3 курс / Фармакология / Essential_Psychopharmacology_2nd_edition

460Essential Psychopharmacology

reader should obtain by consulting standard prescribing guides. Other important management issues for patients with cognitive disturbances also are not covered here, including diagnostic issues and nonpharmacological management, which can be critical to the outcome for a patient. However, a solid concept of how drugs act on the brain's psychopharmacological mechanisms is an important foundation for understanding how to use these agents and why they work.

Enhancement of Attention

Dopamine, Norepinephrine, and the Neuropharmacology of Attention

The catecholamine neurotransmitters dopamine and norepinephrine have the best documented roles in attention, concentration, and associated cognitive functions such as motivation, interest, and learning tasks dependent on being adequately aroused, yet focused. In our earlier discussion of norepinephrine, we emphasized the role of prefrontal noradrenergic pathways in sustaining and focusing attention, as well as in mediating energy, fatigue, motivation, and interest (Chapter 5, Fig. 5—25). In Chapter 10, we emphasized the role of the mesocortical dopamine projection in mediating cognitive functions such as verbal fluency, serial learning, vigilance for executive functioning, sustaining and focusing attention, prioritizing behavior, and modulating behavior based upon social cues (Fig. 10—10). Those discussions were related to how attention is altered in depression (Chapter 5) and schizophrenia (Chapter 10). It should not be surprising if these same pathways and neurotransmitters are implicated in "primary" disorders of attention, such as attention deficit disorder, or in other cognitive disorders such as Alzheimer's disease and various dementias.

Although arousal is usually considered to be a state of increased dopamine and norepinephrine and inattentiveness is considered to reflect deficiencies in these neurotransmitters in these pathways, this is only somewhat true even in persons without a cognitive disorder. Thus, more of these neurotransmitters will enhance attention, but only to a certain extent. Too much of a good thing, like dopamine or norepinephrine, will actually lead to deterioration in cognitive performance. Thus, "hy-perarousal" is more likely to be associated with inability to concentrate than with heightened attention span.

Attention Deficit Disorder

Although there are many disorders of attention, ranging from lack of appropriate sleep or motivation in a normal person, to medication side effects to any number of psychiatric and cognitive disorders, here we will only discuss attention deficit disorder, the disorder of attention for which there is the greatest use of stimulant medications as therapeutic agents.

Diagnostic criteria for an "inattentive" type of attention deficit disorder in adults or children must include at least six symptoms of inattention, lasting for at least 6 months. Such symptoms include

1. Often failing to give close attention to details or making careless mistakes in schoolwork, work, or other activities

FIGURE 12 — 1. Noradrenergic and dopaminergic pathways of attention. The noradrenergic pathway projecting from the locus coeruleus in the brainstem to the frontal cortex and the dopaminergic pathway projecting from the ventral tegmental area in the brainstem to mesocortical and dorsolateral prefrontal cortical areas may be the hypothetical mediators of attention, arousal, concentration, and other related cognitive functions. If they fail to function, inattentiveness and attention deficit may result.

2.Often having difficulty sustaining attention in tasks or play activities

3.Often not seeming to listen when spoken to directly

4.Often not following through on instructions and failing to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions)

5.Often having difficulty organizing tasks and activities

6.Often avoiding, disliking, or being reluctant to engage in tasks that require sustained mental effort (such as schoolwork or homework)

7.Often losing things necessary for tasks or activities (e.g., toys, school as signments, pencils, books, or tools)

8.Being often easily distracted by extraneous stimuli

9.Being often forgetful in daily activities

10.Some symptoms of impairment present before age 7

Full diagnostic criteria may be found in DSM IV.

Such symptoms of inattention may map to dopamine and/or norepinephrine dysfunction in critical areas of the cerebral cortex controlling cognition (Fig. 12 — 1). It seems as though patients with such symptoms need a boost in their dopamine/ norepinephrine actions, and indeed when they are given agents that boost these systems, their symptoms of inattentiveness can improve.

Stimulants and ProdopaminergiclPronoradrenergic Agents as Enhancers of Attention

The most commonly used agents to enhance attention in attention deficit disorder are the stimulants methylphenidate and d-amphetamine. Other effective stimulants are not as widely used, pemoline because of liver toxicity and methamphetamine because of its greater abuse potential. Methylphenidate and d-amphetamine act predominantly by releasing dopamine from presynaptic dopamine terminals (Figs. 12

— 2 and 12 — 3). These agents not only block the dopamine transporter but may actually

462 Essential Psychopharmacology

FIGURE 12 — 2. Icons for d-amphetamine and methylphenidate. Both compounds are classified as stimulants, as they both promote the availability of dopamine, thereby enhancing ("stimulating") attention (see also Fig. 12—3).

reverse its direction and make dopamine reverse out of the nerve terminal. Methylphenidate seems to act less quickly but is longer-acting than d- amphetamine.

Another form of amphetamine, called /-amphetamine, actually releases norepinephrine (Figs. 12—4 and 12 — 5) as well as dopamine (Fig. 12 — 3) by a similar mechanism. Some patients respond better to a mixture of d,l-amphetamine salts than to pure d-amphetamine, perhaps because of the beneficial action of norepinephrine. Other compounds acting on the noradrenergic system that can be beneficial for symptoms of inattentiveness in attention deficit disorder include alpha 2 agonists such as clonidine and guanfacine (Fig. 12—6). Recall that the cognitive effects of norepinephrine in the prefrontal cortex are hypothesized to be mediated in part by postsynaptic alpha 2 adrenergic receptors, as was discussed in Chapter 5 (see Fig. 5 — 25). Both clonidine and guanfacine are direct-acting alpha 2 adrenergic agonists, which may enhance cognition and attention by this mechanism in attention deficit disorder. It is theoretically possibly that the noradrenergic selective reuptake inhibitor reboxetine could have helpful effects in attention deficit disorder. The prodo-paminergic and pronoradrenergic antidepressant bupropion, discussed in Chapter 6 (see Figs. 6—48 and 6—49) can be useful in improving attention in some cases of attention deficit disorder.

Hyperactivity and Impulsivity Associated with Inattentiveness

No discussion of attention deficit disorder would be complete without mentioning that these patients frequently also have problems with hyperactivity and impulse control, characterized by at least six of the following symptoms for at least 6 months.

FIGURE 12 — 3. When d-amphetamine binds to the presynaptic dopamine transporter on the dopamine neuron, it not only blocks dopamine reuptake but actually causes dopamine release. There may be a preference or selectivity for cortical over striatal dopamine presynaptic terminals by d- amphetamine, so lower doses may have preferential effects on attention rather than on motor activity. Methylphenidate has a similar action, which is not quite as rapid but longer-lasting in many patients.

Hyperactivity symptoms

1.Frequent fidgeting with hands or feet or squirming in seat

2.Often leaving seat in classroom or in other situations in which remaining seated is expected

3.Frequent running about or climbing excessively in situations in which it is inappropriate (in adolescents or adults, may be limited to subjective feelings of restlessness)

4.Frequent difficulty playing or engaging in leisure activities quietly

5.Often "on the go" or acting as if "driven by a motor"

6.Frequent excessive talking

Impulsivity symptoms

1.Often blurting out answers before questions have been completed

2.Frequent difficulty awaiting turn

3.Frequent interruption of or intruding on others (e.g., butting into conver sations or games)

464 Essential

Psychopharmacology

FIGURE 12—4. The enantiomer of d-amphetamine is l-amphetamine, which has no preference between the norepinephrine and the dopamine transporters. Thus, it will target both the norepinephrine reuptake site (shown here), as well as the dopamine reuptake site (shown in Fig. 12 — 2). d- Amphetamine is selective for the dopamine transporter.

The symptoms of hyperactivity and impulsivity in this disorder to not appear to be mediated by the same dopaminergic and noradrenergic pathways that mediate the inattentiveness of attention deficit disorder. The most likely candidate to mediate both the hyperactivity and the impulsivity in this condition is the nigrostriatal dopamine pathway (Fig. 12—7). Motor activity is controlled by this pathway. Glutamatergic input from the cortex theoretically also acts as an inhibitory input to the striatum to suppress unwanted obsessions, compulsions, and impulses from other parts of the brain. Although both motor hyperactivity and/or impulsivity and inattentiveness in attention deficit disorder are controlled by dopamine, different pathways are involved (cf. Figs. 12 — 1 and 12—7). Furthermore, clinical experience suggests that when patients with both sets of clinical symptoms are treated with stimulants (not all patients have both types of problems), low doses seem to prefer the cortex, so there are effects on attention that can appear before effects on motor behaviors. This may be due to greater sensitivity to stimulants of mesocortical dopamine terminals as compared with nigrostriatal dopamine terminals in many patients with attention deficit disorder.

Some unexpected clinical observations have become apparent after several decades of treating attention deficit disorder patients with potentially abusable stimulants (the psychopharmacology of stimulant abuse is discussed in Chapter 13). That is,

FIGURE 12 — 5. Here, l-amphetamine is releasing norepinephrine from presynaptic noradrenergic neurons. It also does this from dopamine neurons, just as shown for d-amphetamine in Figure 12 — 3. When l-amphetamine binds to the presynaptic norepinephrine transporter on the norepinephrine presynaptic nerve terminal, it not only blocks norepinephrine reuptake but actually causes norepinephrine release. Thus, l-amphetamine releases both norepinephrine and dopamine, whereas d- amphetamine is selective for dopamine. Since norepinephrine and dopamine can have different if related cognitive functions in different patients, then d- and l-amphetamine can have different cognitive effects as well.

the dopamine systems of these patients do not necessarily behave as do those of other individuals when exposed to chronic treatment with stimulants.

Specifically, in attention deficit disorder patients, there is "paradoxical" calming and mental focusing at low doses as well as reduction of hyperactive motor movements at higher stimulant doses, whereas many "normal" subjects who take stimulants can become overstimulated and "wired" mentally, and hyperactive with fidgety, excessive motor movements. Furthermore, attention deficit disorder patients show little or no evidence of tolerance or the need for escalating doses over time, whereas others who use stimulants often need higher and higher doses to achieve an enhancement of attention. Still another difference is that in attention deficit disorder patients, there is surprisingly little or no evidence of the phenomenon of "reverse tolerance" or sensitization seen in amphetamine and cocaine abusers, causing psychosis and stimulant abuse (see Chapter 13 on drug abuse for discussion of this phenomenon).

On the other hand, there is also the sense among many clinicians that attention deficit disorder is overdiagnosed and stimulants overprescribed and that these observations do not hold when stimulants are too freely prescribed. Nevertheless, there

466 Essential Psychopharmacology

FIGURE 12 — 6. Postsynaptic alpha 2 adrenergic receptors are postulated to mediate cognitive effects of norepinephrine in the frontal cortex. Direct-acting alpha 2 agonists such as clonidine and guanfacine can be helpful in attention deficit disorder, perhaps because of actions at this site.

FIGURE 12 — 7. Motor hyperactivity is mediated by dopaminergic activity in the nigrostriatal pathway. Impulsivity may be inhibited by cortical inhibitory glutamatergic inputs passing through the striatum. Although increasing dopamine in this pathway with stimulants can lead to increased motor behavior and increased impulsivity in normal subjects, it can have a paradoxical motor calming effect and a reduction in behavior impulsivity in patients with attention deficit disorder.

remains a core of individuals with inattentiveness who undoubtedly benefit from stimulant treatment by experiencing a significant enhancement of their attention span and ability to focus and concentrate.

New Developments for Enhancing Attention

Mood stabilizers and atypical antipsychotics may be helpful in patients who fail to have adequate responses to stimulants, alpha 2 adrenergic agonists, or bupropion.

especially if they are misdiagnosed bipolar disorder patients or have comorbid bipolar disorder. Other antidepressants such as venlafaxine may be useful in some cases, and as mentioned earlier, it may be prudent to try reboxetine, although there is little experience with this approach yet.

A new stimulant, modafinil, has been marketed for the treatment of narcolepsy. It has a vague mechanism of action, but may be prodopaminergic, not so much by releasing dopamine as by blocking dopamine reuptake. It may also work through other neurotransmitter systems. There are thus theoretical reasons for considering this agent in disorders of attention. Perceptin (GT2331) is a centrally acting H3 antihistamine, an autoreceptor antagonist whose blockade causes a reduction of histamine release and enhancement of cognitive arousal.

Enhancement of Memory

Acetylcholine and the Neuropharmacology of Memory

Memory is obviously one of the most complex functions of the brain and ultimately involves many neuronal pathways and many neurotransmitter systems. However, we currently know that certain disorders disrupt cholinergic neurotransmission specifically and that new therapeutic agents that boost cholinergic neurotransmission can enhance memory in patients with such disorders. Thus, the modern psychopharmacologist requires a working knowledge of cholinergic pharmacology, the disorders that disrupt it, and the therapeutic agents currently available that can improve memory function by acting upon it.

Acetylcholine synthesis. Acetylcholine (ACh) is a prominent neurotransmitter, which is formed in cholinergic neurons from two precursors, choline and acetyl coenzyme A (AcCoA) (Fig. 12 — 8). Choline is derived from dietary and intraneuronal sources, and AcCoA is synthesized from glucose in the mitochondria of the neuron. These two substrates interact with the synthetic enzyme choline acetyltransferase to produce the neurotransmitter ACh.

Acetylcholine destruction and removal. Acetylcholine is destroyed by an enzyme called acetylcholinesterase (AChE), which turns ACh into inactive products (Fig. 12 — 9) and is one of two cholinesterase enzymes capable of breaking down ACh. The other is butyrylcholinesterase (BuChE), also known as pseudocholinesterase and nonspecific cholinesterase. Although both AChE and BuChE can metabolize ACh, they are quite different in that they are encoded by separate genes and have different tissue distributions and substrate patterns. There may be different clinical effects of inhibiting these two enzymes as well. High levels of AChE are present in brain, especially in neurons that receive ACh input; BuChE is also present in brain, especially in glial cells. As discussed below, some of the new drugs for Alzheimer's disease specifically inhibit AChE, whereas others inhibit both enzymes. It is AChE that is the key enzyme for inactivating ACh at cholinergic synapses (Fig. 12 — 9), although BuChE can take on this activity if ACh diffuses to nearly glia. Acetylcholinesterase is also present in skeletal muscle, red blood cells, lymphocytes, and platelets, and butyrylcholinesterase is also present in plasma, skeletal muscle, placenta, and liver.

468 Essential Psychopharmacology

FIGURE 12-8. Acetylcholine (ACh) is synthesized. Acetylcholine is a prominent neurotransmitter, which is formed in cholinergic neurons from two precursors, choline and acetyl coenzyme A (AcCoA). Choline is derived from dietary and intraneuronal sources, and AcCoA is made from glucose in the mitochondria of the neuron. These two substrates interact with the synthetic enzyme choline acetyltransferase (CAT) to produce the neurotransmitter acetylcholine (ACh).

Acetylcholine is destroyed too quickly and completely by AChE to be available for transport back into the presynaptic neuron, but the choline that is formed by its breakdown can be transported back into the presynaptic cholinergic nerve terminal by a transporter similar to the transporters for other neurotransmitters discussed earlier in relation to norepinephrine, dopamine, and serotonin neurons. Once back in the presynaptic nerve terminal, this choline can be recycled into acetylcholine synthesis (Fig. 12 — 8).

Acetylcholine receptors. There are numerous receptors for ACh (Fig. 12 — 10), of which the major subtypes are nicotinic and muscarinic subtypes of cholinergic receptors. Classically, muscarinic receptors are simulated by the mushroom alkaloid muscarine and nicotinic receptors by the tobacco alkaloid nicotine. Nictotinic receptors are all ligand-gated, rapid-onset, and excitatory ion channels, which are blocked by curare. Muscarinic receptors, by contrast, are G protein—linked, can be excitatory or inhib-