the superior therapeutic responses to clozapine awaits further clarification.⁵⁹ The apparent lack of efficacy of monotherapy with the selective potential role of the 5-HT_2A receptor antagonist M-100907⁷³ indicates that 5HT_2A antagonism alone cannot explain the efficacy of SGAs. Further studies examining combination therapy with D₂ antagonist and M-100907 are necessary to evaluate the potential role of 5HT_2A antagonism.

The ‘fast-off-D₂‘ theory

 To date, there is no evidence showing that an agent without some degree of D₂ binding can act as an effective antipsychotic.⁶ The question has been do pharmacologic effects on dopamine-mediated pathways account for all of the clinical therapeutic effects of antipsychotic drugs. Recent in vitro studies have demonstrated that antipsychotics dissociate from the D₂ receptor at very different rates, expressed as a k_off value.^{22, 74} The SGAs have higher k_off values as a group, that is faster dissociation rates, than the FGAs, but they differ among themselves on this dimension as well (e.g., quetiapine >clozapine >olanzapine >ziprasidone >risperidone).^{6, 56, 75} Kapur and Seeman hypothesized that dissociation from the D₂ receptor quickly makes an antipsychotic agent more accommodating of physiological dopamine transmission, permitting an antipsychotic effect without EPS, hyperprolactinemia, as well as conferring benefits along a variety of clinical dimensions such as cognitive, affective and secondary negative symptoms.⁷⁴ Accordingly, they suggest that sustained D₂ occupancy is not necessary for antipsychotic action. However, this theory cannot explain the greater therapeutic efficacy of clozapine compared with other SGAs, particularly in the management of treatment-resistant schizophrenia. The rapid dissociation of clozapine and quetiapine from D₂ receptors by endogenous dopamine may lead to more rapid clinical relapse after discontinuation of these medications.⁷⁵ At present, it remains unclear how long an antipsychotic agent must bind to the D₂ receptor to maximize therapeutic efficacy while minimizing the risk of D₂-related side effects.³¹ Another limitation of this model is that all antipsychotics have not been studied with it, including the benzamides, low-potency FGAs and partial dopamine agonists (e.g. aripiprazole).

Potential therapeutic significance of targeting other neuroreceptors

 The SGAs, particularly clozapine, have multiple sites of action other than dopamine D₂ receptors, including dopamine (D_1, D₃, D₄), serotonin (5-HT_1A, 5-HT_2C, 5-HT₆, 5-HT₇), muscarinic cholinergic and histamine receptor (Table). Among them, it has been hypothesized that the partial agonist activity of clozapine at serotonin 5-HT_1A receptors may contribute to its efficacy against anxiety, depression, cognitive and negative symptoms of schizophrenia^{76, 77, 78, 79} Preclinical studies have also suggested that 5-HT_1A agonists may potentiate the antipsychotic activity of dopaminergic antagonists,⁸⁰ and activation of inhibitory 5-HT_1A autoreceptors may counteract the induction of EPS due to striatal D₂ receptor blockade.⁸¹ Furthermore, 5-HT_1A agonism has been suggested to contribute to enhancement of prefrontal dopamine release.⁸² Indeed, clozapine, and olanzapine and ziprasidone, but not haloperidol or risperidone, can preferentially augment dopamine and norepinephrine release in the prefrontal cortex relative to the subcortical areas, which may be related to their potential efficacy for negative symptoms and cognitive dysfunction of schizophrenia.⁸³ The prefrontal cortex contains high densities of 5-HT_1A and 5-HT_2A receptors located on affrents to and on pyramidal neurons.⁸⁴ It has been suggested that activation of 5-HT_2A receptors increases the release of glutamate onto pyramidal cells,⁸⁵ whereas serotonin, possibly via activation of 5-HT_1A receptors, inhibits the release of glutamate.⁸⁶ Thus, compounds with 5-HT_2A antagonism and/or 5-HT_1A agonism like clozapine could regulate the physiological balance between excitatory and inhibitory inputs onto prefrontal pyramidal neurons.^{78, 84} Some SGAs, particularly ziprasidone, can also increase serotonin activity in the frontal cortex by virtue of their affinity for the serotonin transporter.^{87, 88} In addition, some of the SGAs, but not FGAs, can increase the release of acetylcholine in the prefrontal cortex, which could be a possible factor contributing to improve cognition in schizophrenia.⁸⁹

Partial dopamine agonists

Aripiprazole (OPC-14597), approved for clinical use in the US and more recently in Europe, is the first of a possible ‘next- generation antipsychotics’ with a mechanism of action that differs from currently marketed FGAs and SGAs.79 It is a partial dopamine agonist with a high affinity for D2 and D3 receptors,131, 132, 133 and demonstrates properties of a functional agonist and antagonist in animal models of dopaminergic hypoactivity and hyperactivity, respectively.131, 134 Aripiprazole acts on both postsynaptic D2 receptors and presynaptic autoreceptors. Partial agonist activity at D2 receptors could stabilize the dopamine system while avoiding the hypodopaminergia that may limit the efficacy and tolerability of FGAs.135 In addition, aripiprazole displays 5-HT1A partial agonism and 5-HT2A antagonism.136 The distinction, pharmacologically, between aripiprazole and the SGAs in this regard is that aripiprazole’s affinity for the D2 receptors exceeds that for serotonin by an order of magnitude.6, 137 It also has very modest affinity for alpha1-adrenergic, histamine (H1), 5-HT6, and 5-HT7 receptors, and no appreciable affinity for D1, histaminergic or cholinergic muscarinic receptors (Table 1).132, 137 The clinical significance of these in vitro receptor-binding affinities as well as its partial 5-HT1A agonism has not been determined apart from their obvious association with side effects.138 It has also been proposed that aripiprazole induces ‘functionally selective’ activation of D2 receptors coupled to diverse G proteins (and hence different functions), thereby explaining its unique clinical effects.132, 137

Aripiprazole neither conforms to the standard 5-HT2A/D2 antagonist nor the fast dissociation theories of atypicality. It has a very high affinity for the D2 receptor (greater than its 5-HT2A affinity) and this is unlikely to have a fast koff. Similarly, the compound has a long half-life and is therefore unlikely to show transient receptor occupancy. PET studies iormal humans indicate that although aripiprazole occupies up to 90% of striatal D2-like dopamine receptors at clinical doses, it does not cause EPS, suggesting that its inherent agonism may provide a mechanism that protects against excessive blockade of the D2 system.139 This underlines aripiprazole’s unique mechanism of action as a partial dopamine receptor agonist,79, 134 and possibly a novel form of treatment for schizophrenia.

From: Miyamoto S, Duncan GE, Marx CE, Lieberman JA. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. – Molecular Psychiatry (2005) 10, 79–104

Therapy of Schizophrenia

Schizophrenia is an endogenous psychosis of episodic character. Its chief symptoms reflect a thought disorder (i.e., distracted, incoherent, illogical thinking; impoverished intellectual content; blockage of ideation; abrupt breaking of a train of thought: claims of being subject to outside agencies that control the patient’s thoughts), and a disturbance of affect (mood inappropriate to the situation) and of psychomotor drive. In addition, patients exhibit delusional paranoia (persecution mania) or hallucinations (fearfulness hearing of voices). Contrasting these “positive” symptoms, the so-called “negative” symptoms, viz., poverty of thought, social withdrawal, and anhedonia, assume added importance in determining the severity of the disease. The disruption and incoherence of ideation is symbolically represented at the top left (A) and the normal psychic state is illustrated.

The term antipsychotic is applied to a group of drugs used to treat psychosis. Common conditions with which antipsychotics might be used include schizophrenia, mania and delusional disorder, although antipsychotics might be used to counter psychosis associated with a wide range of other diagnoses. Antipsychotics also have some effects as mood stabilizers, leading to their frequent use in treating mood disorder (particularly bipolar disorder) even wheo signs of psychosis are present. Some antipsychotics (haloperidol, pimozide) are used off-label to treat Tourette syndrome.

Antipsychotics are also referred to as neuroleptic drugs, or simply neuroleptics. The word neuroleptic is derived from Greek; neuro refers to the nerves and lept means “to take hold of”. Thus the word means “taking hold of one’s nerves”, which implies their role in mood stabilization.

There are currently two main types of antipsychotics in use, the typical antipsychotics and atypical antipsychotics. A new class of antipsychotic drugs has recently been discovered, known as dopamine partial agonists. Clinical development has progressed rapidly on partial dopamine agonists, and one drug in this class (aripiprazole) has already been approved by the Food and Drug Administration. Although the underlying mechanism of this new class is different from all previous typical and atypical antipsychotics, dopamine partial agonists are often categorized as atypicals.

Typical antipsychotics are sometimes referred to as major tranquilizers, because some of them can tranquilize and sedate. This term is increasingly disused because many newer antipsychotics do not have strong sedating properties and the terminology implies a connection with benzodiazepines wheone exists.

 Neuroleptics After administration of a neuroleptic, there is at first only psychomotor dampening. Tormenting paranoid ideas and hallucinations lose their subjective importance  dimming of flashy colors); however, the psychotic processes still persist. In the course of weeks, psychicprocesses gradually normalize; the psychotic episode wanes, although complete normalization often cannot be achieved because of the persistence of negative symptoms. Nonetheless, these changes are significant because the patient experiences relief from the torment of psychotic personality changes; care of the atient is made easier and return to a familiar community environment is accelerated.

The range of interactions can produce different adverse effects including extrapyramidal reactions, including acute dystonias, akathisia, parkinsonism (rigidity and tremor), tardive dyskinesia, tachycardia, hypotension, impotence, lethargy, seizures, and hyperprolactinaemia.

The atypical antipsychotics (especially olanzapine) seem to cause weight gain more commonly than the typical antipsychotics. The well documented metabolic side effects associated with weight gain include diabetes that, not infrequently, can be life threatening.

Clozapine also has a risk of inducing agranulocytosis, a potentially dangerous reduction in the number of white blood cells in the body. Because of this risk, patients prescribed clozapine may need to have regular blood checks to catch the condition early if it does occur, so the patient is io danger.

One of the more serious of these side effects is tardive dyskinesia, in which the sufferer may show repetitive, involuntary, purposeless movements often of the lips, face, legs or torso. It is believed that there is a greater risk of developing tardive dyskinesia with the older, typical antipsychotic drugs, although the newer antipsychotics are now also known to cause this disorder. It is believed by some that the risk of tardive dyskinesia can be reduced by combining the anti-psychotics with diphenhydramine or benztropine, though this has not been established. Central nervous system damage is also associated with irreversible tardive akathisia and/or tardive dysphrenia.

A potentially serious side effect of many antipsychotics is that they tend to lower an individuals seizure threshold. Chlorpromazine and clozapine particularly, have a relatively high seizurogenic potential. Fluphenazine, haloperidol, pimozide and risperidone exhibit a relatively low risk. Caution should be exercised in individuals that have a history of seizurogenic conditions (such as epilepsy, or brain damage).

Another serious side effect is neuroleptic malignant syndrome, in which the drugs appear to cause the temperature regulation centers to fail, resulting in a medical emergency as the patient’s temperature suddenly increases to dangerous levels.

Another problematic side effect of antipsychotics is dysphoria, meaning that it just makes the patient feel bad. This side-effect is a major problem for patients with schizophrenia in that it causes them to discontinue medication, and this produces a relapse of psychotic symptoms.

Whilst this may seem a daunting list, it must be noted that some people suffer few of the obvious side effects from taking antipsychotic medication. Some side effects, such as subtle cognitive problems, may go unnoticed.

Other symptoms of akinesia of antipsychotics include deterioration of teeth due to a lack of saliva. The link between such symptoms and the use of antipsychotics is often overlooked.

While the atypical, second-generation medications were marketed as offering greater efficacy in reducing psychotic symptoms while reducting side effects (and extra-pyramidal symptoms in particular) than typical medications, these results showing these effects often lack robustness. To remediate this problem, the NIMH conducted a recent multi-site, double-blind, study (the CATIE project), which was published in 2005. A phase 2 part of this study roughly replicated these findings.

The conventional (or classical) neuroleptics comprise two classes of compounds with  distinctive chemical structures: 1. the phenothiazines derived  from the antihistamine promethazine(prototype: chlorpromazine), including their analogues (e.g., thioxanthenes); and 2. the butyrophenones (prototype: haloperidol). According to the chemical structure of the side chain, phenothiazines and thioxanthenes can be subdivided into aliphatic (chlorpromazine, triflupromazine,  and piperazine congeners (trifluperazine, fluphenazine, flupentixol). The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at – muscarinic acetylcholine receptors _ atropine-like effects; – б-adrenoceptors for norepinephrine _ disturbances of blood pressure regulation; – dopamine receptors in the nigrostriatal system _ extrapyramidal motordisturbances; in the area postrema _ antiemetic action, and in the pituitary gland _increased secretion of prolactin; – histamine receptors in the cerebral  cortex _ possible cause of sedation. These ancillary effects are also elicited in healthy subjects and vary in intensity among individual substances. Other indications. Acutely, there is sedation with anxiolysis after neuroleptization has been started. This effect can be utilized for: “psychosomatic uncoupling” in disorders with a prominent psychogenic component; neuroleptanalgesia by means of the butyrophenone droperidol in combination with an opioid; tranquilization of overexcited, agitated patients; treatment of delirium tremens with haloperidol; as well as the control of mania. It should be pointed out that neuroleptics do not exert an anticonvulsant action, on the contrary, they may  lower seizure thershold.

Because they inhibit the thermoregulatory center, neuroleptics can be employed for controlled hypothermia. Adverse Effects. Clinically most important and therapy-limiting are extrapyramidal disturbances; these result from dopamine receptor blockade. Acute dystonias occur immediately after neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. After several days to months, a parkinsonian syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkinson drugs of the anticholinergic type, such as biperiden (i.e., in acute dystonia). As a rule, these disturbances disappear after withdrawal of neuroleptic medication. Tardive dyskinesia may become evident after chronic neuroleptization for several years, particularly when the drug is discontinued. It is due to hypersensitivity of the dopamine receptor system and can be exacerbated by administration of anticholinergics.  Chronic use of neuroleptics can, on occasion, give rise to hepatic damage associated with cholestasis. A very rare, but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of intensive countermeasures (including treatment with dantrolene). Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include: antipsychotic efficacy (symbolized by the arrow); the extent of sedation; and the ability to induce extrapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively. Thus, the butyrophenones carry an increased risk of adverse motor reactions because they lack anticholinergic activity and, hence, are prone to upset the balance between striatal cholinergic and dopaminergic activity.

Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphenazine) have greater antipsychotic potency than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflupromazine). However, their antipsychotic effects are qualitatively indistinguishable. As structural analogues of the phenothiazines, thioxanthenes (e.g., chlorprothixene, flupentixol) possess a central nucleus in which the N atom is replaced by a carbon linked via a double bond to the side chain. Unlike the phenothiazines, they display an added thymoleptic activity. Clozapine is the prototype of the so-called atypical neuroleptics, a group that combines a relative lack of extrapyramidal adverse effects with superior efficacy in alleviating negative symptoms. Newer members of this class include risperidone, olanzapine, and sertindole. Two distinguishing features of these atypical agents are a higher affinity for 5-HT2 (or 5-HT6) receptors than for dopamine D2 receptors and relative selectivity for mesolimbic, as opposed to nigrostriatal, dopamine neurons. Clozapine also exhibits high affinity for dopamine receptors of the D4 subtype, in addition to H1 histamine and muscarinic acetylcholine receptors. Clozapine may cause dose–dependent seizures and agranulocytosis, necessitating close hematological monitoring. It is strongly sedating. When esterified with a fatty acid, both fluphenazine and haloperidol can be applied intramuscularly as depot preparations.

Lithium ions

Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin leads to polyuria and thirst. Thyroid function is impaired, with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemically, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion  channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol  bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling. Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist-  receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic.

  Benzodiazepines

Benzodiazepines modify affective responses to sensory perceptions; specifically, they render a subject indifferent towards anxiogenic stimuli, i.e., anxiolytic action. Furthermore, benzodiazepines exert sedating, anticonvulsant, and muscle-relaxant (myotonolytic) effects. All these actions result from augmenting the activity of inhibitory neurons and are mediated by specific benzodiazepine receptors that form an integral part of the GABAA receptor- chloride channel complex. The inhibitory transmitter GABA acts to open the membrane chloride channels.

Increased chloride conductance of the neuronal membrane effectively shortcircuits responses to depolarizing inputs. Benzodiazepine receptor agonists increase the affinity of GABA to its receptor. At a given concentration of GABA, binding to the receptors will, therefore, be increased, resulting in an augmented response. Excitability of the neurons is diminished. Therapeutic indications for  benzodiazepines  include anxiety states associated with neurotic, phobic, and depressive disorders, or myocardial infarction (decrease in cardiac stimulation

due to anxiety); insomnia; preanesthetic (preoperative) medication;  epileptic seizures; and hypertonia of skeletal musculature (spasticity, rigidity). Since GABA-ergic synapses are confined to neural tissues, specific inhibition of central nervous functions can be achieved; for instance, there is little change in blood pressure, heart rate, and body temperature. The therapeutic index of benzodiazepines, calculated with reference to the toxic dose producing respiratory depression, is greater than 100 and thus exceeds that of barbiturates and other sedative-hypnotics  by more than tenfold. Benzodiazepine intoxication can be treated with a specific antidote (see below). Since benzodiazepines depress responsivity to external stimuli, automotive driving skills and other tasks requiring precise sensorimotor coordination will be impaired. Triazolam (t1/2 of elimination ~1.5–5.5 h) is especially likely to impair memory (anterograde amnesia) and to cause rebound anxiety or insomnia and daytime confusion. The severity of these and other adverse reactions (e.g., rage, violent hostility, hallucinations), and their increased frequency in the elderly, has led to curtailed or suspended use of triazolam in some countries (UK). Although benzodiazepines are well tolerated, the possibility of personality changes (nonchalance, paradoxical excitement) and the risk of physical dependence with chronic use must not be overlooked. Conceivably, benzodiazepine dependence results from a kind of habituation, the functional counterparts of which become manifest during abstinence as restlessness and anxiety; even seizures may occur. These symptoms reinforce chronic ingestion of benzodiazepines. Benzodiazepine antagonists, such as flumazenil, possess affinity for benzodiazepine receptors, but they lack intrinsic activity. Flumazenil is an effective antidote in the treatment of benzodiazepine overdosage or can be used postoperatively to arouse patients sedated with a benzodiazepine. Whereas benzodiazepines possessing agonist activity indirectly augment chloride permeability, inverse agonists exert an opposite action. These substances give rise to pronounced restlessness, excitement, anxiety, and convulsive seizures. There is, as yet, no therapeutic indication for their use.

Pharmacokinetics of Benzodiazepines All benzodiazepines exert their actions at specific receptors . The choice between different agents is dictated by their speed, intensity, and duration of  action. These, in turn, reflect physicochemical and pharmacokinetic properties. Individual benzodiazepines remain in the body for very different lengths of time and are chiefly eliminated through biotransformation. Inactivation may entail a single chemical reaction or several steps (e.g., diazepam) before an inactive metabolite suitable for renal elimination is formed. Since the intermediary products may, in part, be pharmacologically active and, in part, be excreted more slowly than the parent substance, metabolites will accumulate with continued regular dosing and contribute significantly to the final effect. Biotransformation begins either at substituents on the diazepine ring (diazepam: N-dealkylation at position 1; midazolam: hydroxylation of the methyl group on the imidazole ring) or at the diazepine ring itself. Hydroxylated midazolam is quickly eliminated following glucuronidation (t1/2 ~ 2 h).

N-demethyldiazepam (nordazepam) is biologically active and undergoes hydroxylation at position 3 on the diazepine ring. The hydroxylated product (oxazepam) again is pharmacologically active. By virtue of their long half-lives, diazepam (t1/2 ~ 32 h) and, still more so, its metabolite, nordazepam (t1/2 50–90 h), are eliminated slowly and accumulate during repeated intake. Oxazepam undergoes conjugation to glucuronic acid via its hydroxyl group (t1/2 = 8 h) and renal excretion (A). The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B).

Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area) because they permit maintenance of steady plasma levels with single daily dosing. Midazolam enjoys use by the i.v. route in preanesthetic medication and anesthetic combination regimens. Benzodiazepine Dependence Prolonged regular use of benzodiazepines can lead to physical dependence. With the long-acting substances marketed initially, this problem was less obvious in comparison with other dependence- producing drugs because of the delayed appearance of withdrawal symptoms. The severity of the abstinence syndrome is inversely related to the elimination t1/2, ranging from mild to moderate (restlessness, irritability,  sensitivity to sound and light, insomnia,and tremulousness) to dramatic (depression, panic, delirium, grand mal seizures). Some of these symptoms pose diagnostic difficulties, being indistinguishable from the ones originally treated. Administration of a benzodiazepine  antagonist would abruptly provoke abstinence signs. There are indications that substances with intermediate elimination  half-lives are most frequently abused (violet area in B).

Tranquilizers

Tranquilizers are depressant drugs that slow down the central nervous system (CNS), and thus are similar to such other CNS depressants as alcohol and barbituates.

The term “major tranquilizer” was formerly applied to drugs used to treat severe mental illnesses, such as schizophrenia. However, these drugs are now more commonly called neuroleptics; their action specifically relieves the symptoms of mental illness, and they are rarely misused for other purposes. This paper therefore deals with the anti-anxiety agents, or anxiolytics (formerly called “minor” tranquilizers).

Anti-anxiety agents share many similiarities with barbituates; both are classified as sedative/hypnotics. These newer agents were introduced under the term “tranquilizer” because, it was claimed, they provided a calming effect without sleepiness. Today, tranquilizers have largely replaced barbiturates in the treatment of both anxiety and insomnia because they are safer and more effective. The degree of sleepiness induced depends on the dosage. Tranquilizers are also used as sedatives before some surgical and medical procedures, and they are sometimes used medically during alcohol withdrawal.

Although tranquilizers do not exhibit the serious dependence characteristics of barbiturates, they nevertheless can produce tolerance and dependence. They may also be misused and abused.

The first drug to be labelled a tranquilizer was meprobamate – under the trade name Miltown – in 1954. Today, however, the most popular anti-anxiety agents are the benzodiazepines (e.g. Valium, Halcion, and Ativan).

 

The first benzodiazepine developed was chlordiazepoxide, which is sold under such trade names as Librium and Novopoxide. The next was diazepam; it is marketed, among other brand names, as Valium, E-Pam, and Vivol. In the early 1970s diazepam was the most widely prescribed drug in North America.

 

Now Halcion and Ativan – drugs from the same family as diazepam but eliminated more rapidly from the body – account for most benzodiazepine prescriptions. Some are prescribed as anti-anxiety drugs (e.g. Valium, Librium); others are recommended as sleeping medications (e.g. Dalmane, Somnol, Novoflupam, and Halcion).

Effects

The effects of any drug depend on several factors:

• the amount taken at one time.

• the user’s past drug experience.

• the manner in which the drug is taken.

• the circumstances under which the drug is taken (the place, the user’s psychological and emotional stability, the presence of other people, the simultaneous use of alcohol or other drugs, etc.).

With tranquilizers, a therapeutic dose (i.e. what is medically prescribed) relieves anxiety and may, in some people, induce a loss of inhibition and a feeling of well-being. Responses vary, however. Some people report lethargy, drowsiness, or dizziness. Tranquilizers, though, have very few side effects.

As the dose of a tranquilizer is increased, so is sedation and impairment of mental acuity and physical coordination. Lower doses are recommended for older people or for those with certain chronic diseases, since their bodies tend to metabolize these drugs more slowly.

Studies show that anti-anxiety agents, even at the usually recommended and prescribed doses, may disrupt the user’s ability to perform certain physical, intellectual, and perceptual functions. For these reasons, users should not operate a motor vehicle or engage in tasks calling for concentration and coordination. Such activities are particularly hazardous if tranquilizers are used together with alcohol and/or barbiturates (i.e. other sedative/hypnotics) or antihistamines (in cold, cough, and allergy remedies). These effects occur early in therapy, however, and wane over time with increased tolerance (when more of the drug is needed to produce the same effect).

Because some tranquilizers (such as diazepam) are metabolized quite slowly, residue can accumulate in body tissues with long- term use and can heighten such effects as lethargy and sluggishness.

Toxic Effects

Tranquilizer overdose, particularly with benzodiazepines, has become increasingly common since the 1960s. While these drugs are usually safe even when an overdose is taken (death rarely results from benzodiazepine use alone), they can be fatal in combination with alcohol and other drugs that depress the central nervous system.

In Canada, as elsewhere, tranquilizer-related poisonings and overdoses have kept pace with the drug’s availability. It is a fact that the drugs used in suicide attempts are those most widely prescribed and available. (The majority of these drug-related suicide attempts are by women under 30.)

Tolerance and Dependence

Because tolerance to the mood-altering effects of tranquilizers can develop with regular use, higher daily doses become necessary to maintain the desired effects. Tolerance may occur even at prescribed doses.

Chronic users may become both psychologically and physically dependent on tranquilizers.

Psychological dependence exists when a drug is so central to a person’s thoughts, emotions, and activities that the need to continue its use becomes a craving or compulsion.

With chronic use, especially at higher doses, physical dependence can also occur. The user’s body has adapted to the presence of the drug and suffers withdrawal symptoms when use is stopped. The frequency and severity of the withdrawal syndrome depends on the dose, duration of use, and whether use is stopped abruptly or tapered off. Symptoms range in intensity from progressive anxiety, restlessness, insomnia, and irritability in mild cases to delirium and convulsions in severe cases.

Dependence may also occur following long-term therapeutic use, but withdrawal symptoms in such cases are mild. Patients complain of gastrointestinal problems, loss of appetite, sleep disturbances, sweating, trembling, weakness, anxiety, and changes in perception (e.g. increased sensitivity to light, sound, and smells).

Risk of dependency increases if tranquilizers are taken regularly for more than a few months, although problems have been reported within shorter periods. The onset and severity of withdrawal differ between the benzodiazepines that are rapidly eliminated from the body (e.g. Halcion) and those that are slowly eliminated (e.g. Valium). In the former case, symptoms appear within a few hours after stopping the drug and may be more severe. In the latter case, symptoms usually take a few days to appear.

Tranquilizers and Pregnancy

If a woman uses tranquilizers regularly, the drug can affect the baby for up to 10 days after birth. Babies may exhibit the withdrawal symptoms common to such other depressant drugs as alcohol and barbituates. These symptoms include feeding difficulties, disturbed sleep, sweating, irritability, and fever. Symptoms will be more severe if the doses the mother took are higher.

Administration of diazepam during labor has been linked to decreased responsiveness and respiratory problems in some newborns.

 

 

 

Activating CNS drugs: analeptics, antidepressants, metabolic cerebral protectors and adaptogens

The central nervous system (CNS) represents the largest part of the nervous system, including the brain and the spinal cord. Together with the peripheral nervous system, it has a fundamental role in the control of behavior. The CNS is contained within the dorsal cavity, with the brain within the cranial subcavity, and the spinal cord in the spinal cavity.

Since the strong theoretical influence of cybernetics in the fifties, the CNS is conceived as a system devoted to information processing, where an appropriate motor output is computed as a response to a sensory input. Yet, many threads of research suggest that motor activity exists well before the maturation of the sensory systems and then, that the senses only influence behavior without dictating it. This has brought the conception of the CNS as an autonomous system.

In the developing fetus, the CNS originates from the neural plate, a specialised region of the ectoderm, the most external of the three embryonic layers. During embryonic development, the neural plate folds and forms the neural tube. The internal cavity of the neural tube will give rise to the ventricular system. The regions of the neural tube will differentiate progressively into transversal systems. First, the whole neural tube will differentiate into its two major subdivisions: spinal cord (caudal) and brain (rostral/cephalic). Consecutively, the brain will differentiate into brainstem and prosencephalon. Later, the brainstem will subdivide into rhombencephalon and mesencephalon, and the prosencephalon into diencephalon and telencephalon.

The CNS is covered by the meninges, the brain is protected by the skull and the spinal cord by the vertebrae. The rhombencephalon gives rise to the pons, the cerebellum and the medulla oblongata, its cavity becomes the fourth ventricle. The mesencephalon gives rise to the tectum, pretectum, cerebral peduncle and its cavity develops into the mesencephalic duct or cerebral aqueduct. The diencephalon give rise to the subthalamus, hypothalamus, thalamus and epithalamus, its cavity to the third ventricle. Finally, the telencephalon gives rise to the striatum (caudate nucleus and putamen), the hippocampus and the neocortex, its cavity becomes the lateral (first and second) ventricles.

Neuroanatomy

The basic pattern of the CNS is highly conserved throughout the different species of vertebrates and during evolution. The major trend that can be observed is towards a progressive telencephalisation: while in the reptilian brain that region is only an appendix to the large olfactory bulb, it represent most of the volume of the mammalian CNS. In the human brain, the telencephalon covers most of the diencephalon and the mesencephalon. Indeed, the allometric study of brain size among different species shows a striking continuity from rats to whales, and allows us to complete the knowledge about the evolution of the CNS obtained through cranial endocasts.

 

Therapy of Manic-Depressive Illness

Manic-depressive illness connotes a psychotic disorder of affect that occurs episodically without external cause. In endogenous depression (melancholia), mood is persistently low. Mania refers to the opposite condition. Patients may oscillate between these two extremes with interludes of normal mood. Depending on the type of disorder, mood swings may alternate between the two directions (bipolar depression, cyclothymia) or occur in only one direction (unipolar depression).

Proposed mechanism of action of selective serotonin/norepinephrine re-uptake inhibitor antidepressant drugs.

 

I. Endogenous Depression

In this condition, the patient experiences profound misery (beyond the observer’s empathy) and feelings of severe guilt because of imaginary misconduct. The drive to act or move is inhibited. In addition, there are disturbances mostly of a somatic nature (insomnia, loss of appetite, constipation, palpitations, loss of libido, impotence, etc.). Although the patient may have suicidal thoughts, psychomotor retardation prevents suicidal impulses from being carried out. In A, endogenous depression is illustrated by the layers of somber colors; psychomotor drive, symbolized by a sine oscillation, is strongly reduced. Therapeutic agents fall into two groups:

_ Thymoleptics, possessing a pronounced ability to re-elevate depressed mood e.g., the tricyclic antidepressants;

_ Thymeretics, having a predominant activating effect on psychomotor drive, e g., monoamine oxidase inhibitors.

It would be wrong to administer  drive-enhancing drugs, such as amphetamines,to a patient with endogenous depression. Because this therapy fails to elevate mood but removes psychomotor inhibition (A), the danger of suicide increases.

History: Imipramine is considered the prototype tricyclic antidepressant. The tricyclic antidepressants are chemically derived from a three-ring aromatic nucleus that has three forms: dibenzazepine (imipramine), dibenzocycloheptene (amitriptyline), or dibenzoxepin (doxepin).

Imipramine was first synthesized in the late 1940s and was approved for use for depression in 1959 and for enuresis in 1973. Recently, clomipramine was introduced, but it is indicated for treatment of obsessive-compulsive disorder, not depression. Since the introduction of the selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (see Heterocyclic Antidepressants Overview), the use of tricyclic antidepressants has decreased. The SSRIs have a more well-tolerated adverse effect profile than the tricyclic type antidepressants in depression and obsessive-compulsive disorder. Fluoxetine, and presumably other serotonin-specific agents, appear to be inferior, however, to desipramine and other norepinephrine-active drugs in the treatment of diabetic neuropathy.

 

Tricyclic antidepressants (TCA; prototype: imipramine)

have had the longest and most extensive therapeutic use; however, in the past decade, they have been increasingly superseded by the serotonin-selective reuptake inhibitors (SSRI; prototype: fluoxetine). The central seven-membered ring of the TCAs imposes a 120° angle between the two flanking aromatic rings, in contradistinction to the flat ring system present in phenothiazine type neuroleptics. The side chaiitrogen is predominantly protonated at physiological pH. The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine  and serotonin is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, б-adrenoceptors, and certain 5-HT and histamine (H1) receptors are blocked. Interference with the dopamine system is relatively minor. How interference with these transmitter/ modulator substances translates into an antidepressant effect is still hypothetical. The clinical effect emerges only after prolonged intake, i.e., 2–3 wk, as evidenced by an elevation of mood and drive. However, the alteration in monoamine metabolism occurs as soon as therapy is started. Conceivably, adaptive processes (such as downregulation of cortical serotonin and в-adrenoceptors) are ultimately responsible. In healthy subjects, the TCAs do not improve mood (no euphoria). Apart from the antidepressant effect, acute effects occur that are evident also in healthy individuals. These vary in degree among individual substances and thus provide a rationale for differentiated clinical use, based upon the divergent patterns of interference with amine transmitters/modulators.

Mechanism of action antidepressants

The precise mechanism of action of tricyclic antidepressants is not fully understood. It is believed that these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. This results in a potentiation of the neurotransmitter at the post-synaptic receptor. Imipramine, a tertiary amine, inhibits the reuptake of serotonin more than do secondary amines, which inhibit primarily norepinephrine. Because imipramine is metabolized to a secondary amine (desipramine), however, classification of tricyclic antidepressants according to type of neurotransmitter affected is problematic.

 

The mechanism of action of tricyclic antidepressants (adverse effects)

Mood elevation secondary to antidepressant therapy occurs only in depressed individuals and may require 2-3 weeks of therapy. Adverse effects, however, can be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory because blockade of neurotransmitter reuptake occurs much more rapidly than the clinical antidepressant effect. Improvement in the depressive state might result from the correction of an abnormal neurotransmitter-receptor relationship.

Amitriptyline exerts anxiolytic, sedative and psychomotor dampening effects. These are useful in depressive patients who are anxious and agitated.

Effect of Amitriptyline

In contrast, desipramine produces psychomotor activation. Imipramine occupies an intermediate position. It should be noted that, in the organism, biotransformation of imipramine leads to desipramine (N-desmethylimipramine). Likewise, the desmethyl derivative of amitriptyline (nortriptyline) is less dampening. Iondepressive patients whose complaints are of predominantly psychogenic origin, the anxiolytic-sedative effect may be useful in efforts to bring about a temporary “psychosomatic uncoupling.” In this connection, clinical use as “co-analgesics”  may be noted. The side effects of tricyclic antidepressants are largely attributable to the ability of these compounds to bind to and block receptors for endogenous transmitter substances.

 

The serotonin pathways in panic disorder

These effects develop acutely. Antagonism at muscarinic cholinoceptors leads to atropinelike effects such as tachycardia, inhibition of exocrine glands, constipation, impaired micturition, and blurred vision. Changes in adrenergic function are complex. Inhibition of neuronal catecholamine reuptake gives rise to superimposed indirect sympathomimetic stimulation. Patients are supersensitive to catecholamines (e.g., epinephrine in local anesthetic injections must be avoided). On the other hand, blockade of б1-receptors may lead to orthostatic hypotension. Due to their cationic amphiphilic nature, the TCA exert membrane-stabilizing effects that can lead to disturbances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite. Maprotiline, a tetracyclic compound, largely resembles tricyclic agents in terms of its pharmacological and clinical actions. Mianserine also possesses a tetracyclic structure, but differs insofar as it increases intrasynaptic concentrations of norepinephrine by blocking presynaptic б2-receptors, rather than reuptake.

Distinguishing Features: The tricyclic antidepressants can be differentiated by several features. The most important clinical distinction is based on the number of ligands bonded to the nitrogen on the “tail” attached to the tricyclic ring system: tertiary or secondary amines. The tertiary-amine tricyclic antidepressants (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine) tend to be more sedating and have greater anticholinergic effects. The secondary amines (desipramine and nortriptyline) are metabolites of the tertiary amines (imipramine and amitriptyline, respectively). The secondary-amine tricyclic antidepressants are generally better tolerated.

Besides major depression, the tricyclic antidepressants are useful in a number of other clinical conditions. Imipramine has been used for childhood enuresis, amitriptyline has been successful for short-term treatment of fibromyalgia, and protriptyline has been used as a respiratory stimulant in patients with chronic obstructive pulmonary disease. Amitriptyline, desipramine, doxepin and presumably other tricyclic antidepressants with activity oorepinephrine are effective agents for diabetic neuropathy. Tricyclic antidepressants have also been used in the management of neurogenic pain, attention-deficit hyperactivity disorder (ADHD) in children over age 6 (usually only after therapy with methylphenidate and pemoline fail), eating disorders, and panic or phobic disorder, although these are not FDA-approved uses.

The tricyclic antidepressants can also be differentiated based on the dosing and plasma concentration range: amitriptyline (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 60-200 ng/mL); clomipramine (starting dose 25 mg TID, dosage range 50-300 mg/day); desipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range 125-250 ng/mL); doxepin (starting dose 25 mg TID, dosage range 75-300 mg/day, therapeutic Cp range 110-250 ng/mL); imipramine (starting dose 25 mg TID, dosage range 50-300 mg/day, therapeutic Cp range >180 ng/mL); nortriptyline (starting dose 25 mg TID, dosage range 50-200 mg/day, therapeutic Cp range 50-150 ng/mL); protriptyline (starting dose 5 mg TID, dosage range 15-60 mg/day, therapeutic Cp range 100-200 ng/mL); and trimipramine (starting dose 25 mg TID, dosage range 15-90 mg/day). Of all the tricyclic antidepressants, nortriptyline has the most well-studied relationship between response and plasma concentration. Tricyclic antidepressant plasma concentrations are always measured 12 hours after the evening dose and before any morning dose. If the drug has active metabolites, they are measured as well and added together.

Adverse Reactions: A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants because they exert a direct quinidine-like action, possess strong anticholinergic activity, and potentiate norepinephrine. Drowsiness is the most frequent central nervous system (CNS) adverse effect. The adverse effect of sedation may be used therapeutically by administering the tricyclic antidepressant at bedtime. Tremors can result from norepinephrine-reuptake blockade. Seizures and alterations in EEG patterns have been observed more commonly in children than in adults.

Ocular manifestations of the high anticholinergic activity of the tricyclic antidepressants can result in blurred vision due to loss of accommodation, mydriasis, and increased intraocular pressure. Increased intraocular pressure can precipitate a crisis in patients with angle-closure glaucoma. Gastrointestinal manifestations of these drugs’ high anticholinergic activity include dry mouth (xerostomia), constipation, urinary retention, paralytic ileus, abdominal cramps, nausea, vomiting, anorexia, diarrhea, and jaundice.

The effects of tricyclics on the endocrine system can cause sexual dysfunction including libido changes, impotence, testicular swelling, painful ejaculation, breast engorgement and galactorrhea in females, and gynecomastia in males. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Glucose metabolism can be altered and should be monitored in patients with diabetes mellitus.

Photosensitivity, rash, erythema, urticaria, fever, and pruritus are generally indicative of allergic reactions.

Proposed mechanism of action of selective serotonin re-uptake inhibitors (SSRI) and tricyclic antidepressant (TCA) drugs.

 

Heterocyclic antidepressants

History: The heterocyclic antidepressants are a chemically and pharmacologically diverse group of drugs. Many of the antidepressants in this category (e.g., amoxapine, maprotiline, and trazodone) are now considered third or fourth line agents. At this time, the most important subgroup of the heterocyclic antidepressants are the serotonin specific reuptake inhibitors (SSRIs) which have revolutionized the treatment of depression. Fluoxetine, released in 1987, is the prototype of the SSRIs. Fluoxetine has been used in the treatment of major depression, alcohol dependence, anorexia nervosa, borderline personality disorder, bulemia nervosa, eating disorders, obesity, obsessive-compulsive disorder, and panic disorder. Since then, sertraline (1991), paroxetine (1992), and fluvoxamine (1994) have been approved for use.

Mechanism of Action: The precise mechanism of action of antidepressants is not fully understood. It is thought these drugs interfere with the reuptake of various neurotransmitters at the neuronal membrane. The SSRIs are very specific in their ability to inhibit the reuptake of serotonin resulting in potentiation of the neurotransmitter at the post-synaptic receptor.

Mood-elevation occurs only in depressed individuals and may require 2-3 weeksof therapy. Adverse effects, however, may be seen within a few hours. The delayed antidepressant effect has led to reconsideration of the reuptake theory, since blockade of neurotransmitter reuptake occurs much more rapidly the a clinical antidepressant action. Improvement in the depressive state may result from the correction of an abnormal neurotransmitter-receptor relationship.

Distinguishing Features: All of the antidepressants have clinically indistinguishable efficacy, with the possible exception of trazodone. Trazodone may have significantly lower efficacy than other antidepressants, based on meta-analysis of double blind clinical trials.

The most important clinical distinction of the SSRIs from all other antidepressants is their very high specificity for blocking the reuptake of serotonin compared to their effects on other knoweurotransmitters such as norepinephrine, acetylcholine, histamine, or dopamine. Fluoxetine has the longest half-life of all the SSRIs. Half-life values for paroxetine, sertraline, and newly-released fluvoxamine range 15-26 hours in patients without hepatic disease. None of these 3 antidepressants have active metabolites. Fluoxetine has an elimination T1/2 of 2-3 days and an active metabolite with an elimination T1/2 of 7-9 days.

Adverse Reactions: Nausea, vomiting, diarrhea, dyspepsia, and anorexia are the most commonly experienced adverse reactions. Nausea usually subsides after a few weeks therapy, but occasionally is severe enough to necessitate discontinuation of the drug, and occurs more frequently with SSRIs than with tricyclic antidepressant drugs or the other heterocyclic antidepressants. Fluvoxamine has been associated with a higher incidence of nausea (37%) than the other SSRI antidepressants, but this may have been due, in part, to excessively high initial dosages. Diarrhea, anorexia, xerostomia, and dyspepsia are also fairly common and may require medical attention if severe. Weight loss exceeding 5% of body weight has been reported in 10-15% of fluoxetine treated patients, mostly at higher doses. All of the gastrointestinal effects appear to be dose-related and respond in most patients to dosage reduction.

CNS side effects occur in a number of patients and include, anxiety, nervousness, insomnia, drowsiness, fatigue, dizziness, tremor, and headache. Among the SSRI antidepressants, fluvoxamine and paroxetine are more sedating while fluoxetine and sertraline are more excitatory. Headache is a commonly reported ADR. All effective antidepressants can cause a switch from depression to mania in predisposed individuals. Overdose or a pre-existing seizure disorder may cause a drug-induced seizure, particularly with bupropion. Extrapyramidal symptoms (dystonia, torticollis, and akathisia) have occurred in some patients, particularly with amoxapine. The possibility of tardive dyskinesia from amoxapine, limits its use to patients with psychotic depression. All antidepressants should be used with caution because of the possibility of suicidal ideation. Despite the widespread attention that fluoxetine has received, there is no evidence that one antidepressant has a higher potential for inducing patients to attempt suicide.

Hypoglycemia has been observed rarely in patients treated with SSRIs. Hyperglycemia has been observed following discontinuation of SSRIs. . Patients experience visual disturbance, including blurred vision in ~3% of cases. Sexual dysfunction (including delayed ejaculation or impotence in men, anorgasmia in women) have been reported in a significant number of patients, most commonly when sertraline is used. Rash and other dermatologic reactions can occur with any drug, however, this is most common with maprotiline.

 

Some commonly observed adverse effects of selective serotonin re-uptake inhibitors.

 

Pruritus and rash occur during the first few weeks of therapy in a small number of patients receiving heterocyclic antidepressants.

Overdoses of amoxapine are characterized by severe neurotoxicity, with seizures that are difficult to control. Overdoses of maprotiline also have a tendency to cause seizures as well as cardiotoxicity.

Overdoses of the other heterocyclic drugs appear to create only minor problems and can usually be managed with purely supportive measures. For example, in one recorded case even 11 g of nefazodone failed to cause serious injury.

Moreover, it has less pronounced atropine-like activity. Fluoxetine, along with sertraline, fluvoxamine, and paroxetine, belongs to the more recently developed group of SSRI. The clinical efficacy of SSRI is considered comparable to that of established antidepressants. Added advantages include: absence of cardiotoxicity, fewer autonomic nervous side effects, and relative safety with overdosage. Fluoxetine causes loss of appetite and weight reduction. Its main adverse effects include: overarousal, insomnia, tremor, akathisia, anxiety, and disturbances of sexual function.

Moclobemide is a new representative of the group of MAO inhibitors. Inhibition of intraneuronal degradation of serotonin and norepinephrine causes an increase in extracellular amine levels.

A psychomotor stimulant thymeretic action is the predominant feature of MAO inhibitors. An older member of this group, tranylcypromine, causes irreversible inhibition of the two isozymes MAOA and MAOB.

Therefore, presystemic elimination in the liver of biogenic amines, such as tyramine, which are ingested in food (e.g., aged cheese and Chianti), will be impaired.

To avoid the danger of a hypertensive crisis, therapy with tranylcypromine or other nonselective MAO inhibitors calls for stringent dietary rules. With moclobemide, this hazard is much reduced because it inactivates only MAOA and does so in a reversible manner.

II. Mania

The manic phase is characterized by exaggerated elation, flight of ideas, and a pathologically increased psychomotor drive. This is symbolically illustrated in A by a disjointed structure and aggressive color tones. The patients are overconfident, continuously active, show  progressive incoherence of thought and loosening of associations, and act irresponsibly (financially, sexually etc.).

Lithium ions

 

Lithium salts (e.g., acetate, carbonate) are effective in controlling the manic phase. The effect becomes evident approx. 10 d after the start of therapy. The small therapeutic index necessitates frequent monitoring of Li+ serum levels. Therapeutic levels should be kept between 0.8–1.0 mM in fasting morning blood samples. At higher values there is a risk of adverse effects. CNS symptoms include fine tremor, ataxia or seizures. Inhibition of the renal actions of vasopressin leads to polyuria and thirst. Thyroid function is impaired, with compensatory development of (euthyroid) goiter. The mechanism of action of Li ions remains to be fully elucidated. Chemically, lithium is the lightest of the alkali metals, which include such biologically important elements as sodium and potassium. Apart from interference with transmembrane cation fluxes (via ion  channels and pumps), a lithium effect of major significance appears to be membrane depletion of phosphatidylinositol  bisphosphates, the principal lipid substrate used by various receptors in transmembrane signalling. Blockade of this important signal transduction pathway leads to impaired ability of neurons to respond to activation of membrane receptors for transmitters or other chemical signals. Another site of action of lithium may be GTP-binding proteins responsible for signal transduction initiated by formation of the agonist–  receptor complex. Rapid control of an acute attack of mania may require the use of a neuroleptic.

Alternate treatments. Mood-stabilization and control of manic or hypomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively.

 III. Prophylaxis With continued treatment for 6 to 12 months, lithium salts prevent the recurrence of either manic or depressive states, effectively stabilizing mood at a

normal level.

 

Preparations Available

Tricyclics

Amitriptyline (generic, Elavil, others)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Parenteral: 10 mg/mL for IM injection

Clomipramine (generic, Anafranil; labeled only for obsessive-compulsive disorder)

Oral: 25, 50, 75 mg capsules

Desipramine (generic, Norpramin, Pertofrane)

Oral: 10, 25, 50, 75, 100, 150 mg tablets

Doxepin (generic, Sinequan, others)

Oral: 10, 25, 50, 75, 100, 150 mg capsules; 10 mg/mL concentrate

Imipramine (generic, Tofranil, others)

Oral: 10, 25, 50 mg tablets (as hydrochloride); 75, 100, 125, 150 mg capsules (as pamoate)

Parenteral: 25 mg/2 mL for IM injection

Nortriptyline (generic, Aventyl, Pamelor)

Oral: 10, 25, 50, 75 mg capsules; 10 mg/5 mL solution

Protriptyline (generic, Vivactil)

Oral: 5, 10 mg tablets

Trimipramine (Surmontil)

Oral: 25, 50, 100 mg capsules

Second- & Third-Generation Drugs

Amoxapine (generic, Asendin)

Oral: 25, 50, 100, 150 mg tablets

Bupropion (generic, Wellbutrin)

Oral: 75, 100 mg tablets; 100, 150 mg sustained-release tablets

Maprotiline (generic, Ludiomil)

Oral: 25, 50, 75 mg tablets

Mirtazapine (Remeron)

Oral: 15, 30, 45 mg tablets

Nefazodone (Serzone)

Oral: 50, 100, 150, 200, 250 mg tablets

Trazodone (generic, Desyrel)

Oral: 50, 100, 150, 300 mg tablets

Venlafaxine (Effexor)

Oral: 25, 37.5, 50, 75, 100 mg tablets; 37.5, 75, 150 mg extended-release tablets

Selective Serotonin Reuptake Inhibitors

Citalopram (Celexa)

Oral: 20, 40 mg tablets

Escitalopram (Lexapro)

Oral: 5, 10, 20 mg tablets

Fluoxetine (generic, Prozac)

Oral: 10, 20 mg pulvules; 10 mg tablets; 20 mg/5 mL liquid

Oral delayed release (Prozac Weekly): 90 mg capsules

Fluvoxamine (Luvox, labeled only for obsessive- compulsive disorder)

Oral: 25, 50, 100 mg tablets

Paroxetine (Paxil)

Oral: 10, 20, 30, 40 mg tablets; 10 mg/5 mL suspension; 12.5, 25, 37.5 mg controlled-release tablets

Sertraline (Zoloft)

Oral: 25, 50, 100 mg tablets

Monoamine Oxidase Inhibitors

Phenelzine (Nardil)

Oral: 15 mg tablets

Tranylcypromine (Parnate)

Oral: 10 mg tablets

Other

Atomoxetine (Strattera)

Oral: 10, 18, 25, 40, 60 mg capsules

Proposed mechanism of action of selective serotonin/norepinephrine re-uptake inhibitor antidepressant drugs.

 

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